1,121
Views
500
CrossRef citations to date
0
Altmetric
Invited Review

PPARα Agonist-Induced Rodent Tumors: Modes of Action and Human Relevance

, , , , , , , , , , & show all
Pages 655-780 | Published online: 29 Sep 2008

References

  • Abdellatif, A.G., Preat, V., Taper, H.S., and Roberfroid, M. (1991). The modulation of rat liver carcinogen- esis by perfluorooctanoic acid, a peroxisome pro- liferator. Toxicol. Appl. Pharmacol. 111:530–537.
  • Adler, G. (1997). Regulation of human pancreatic secre- tion. Digestion 58(Suppl. 1):39–41.
  • Adler, G., Nelson, D.K., Katschinski, M., and Beglinger, C. (1995). Neurohormonal control of human pan- creatic exocrine secretion. Pancreas 10:1–13.
  • Albro, P.W., and Thomas, R.O. (1973). Enzymatic hy- drolysis of di-(2-ethylhexyl)phthalate by lipases. Biochim. Biophys. Acta 306:380–390.
  • Alegret, M., Ferrando, R., Vazquez, M., Adzet, T., Merlos, M., and Leguna, J.C. (1994). Relationship between plasma lipids and palmitoyl CoA hydrolase and synthestase activities with peroxisomal prolifera-tion in rats treated with fibrates. Brit. J. Pharmacol. 112:551–556.
  • Alison, R.H., Capen, C.C., and Prentice, D.E. (1994). Neoplastic lesions of questionable significance to humans. Toxicol. Pathol. 22(2):179–186.
  • Alison, M.R., and Sarraf, C.E. (1995). Apoptosis: Regu- lation and relevance to toxicology. Hum. Exp. Tox- icol. 14:234–247.
  • Amacher, D.E., Beck, R., Schomaker, S.J., and Kenny, C.V. (1997). Hepatic microsomal enzyme induc- tion, beta-oxidation, and cell proliferation follow- ing administration of clofibrate, gemfibrozil, or bezafibrate in the CD rat. Toxicol. Appl. Pharma- col. 142(1):143–150.
  • Anderson, S.P., Dunn, C.S., Cattley, R.C., and Corton, J.C. (2001). Hepatocellular proliferation in response to a peroxisome proliferator does not require TNFal- pha signaling. Carcinogenesis 22:1843–1851.
  • Anderson, W.A.C., Castle, L., Scotter, M.J., Massey, R., and Springall, C. (2001). A biomarker approach to measuring human dietary exposure to certain phthalate diesters. Food Addit. Contam. 18:1068–1074.
  • Andersson, Y., Majd, Z., Lefebvre, A.M., Martin, G., Sechkin, A.V., Kosykh, V., Fruchart, J.C., Najib, J., and Staels, B. (1999). Developmental and phar- macological regulation of apolipoprotein C-II gene expression. Comparison with apo C-I and apo C-III gene regulation. Arterioscler. Thromb. Vasc. Biol. 19:115–121.
  • Andren-Sandberg, A.A., Dawiskiba, S., and Ihse, I. (1984). Studies of the effect of cerulein adminis- tration on experimental pancreatic carcinogenesis. Scand. J. Gastroenterol. 19:122–128.
  • Aoyama, A., Peters, J.M., Iritani, N., Nasu-Nakajima, T., Furihata, K., Hashimoto, T., and Gonzalez, F.J. (1998). Altered constitutive expression of fatty acid-metabolizing enzymes in mice lacking the peroxisome proliferator-activated receptor alpha (PPARa). J. Biol. Chem. 273:5678–5684.
  • Ashby, J., Brady, A., Elcombe, C.R., Elliott, B.M., Ishmael, J., Odum, J., Tugwood, J.D., Kettle, S., and Purchase, I.F. (1994). Mechanistically- based human hazard assessment of peroxisome proliferator-induced hepatocarcinogenesis. Hum. Exp. Toxicol. 13:S1–117.
  • Astill, B.D. (1989). Metabolism of DEHP: Effects of prefeeding and dose variation, and comparative studies in rodents and the cynomolgus monkey (CMA studies). Drug Metab. Review 21:35–53.
  • Astill, B.D., Gingell, R., Quest, D., Hellwig, J., Hodgson, J.R., Kuettler, K., Mellert, W., Murphy, S.R., Sielken, R.L., Jr., and Tyler, T.R. (1996). Onco- genicity testing of 2-ethylhexanol in Fischer 344 rats and B6C3F1 mice. Fundam. Appl. Toxicol. 31:29–41.
  • Auwerx, J., Schoonjans, K., Fruchart, J. C., and Staels, B. (1996). Transcriptional control of triglyceride metabolism: Fibrates and fatty acids change the expression of the LPL and apo C-III genes by acti- vating the nuclear receptor PPAR. Arteriosclerosis. 124:S29–S37.
  • Awasthi, Y.C., Singh, S.V., Goel, S.K., and Reddy, J.K. (1984). Irreversible inhibition of hepatic glu- tathione S-transferase by ciprofibrate, a peroxi- some proliferator. Biochem. Biophys. Res. Com- mun. 123:012–1018.
  • Baker, T., Kalimi, G., Lington, A., Isenberg, J., Klaunig, J., and Nikiforov, A. (1996). Gap junctional inter- cellular communication (GJIC) studies on 5 phtha- late monoesters in hepatocytes of four species: Im- plications for cancer risk assessment. Toxicologist 30:208.
  • Baldwin, J.R., Witiak, D.T., and Feller, D.R. (1980). Dis- position of clofibrate in the rat. Acute and chronic administration. Biochem. Pharmacol. 29:3143–3154.
  • Bar, A. (1992). Significance of Leydig cell neoplasia in rats fed lactitol or lactose. J. Am. Coll. Toxicol. 11:189–207.
  • Barber, E.D., Astill, B.D., Moran, E.J., Schneider, B.F., Gray, T.J.B., Lake, B.G., and Evans, J.G. (1987). Peroxisome induction studies on seven phthalate esters. Toxicol. Ind. Health 3:17–21.
  • Barbier, O., Torra, I.P., Duguay, Y., Blanquart, C., Fruchart, J.C., Glineur, C., and Staels, B. (2002). Pleiotropic actions of peroxisome proliferator- activated receptors in lipid metabolism and atherosclerosis. Arterioscler. Thromb. Vasc. Biol. 22:717–726.
  • Barrass, N.C., Price, R.J., Lake, B.G., and Orton, T.C. (1993). Comparison of the acute and chronic mi- togenic effects of the peroxisome proliferators methylclofenapate and clofibric acid in rat liver. Carcinogenesis 14:1451–1456.
  • Bayly, A.C., Roberts, R.A., and Dive, C. (1994). Sup- pression of liver cell apoptosis in vitro by the non-genotoxic hepatocarcinogen and peroxisome proliferator, nafenopin. J. Cell Biol. 125:197–203.
  • Bell, A.R., Savory, R., Horley, N.J., Choudhury, A.I., Dickins, M., Gray, T.J., Salter, A.M., and Bell, D.R. (1998). Molecular basis of non-responsiveness to peroxisome proliferators: The guinea-pig PPA- Ralpha is functional and mediates peroxisome proliferator-induced hypolipidaemia. Biochem J. 332:689–693.
  • Bell, R.H., Jr., Kuhlmann, E.T., Jensen, R.T., and Longnecker, D.S. (1992). Overexpression of cholecystokinin receptors in azaserine-induced neoplasms of the rat pancreas. Cancer Res. 52:3295–3299.
  • Bendele, A.M., Hoover, D.M., Van Lier, R.B.L., Foxwor- thy, P.S., and Eacho, P.I. (1990). Effects of chronic treatment with the leukotriene d4-antagonist com- pound LY171883 on B6C3F1 mice. Fundam. Appl. Toxicol. 15:676–682.
  • Bentley, P., Calder, I., Elcombe, C., Grasso, P., Stringer, D., and Wiegand, H.J. (1993). Hepatic peroxisome proliferation in rodents and its significance for hu- mans. Food Chem. Toxicol. 31:857–907.
  • Berger, J., Bailey, P., Biswas, C., Cullinan, C.A., Doebber, T.W., Hayes, N.S., Sapersten, R., Smith, R.G., and Leibowitz, M.D. (1996). Thiazolidinediones produce a conformational change in peroxiso- mal proliferator-activated receptor-gamma: Bind- ing and activation correlate with antidiabetic actions in db/db mice. Endocrinology 137:4189–4195.
  • Berger, M.R. (1995). Combination effect of three non- genotoxic carcinogens in male SD rats. Carcino- genesis 36:788.
  • Berthou, L., Saladin, R., Yaqoob, P., Branellec, D., Calder, P., Fruchart, J.C., Denefle, P., Auwerx, J., and Stael, B. (1995). Regulation of rat liver apolipoprotein A-I, apolipoprotein A-II and acyl-coenzyme A ox- idase gene expression by fibrates and dietary fatty acids. Eur. J. Biochem. 232:179–187.
  • Besnard, P., Mallordy, A., Carlier, H., Besnard, P., Mallordy, A., Carlier, H., and Besnard, P. (1993). Transcriptional induction of the fatty acid binding protein gene in mouse liver by bezafibrate. FEBS Lett. 327:219–223.
  • BIBRA. (1985). A 21-day feeding study of butylben- zylphthalate to rats: Effects on the liver and liver lipids. CMA Unpublished report, British Industrial Biological Research Association. Carshalton, UK.
  • Bichet, N., Chard, D., Fabre, G., Remandet, B., Gouy, D., and Gano, J.P. (1990). Toxicological studies on a benzofuran derivative. III. Comparison of per- oxisome proliferation in rat and human hepato- cytes in primary culture. Toxicol. Appl. Pharmacol. 106:509–517.
  • Biegel, L.B., Hurrt, M.E., Frame, S.R., Applegate, M., O’Connor, J.C., and Cook, J.C. (1992). Compar- ison of the effects of Wyeth-14,643 in Crl: CDBR and Fisher-344 rats. Fundam. Appl. Toxicol. 19:590–597.
  • Biegel, L.B., Hurtt, M.E., Frame, S.R., O’Conner, J.C., and Cook, J. (2001). Mechanisms of extrahep- atic tumor induction by peroxisome proliferators in male CD rats. Toxicol. Sci. 60:44–55.
  • Biegel, L.B., Liu, R.C.M., Hurtt, M.E., and Cook, J.C. (1995). Effects of ammonium perfluorooctanoate on Leydig cell function: In vitro, in vivo, and ex vivo studies. Toxicol. Appl. Pharmacol. 134:18–25.
  • Bio/Dynamics, Inc. (1986). A chronic toxicity carcino- genicity feeding study in rats with Santicizer 900. Bio/Dynamics, Inc. Project number 81-2572. June 20. EPA document no. 86-870000362. Cambridge, MA. Blumcke, S., Schwartzkopff, W., Lobeck, H., Edmondson, N.A., Prentice, D.E., and Blane, G.F. (1983). Influence of fenofibrate on cellular and subcellular liver structure in hyperlipidemic patients. Atherosclerosis. 46:105–116.
  • Bocher, V., Pineda-Torra, I., Fruchart, J.C., and Staels, B. (2002). PPARs: Transcription factors controlling lipid and lipoprotein metabolism. Ann. NY Acad. Sci. 967:7–18.
  • Bojes, H.K., Germolec, D.R., Simeonova, P., Bruccolrei, A., Schoonhoven, R., Luster, M.I., and Thurman, R.G. (1997). Antibodies to tumor necrosis factor- alpha prevent increases in cell replication in liver due to the potent peroxisome proliferator WY 14,643. Carcinogenesis. 18:669–674.
  • Bojes, H.K., and Thurman, R.G. (1996). Peroxisome pro- liferators activate Kupffer cells in vivo. Cancer Res. 56:1–4.
  • Booth, A.N., Robbins, D.J., Ribelin, W.E., and Deeds, F. (1960). Effects of raw soybean meal and amino acids on pancreatic hypertrophy in rats. Proc. Soc. Exp. Biol. Med. 104:681–683.
  • Bosland, M.C. (1994). Male reproductive system. In: Car- cinogenesis, M.P. Waalkes and J.M. Ward, eds., pp. 339–402. Raven Press, New York.
  • Bosland, M.C. (1996). Hormonal factors in carcinogene- sis of the prostate and testis in humans and in animal models. Prog. Clin. Biol. Res. 394:309–352.
  • Bourassa, J., Laine, J., Kruse, M.L., Gagnon, M.C., Calvo, E., and Morisset, J. (1999). Ontogeny and species differences in the pancreatic expression and local- ization of the CCKA receptors. Biochem. Res. Com- mun. 260:820–828.
  • Bosse, Y., Pascot, A., Dumont, M., Brochu, M., Prud’homme, D., Bergeron, J., Despres, J.P., and Vohl, M.C. (2002). Influences of the PPAR alpha-L162V polymorphism on plasma HDL(2)- cholesterol response of abdominally obese men treated with gemfibrozil. Genet. Med. 4:311–315.
  • Brandt, J.M., Djouadi, F., and Kelly, D.P. (1998). Fatty acids activate transcription of the muscle carnitine palmitoyltransferase I gene in cardiac myocytes via the peroxisome proliferator-activated receptor al- pha. J. Biol. Chem. 273:23786–23792.
  • Braissant, O., Foufell, F., Scotto, C., Dauca, M., and Wahli, W. (1996). Differential expression of per- oxisome proliferator-activated receptors (PPAR): Tissue distribution of PPAR-α, -β, and -γ in the adult rat. Endocrinology 137:354–366.
  • Brand, S.J., and Morgan, R.G.H. (1982). Stimulation of pancreatic secretion and growth in the rat after feeding cholestyramine. Gastroenterology 83:851–859.
  • Brun, R.P., Tontonoz, P., Forman, B.M., Ellis, R., and Chen, J. (1996). Differential activation of adipo- genesis by multiple PPAR isoforms. Genes Dev. 10:974–984.
  • Budunova, L., and Slaga, T. (1994). Alteration of gap junctional intercellular communication during car- cinogenesis. Cancer J. 7:228–237.
  • Burkhardt, S., Mellert, W., Reinacher, M., and Bahnen- mann, R. (2001). Zonal evaluation of proliferation and apoptosis in mice reveals new mechanistic data for PB, WY 14,643 and CH. Toxicologist 60:286.
  • Bursch, B., Lauer, B., Timmerman-Trosiener, I., Barthel, G., Schuppler, J., and Schulte-Hermann, R. (1984). Controlled death (apoptosis) of normal and pre- neoplastic cells in rat liver following withdrawal of tumor promoters. Carcinogenesis 5:453–458.
  • Butala, J.H., Moore, M.R., and Cifone, M.A. (1997). Oncogenicity study of diisononyl phthalate in mice. Toxicologist 36:173.
  • Butala, J., Moore, M., Cifone, M., Bankston, J., and Astill, B. (1996). Oncogenicity study of di(isononyl) ph- thalate in rats. Toxicologist 30:202.
  • Butenhoff, J., Costa, G., Elcombe, C., Farrar, D., Hansen, K., Iwai, H., Jung, R., Kennedy Jr., G., Lieder, P., Olsen, G., and Thomford, P. (2002). Toxic- ity of ammonium perfluorooctanoate (APFO) in male cynomolgus monkeys after oral dosing for six months. Toxicol. Sci. 69:244–257.
  • Butterworth, B.E. (1990). Consideration of both geno- toxic and nongenotoxic mechanisms in predicting carcinogenic potential. Mutat. Res. 239:117–32.
  • Caira, F., Antonson, P., Pelto-Huikko, M., Treuter, E., and Gustafsson, J.A. (2000). Cloning and characteriza- tion of RAP250, a novel nuclear receptor coactiva- tor. J. Biol. Chem. 275:5308–5317.
  • Canitrot, Y., Cazaux, C., Frechet, M., Bouayadi, K., Lesca, C., Salles, B., and Hoffmann, J.S. (1998). Overexpression of DNA polymerase beta in cell re- sults in a mutator phenotype and a decreased sen- sitivity to anticancer drugs. Proc. Natl. Acad. Sci. USA 95:12586–12590.
  • Canitrot, Y., Frechet, M., Servant, L., Cazaux, C., and Hoffmann, J.S. (1999). Overexpression of DNA polymerase beta: A genomic instability enhancer process. FASEB J. 13:1107–1111.
  • Carter, J.E., Roll, D.B., and Petersen, R.V. (1974). The in vitro hydrolysis of di-(2-ethylhexyl) phthalate by rat tissues. Drug Metab. Dispos. 2:341–344.
  • Cattley, R.C., Conway, J.G., and Popp, J.A. (1987). Asso- ciation of persistent peroxisome proliferation and oxidative injury with hepatocarcinogenicity in fe- male F-344 rats fed di(2-ethylhexyl)phthalate for 2 years. Cancer Lett. 38:15–22.
  • Cattley, R.C., DeLuca, J., Elcombe, C., Fenner-Crisp, P., Lake, B.G., Marsman, D.S., Pastoor, T.A., Popp, J.A., Robinson, D.E., Schwetz, B., Tugwood, J., and Wahli, W. (1998). Do peroxisome proliferat- ing compounds pose a hepatocarcinogenic risk to humans? Regul. Toxicol. Pharmacol. 27:47–60.
  • Cattley, R.C., and Glover, S.E. (1993). Elevated 8- hydroxydeoxyguanosine in hepatic DNA of rats following exposure to peroxisome proliferators: Relationship to carcinogenesis and nuclear local- ization. Carcinogenesis 14:2495–2499.
  • Cattley, R.C., Kato, M., Popp, J.A., Teets, V.J., and Voss, K.S. (1994). Initiator-specific promotion of hepa- tocarcinogenesis by WY 14,643-14,643 and clofi- brate. Carcinogenesis 15:1763–1766.
  • Cattley, R.C., Marsman, D.S., and Popp, J.A. (1991). Age- related susceptibility to the carcinogenic effect of the peroxisome proliferator WY 14,643 in rat liver. Carcinogenesis 12:469–473.
  • Cattley, R.C., and Popp, J.A. (1989). Differences between the promoting activities of the peroxisome prolif- erator WY 14,643 and phenobarbital in rat liver. Cancer Res. 49:3246–3251.
  • Cayen, M.N., Ferdinandi, E.S., Greselin, E., Robin- son, W.T., and Dvornik, D. (1977). Clofibrate and clofibric acid: Comparison of the metabolic dispo- sition in rats and dogs. J. Pharmacol. Exp. Ther. 200:33–43.
  • Chema, S.K., and Agellon, L.B. (2000). The murine and human cholesterol 7 alpha-hydroxylase gene promoters are differentially responsive to regu- lation by fatty acids mediated via peroxisome proliferator-activated receptor alpha. J. Biol. Chem. 275:12530–12536.
  • Christensen, A.K., and Peacock, K.C. (1980). Increase in Leydig cell number in testes of adult rats treated chronologically with an excess of hCG. Biol. Re- prod. 22:383–391.
  • Christensen, J., Gonzalez, A., Cattley, R., and Goldsworthy, T. (1998). Regulation of apoptosis in mouse hepatocytes and alteration of apopto- sis by nongenotoxic carcinogens. Cell growth and differentiation. Cell Growth Differ. 9:815–825.
  • Chu, S., Huang, Q., Alvares, K., Yeldandi, A.V., Rao, M.S., and Reddy, J.K. (1995). Transformation of mammalian cells by overexpressing H2O2- generating peroxisomal fatty acyl CoA oxidase. Proc. Natl. Acad. Sci. USA 92:7080–7084.
  • Cimini, A., Cristiano, L., Bernardo, A., Farioli-Vecchioli, S., Stefanini, S., and Ceru, M.P. (2000). Pres- ence and inducibility of peroxisomes in a hu- man glioblastoma cell line. Biochim. Biophys. Acta 1474:397–409.
  • Ciriolo, M.R., Mavelli, I., Rotilio, G., Borzatta, V., Cristo- fari, M., and Stanzani, L. (1982). Decrease of superoxide dismutase and glutathione peroxidase in liver of rats treated with hypolipidemic drugs. FEBS Lett. 144:264–268.
  • Collins, A.R. (1999). Oxidative DNA damage, antixodi- ants, and cancer. BioEssays 21:238–246.
  • Committee of Principal Investigators. (1978). A coopera- tive trial in the primary prevention of ischemic heart disease using clofibrate. Br. Heart J. 40:1069–1118.
  • Committee of Principal Investigators. (1980). WHO co- operative trial on the primary prevention of is- chemic heart disease using clofibrate to lower serum cholesterol: Mortality follow-up. Lancet ii:379–385.
  • Committee of Principal Investigators. (1984). WHO co- operative trial on primary prevention of ischaemic heart disease with clofibrate to lower serum choles- terol: Final mortality follow-up. Lancet ii:600-604.
  • Consumer Product Safety Commission. (2001). Report to the U.S. Consumer Product Safety Commission by the Chronic Hazard Advisory Panel on Diisononyl Phthalate (DINP).
  • Conway, J.G., Tomaszewski, K.E., Olson, M.J., Cattley, R.C., Marsman, D.S., and Popp, J.A. (1989). Relationship of oxidative damage to carcino- genicity with peroxisome proliferators di(2- ethylhexyl)phthalate (DEHP) and WY 14,643 (WY 14,643). Carcinogenesis 10:513–520.
  • Cook, J.C., Klinefelter, G.R., Hardisty, J.F., Sharpe, R.M., and Foster, P.M. (1999). Rodent Leydig cell tumorigenesis: A review of the physiology,pathology, mechanisms and relevance to humans. Crit. Rev. Toxicol. 29:169–261.
  • Cook, J.C., Murray, S.M., Frame, S.R., and Hurrt, M.E. (1992). Induction of Leydig cell adeno- mas by ammonium perfluorooctanoate: A possible endocrine-related mechanism Toxicol. Appl. Phar- macol. 113:209–217.
  • Cook, J.C., Mullin, L.S., Frame, S.R., and Biegel, L.B. (1993). Investigation for a mechanism for Leydig cell tumorigenesis by linuron in rats. J. Biol. Chem. 275:5308–5317.
  • Corbin, C.J., Trant, J.M., and Conley, A.J. (2001). Porcine gonadal and placental isozymes of aromatase cy- tochrome P450: Sub-cellular distribution and sup- port by NADPH-cytochrome P450 reductase. Mol. Cell. Endocrinol. 172:115–124.
  • Corton, J.C., Bocos, C., Moreno, E.S., Merritt, A., Cat- tley, R.C., and Gustafsson, J.A. (1997). Peroxi- some proliferators alter the expression of estrogen- metabolizing enzymes. Biochimie. 79:151–162.
  • Corton, J.C., Fan, L.Q., Brown, S., Anderson, S.P., Bocos, C., Cattley, R.C., Mode, A., and Gustafsson, J.A. (1998). Down-regulation of cytochrome P450 2C family members and positive acute-phase response gene expression by peroxisome proliferator chem- icals. Mol. Pharmacol. 54:463–473.
  • Cornu-Chagnon, M.C., Dupont, H., and Edgar, A. (1995). Fenofibrate: Metabolism and species differences for peroxisome proliferation in cultured hepato- cytes. Fundam. Appl. Toxicol. 26:63–74.
  • Costet, P., Legendre, C., More, J., Edgar, A., Galtier, P., and Pineau, T. (1998). Peroxisome proliferator- activated receptor alpha-isoform deficiency leads to progressive dyslipidemia with sexually di- morphic obesity and steatosis. J. Biol. Chem. 273:29577–29585.
  • Cotran, R.S., Kumar, V., and Robbins, S.L. (1989). The pancreas. In: Pathologic Basis of Disease, pp. 981-1010. W.B. Saunders, Philadelphia.
  • Cruciani, V., Rast, C., Durand, M.-J., Nguyen-Ba, G., and Vasseur, P. (1997). Comparative effects of clofibrate and methylclofenapate on morphological transformation and intercellular communicaiton of Syrian hamster embryo cells. Carcinogenesis 18:701–706.
  • Cunningham, M.L., Soliman, M.S., Badr, M.Z., and Mathews, H.B. (1995). Rotenone, an anticarcino- gen, inhibits cellular proliferation but not perox- isome proliferation in mouse liver. Cancer Lett. 95:93–97.
  • David, R.M., Moore, M.R., Cifone, M.A., Finney, D.C., and Guest, D. (1999). Chronic peroxi- some proliferation and hepatomegaly associated with the hepatocellular tumorigenesis of di(2- ethylhexyl)phthalate and the effects of recovery. Toxicol. Sci. 50:195–205.
  • David, R.M., Moore, M.R., Finney, D.C., and Guest, D. (2000a). Chronic toxicity of di(2-(ethylhexyl) ph- thalate in rats. Toxicol. Sci. 55(2):433–443.
  • David, R.M., Moore, M.R., Finney, D.C., and Guest, D. (2000b). Chronic toxicity of di(2-(ethylhexyl) ph- thalate in mice. Toxicol. Sci. 58(2):377–385.
  • de Duve, C. (1996). The peroxisome in retrospect. In: Peroxisomes: Biology and Role in Toxicology and Disease, J.K. Reddy, T. Suga, G.P. Mannaerts, P.B. Lazarow, and S. Subramani, eds. Ann. NY Acad. Sci. 804:1–10.
  • De Groot, L.J., Besser, M., Burger, H.G., Jameson, J.L., Loriaux, D.L., Marshall, J.C., Odell, W.D., Potts, J.T. Jr., and Rubenstein, A.H. (1995). Endocrinol- ogy, 3rd ed. W.B. Saunders, Philadelphia.
  • de la Iglesia, F.A., Lewis, J.E., Buchanan, R.A., Marcus, E.L., and McMahon, G. (1982). Light and elec- tron microscopy of liver in hyperlipoproteinemic patients under long-term gemfibrozil treatment. Atherosclerosis 43:19–37.
  • DeLuca,J.G.,Doebber,T.W.,Kelly,L.J.,Kemp, R.K., Molon-Noblot, S., Sahoo, S.P., Ventre, J., Wu, M.S., Peters, J.M., Gonzalez, F.J., and Moller, D.E. (2000). Evidence for peroxisome proliferator-activated receptor (PPAR)alpha- independent peroxisome proliferation: Effects of PPARgamma/delta-specific agonists in PPARalpha-null mice. Mol. Pharmacol. 58:470–476.
  • Delzenne N.M., Taper, H.S., and Roberfroid, M. (1994). Modifications of liver bile acids pool during modu- lation of rat hepatocarcinogenesis by phenobarbital and nafenopin. Arch. Toxicol. 68:394–397.
  • Desvergne, B., Ijpenberg, A., Devchand, P.R., and Wahli, W. (1998). The peroxisome proliferator-activated receptors at the cross-road of diet and hormonal signalling. J. Steroid Biochem. Mol. Biol. 65:65–74.
  • Desvergne, B., and Wahli, W. (1999). Peroxisome proliferator-activated receptors: Nuclear control of metabolism. Endocr. Rev. 20:649–688.
  • Devchand, P.R., Keller, H., Peters, J.M., Vazquez, M., Gonzalez, F.J., and Wahli, W. (1996). The PPARalpha-leukotriene B4 pathway to inflamma- tion control. Nature 384:39–43.
  • Donaubauer, H.H., Kramer, M., Krieg, K., Mayer, D., Von Rechenberg, W., Sandow, J., and Schutz, E. (1987). Investigations of thecarcinogenicity of the LH-RHanalog buserelin (HOE 766) in rats using the sub- cutaneous route of administration. Fundam. Appl. Toxicol. 9:738–752.
  • Doull, J., Cattley, R., Elcombe, C., Lake, B.G., Swen- berg, J., Wilkinson, C., Williams, G., and van Gemert, M. (1999). A cancer risk assessment of di(2-ethylhexyl)phthalate: Application of the new U.S. EPA Risk Assessment Guidelines. Regul. Tox- icol. Pharmacol. 29:327–357.
  • Dowell, P., Ishmael, J.E., Avram, D., Peterson, V.J., Nevrivy, D.J., and Leid, M. (1997a). p300 functions as a coactivator for the peroxisome proliferator-activated receptor alpha. J. Biol. Chem. 272:33435–33443.
  • Dowell, P., Ishmael, J.E., Avram, D., Peterson, V.J., Nevrivy, D.J., and Leid, M. (1999). Identifica- tion of nuclear receptor corepressor as a peroxi- some proliferator-activated receptor alpha interact- ing protein. J. Biol. Chem. 274:15901–15907.
  • Dowell, P., Peterson, V.J., Zabriskie, T.M., and Leid, M. (1997b). Ligand-induced peroxisome proliferator- activated receptor alpha conformational change. J. Biol. Chem. 272:2013–2020.
  • Dreyer, C., Krey, G., Keller, H., Givel, F., Helftenbein, G., and Wahli, W. (1992). Control of the peroxiso- mal beta-oxidation pathway by a novel family of nuclear hormone receptors. Cell 68:879–887.
  • Dubois, M., Pattou, F., Kerr-Conte, J., Gmyr, V., Van- dewalle, B., Desreumaux, P., Auwerx, J., Schoon- jans, K., and Lefebvre, J. (2000). Expression of peroxisome proliferator-activated receptor gamma (PPARgamma) in normal pancreatic islet cells. Di- abetologia 9:1165–1169.
  • Duclos, S., Bride, J., Ramirez, L.C., and Bournot, P. (1997). Peroxisome proliferation and beta- oxidation in Fao and MH1C1 rat hepatoma cells, HepG2 human hepatoblastoma cells and cultured human hepatocytes: Effect of ciprofibrate. Eur. J. Cell Biol. 72:314–323.
  • Dirven, H.A., van den Broek, P.H., and Jongeneelen, F.J. (1990). Effects of di(2-ethylhexyl) phthalate on en- zyme activity levels in liver and serum of rats. Tox- icology 65:199–207.
  • Dirven, H.A., van den Broek, P.H., Peters, J.G., Noord- hoek, J., and Jongeneelen, F.J. (1992). Microsomal lauric acid hydroxylase activities after treatment of rats with three classical cytochrome P450 in- ducers and peroxisome proliferating compounds. Biochem. Pharmacol. 43:2621–2629.
  • Dirven, H.A., van den Broek, P.H., Peeters, M.C., Peters, J.G., Mennes, W.C., Blaauboer, B.J., Noordhoek, J., and Jongeneelen, F.J. (1993). Effects of the peroxisome proliferator mono(2-ethylhexyl)phthalate in primary hepatocyte cultures derived from rat, guinea pig, rabbit and monkey. Biochem. Pharma- col. 45:2425–2434.
  • Dwivedi, R.S., Alvares, K., Nemail, M.R., Subbarno, V., Reddy, M.K., Usman, M.I., Rademacher, A.W., Reddy, J.K., and Rao, M.S. (1989) Comparison of the peroxisome proliferator-induced pleiotropic re- sponse in the liver of nine strains of mice. Toxicol. Pathol. 17:16–26.
  • Dybing, E., Mikalsen, S.-O., Huttunen, J., and Sanner, T. (1995). Peroxisome proliferation, genotoxicity and carcinogenicity. IARC Technical Report. 24:55–85.
  • Eacho, P.I., Lanier, T.L., and Brodhecker, C.A. (1991). Hepatocellular DNA synthesis in rats given per- oxisome proliferating agents: Comparison of WY 14,643 to clofibric acid, nafenopin and LY171883. Carcinogenesis 12:1557–1561.
  • Eagon, P.K., Chander, N., Epley, M.J., Elm, M.S., Brady, E.P., and Rao, K.N. (1994a). Di(2- ethylhexyl)phthalate-induced changes in liver es- trogen metabolism and hyperplasia. Int. J. Cancer 58:736–743.
  • Eagon, P.K., Epley, M.J., Elm, M.S., Brady, E.P., Chandar, N., and Rao, K.N. (1994b). Alterations in estrogen metabolism induced by peroxisome proliferators: Potential role in carcinogenicity. Proc. Am. Assoc. Cancer. Res. 35:141 [Abst. 844].
  • Edvardsson, U., Bergstrom, M., Alexandersson, M. Bam- berg, K., Ljung, B., and Dahllof, B. (1999). Rosigli- tazone (BRL49653), a PPARgamma-selective ag- onist, causes peroxisome proliferator-like liver ef- fects in obese mice. J. Lipid Res. 40:1177–1184.
  • Eibl, G., Wente, M.N., Reber, H.A., and Hines, O.J. (2001). Peroxisome proliferator-activated receptor gamma induces pancreatic cancer cell apoptosis. Biochem. Biophys. Res. Comm. 287:522–529.
  • Elcock, F., Chipman, J., and Roberts, R. (1998). The ro- dent hepatocarcinogen and peroxisome prolifera- tor nafenopin inhibits intercellular communication in rat but not guinea-pig hepatocytes perturbing S-phase but not apoptosis. Arch. Toxicol. 72:439–444.
  • Elcombe, C.R. (1985). Species differences in carcino- genicity and peroxisome proliferation due to trichloroethylene: A biochemical human hazard as- sessment. Arch. Toxicol. 8:S6–S17.
  • Elcombe, C.R., Bell, D.R., Elias, E., Hasmall, S.C., and Plant, N.J. (1996). Peroxisome proliferators: Species differences in response of primary hepato- cyte cultures. Ann. NY Acad. Sci. 804:628–635.
  • Elcombe, C.R., and Mitchell, A.M. (1986). Peroxi- some proliferation due to di(2-ethylhexyl) ph- thalate (DEHP): Species difference and possible mechanisms. Environ. Health Perspect. 70:211–219.
  • Elcombe, C.R., Rose, M.S., and Pratt, I.S. (1985). Biochemical, histological, and unltra-structural changes in rat and mouse liver following the admin- istration of trichloroethylene: Possible relevance to species differences in hepatocarcinogenicity. Tox- icol. Appl. Pharmacol. 79:365–376.
  • Elliott, B.M., Dodd, N.J., and Elcombe, C.R. (1986). In- creased hydroxyl radical production in liver perox- isomal fractions from rats treated with peroxisome proliferators. Carcinogenesis 7:795–799.
  • Emudianughe, T.S., Caldwell, J., Sinclair, K.A., and Smith, R.L. (1983). Species differences in the metabolic conjugation of clofibric acid and clofi- brate in laboratory animals and man. Drug Metab. Dispos. 11:97–102.
  • Escher, P., and Wahli, W. (2000). Peroxisome proliferator- activated receptors: Insight into multiple cellular functions. Mutat. Res. 448:121–138.
  • Faccini, J.M., Nachbaur, J., and Monro, A.M. (1979). Tib- ric acid (CP-18,524)—24-Month study in rats (di- etary administration of drug). Pfizer Laboratories, Research Center, Ambois, France.
  • Fahl, W.E., Lalwani, N.D., Watanabe, T., Goel, S.K., and Reddy, J.K. (1984). DNA damage related to in- creased hydrogen peroxide generation by hypolipi- demic drug-induced liver peroxisomes. Proc. Natl. Acad. Sci. USA 81:7827–7830.
  • Fan, C.Y., Pan, J., Usuda, N., Yeldandi, A.V., Rao, M.S., and Reddy, J.K. (1998). Steatohepatitis, sponta- neous peroxisome proliferation and liver tumors in mice lacking peroxisomal fatty acyl-CoA oxidase. Implications for peroxisome proliferator-activated receptor alpha natural ligand metabolism. J. Biol. Chem. 273:15639–15645.
  • Fan, L.Q., Cattley, R.C., and Corton, J.C. (1998). Tissue-specific induction of 17 beta-hydroxtsteroid dehydrogenase type IV by peroxisome prolif- erator chemicals is dependent on the peroxi- some proliferator-activated receptor alpha J. Endo. 158(2):237–246.
  • Fitzgerald, J.E., Sanyer, J.L., Schardein, J.L., Lake, R.S., McGuire, E.J., and de la Iglesia, F.A. (1981). Car- cinogen bioassay and mutagenicity studies with the hypolididemic agent gemfibrozil. JNCI 67:1105–1116.
  • Floyd, R.A., Lewis, C.A., and Wong, P.K. (1984). High- pressure liquid chromatography—electrochemical detection of oxygen free radicals. Methods Enzy- mol. 105:231–237.
  • Forman, B.M., Chen, J., and Evans, R.M. (1997). Hypolipidemic drugs, polyunsaturated fatty acids, and eicosanoids are ligands for peroxi- some proliferator-activated receptors alpha and delta. Proc. Natl. Acad. Sci. USA 94:4312–4317.
  • Fort, F.L., Miyajima, H., Ando, T., Suzuki, T., Yamamoto, M., Hamashima, T., Sato, S., Kitazaki, T., Mahony, M.H., and Hodgen, G.D. (1995). Mechanism for species-specific induction of Leydig cell tumors in rats. Fundam. Appl. Toxicol. 26:191–202.
  • Foxworthy, P.S., and Eacho, P.I. (1986). Conditions influ- encing the induction of peroxisomal beta-oxidation in cultured rat hepatocytes. Toxicol. Lett. 30:189–196.
  • Frick, M.H., Elo, O., Haapa, K., Heinonen, O.P., Hein- salmi, P., Helo, P., Huttenen, J.K., Kaitaniemi, P., Koskinen, P., Manninen, V., Ma¨enpa¨a¨, H., Ma¨lko¨nen, M., Ma¨nttta¨ri, M., Norola, S., Paster- nack, A., Pikkareinen, J., Romo, M., Sjo¨blom, T., and Nikkila, E.A. (1987). Helsinki Heart Study: Primary prevention tool with gemfibrozil in middle-aged men with dyslipidemia. Safety of treatment, changes in risk factors, and incidence or coronary heart disease. N. Engl. J. Med. 317:1237–1245.
  • Ganning, A.E., Olsson, M.J., Brunk, U., and Dallner, G. (1991). Effects of prolonged treatment with phtha- late ester on rat liver. Pharmacol. Toxicol. 68:392–401.
  • Gariot, P., Barrat, E., Drouin, P., Genton, P., Pointel, J.P., Foliguet, B., Kolopp, M., and Debry, G. (1987). Morphometric study of human hepatic cell modifications induced by fenofibrate. Metabolism 36:203–210.
  • Gavin, C.E., Malnoske, J.A., White, J., and Schlosser, M.J. (1997). Species differences in expression of pancreatic cholecystokinin-A receptors. Toxicolo- gist 36:232.
  • Gazouli, M., Yao, Z.-X., Boujrad, N., Corton, J.C., Culty, M., and Papadopoulos, V. (2002). Ef- fect of peroxisome proliferators on Leydig cell peripheral-type benzodiazepine receptor gene ex- pression, hormone-stimulated cholesterol trans- port, and steroidogenesis: Role of the peroxisome proliferator-activator receptor α. Endocrinology 143:2571–2583.
  • Gervois, P., Torra, I.P., Chinetti, G., Grotzinger, T., Dubois, G., Fruchart, J.C., Fruchart-Najib, J., Leit- ersdorf, E., and Staels, B. (1999). A truncated human peroxisome proliferator-activated receptoralpha splice variant with dominant negative activ- ity. Mol. Endocrinol. 13:1535–1549.
  • Ghanekar, D., Hadac, E.M., Holicky, E.L., and Miller, L.J. (1997). Differences in partial agonist action at cholecystokinin receptors of mouse and rat are dependent on parameters extrinsic to receptor structure: Molecular cloning, expression andfunctional characterization of the mouse type a chole- cystokinin receptor. J. Pharmacol. Exp. Therap. 282:1206–1212.
  • Gibson, J.P., Newberne, J.W., Kuhn, W.L., and Elsea, J.R., (1967) Comparative chronic toxicity of three oral estrogens in rats. Toxicol. Appl. Pharmacol. 11:489–510.
  • Gill, J.H., Roberts, R.A., and Dive, C. (1998). The nongenotoxic hepatocarcinogen nafnopin sup- presses rodent hepatocyte apoptosis induced by TGFb1, DNA damage and FAS. Carcinogenesis. 19:299–304.
  • Gilliland, F.D., and Mandel, J.S. (1996). Serum perfluo- rooctanoic acid and hepatic enzymes, lipoproteins, and cholesterol: A study of occupationally exposed men. Am. J. Ind. Med. 29(5):560–568.
  • Givler, B., Alberts, D., Wollenberg, G., Pitzenberger, M., Deluca, J., and Lawrence, J. (2000). TNFα is not required for WY 14,643-induced proliferation in mice. Toxicologist 54:A1975.
  • Glauert, H.P., Beaty, M.M., Clark, T.D., Greenwell, W.S., Tatum, V., Chen, L.C., Borges, T., Clark, T.L., Srinivasan, S.R., and Chow, C.K. (1990). Effect of dietary vitamin E on the development of altered hepatic foci and hepatic tumors induced by the per- oxisome proliferator ciprofibrate. J. Cancer Res. Clin. Oncol. 116:351–356.
  • Go, V.L.W., DiMagno, E.P., Gardner, J.D., Lebenthal, E., Reber, H.A., and Scheele, G.A. (1993). The Pan- creas. Biology, Pathobiology, and Disease. Raven Press, New York.
  • Goel, S.K., Lalwani, N.D., and Reddy, J.K. (1986). Per- oxisome proliferation and lipid peroxidation in rat liver. Cancer Res. 46:1324–1330.
  • Goke, B., Fenchel, K., Knobloch, S., Arnold, R.R., and Adler, G. (1988). Increased CCK-response to pro- teinase inhibitor feeding after induction of pancre- atic hypertrophy in rats. Pancreas 3:576–579.
  • Gold, L.S., and Zeiger, E. (1997). Handbook of Carcino- genic Potency and Genotoxicity Databases. CRC Press, New York.
  • Goldsworthy, T.L., and Popp, J.A. (1987). Chlorinated hydrocarbon-induced peroxisomal enzyme activity in relation to species and organ carcinogenicity. Toxicol. Appl. Pharmacol. 88:225–233.
  • Goll, V., Alexandre, E., Viollon-Abadie, C., Nicod, L., Jaeck, D., and Richert, L. (1999). Comparison of the effects of various peroxisome proliferators on peroxisomal enzyme activities, DNA synthesis, and apoptosis in rat and human hepatocyte cultures. Toxicol. Appl. Pharmacol. 160:21–32.
  • Gomez, G., Upp, J.R., Lluis, F., Alexander, R.W., Poston, G.J., Greeley, G.H., and Thompson, J.C. (1988). Regulation of the release of cholecystokinin by bile salts in dogs. Gastroenterology 94:1036–1046.
  • Gottlicher, M., Widmark, E., Li, Q., and Gustafsson, J.A. (1992). Fatty acids activate a chimera of the clofib- ric acid-activated receptor and the glucocorticoid receptor. Proc. Natl. Acad. Sci. USA 89:4653–4657.
  • Graddy, L.G., Kowalski, A.A., Simmen, F.A., Davis, S.L.F., Baumgartner, W.W., and Simmen, R.C.M. (2000). Multiple isoforms of porcine aromatase are encoded by three distinct genes. J. Steroid Biochem. Mol. Biol. 73:49–57.
  • Graham, M.J., Wilson, S.A., Winham, M.A., Spencer, A.J., Rees, J.A., Old, S.L., and Bonner, F.W. (1994). Lack of peroxisome proliferation in mar- moset liver following treatment with ciprofibrate for 3 years. Fundam. Appl. Toxicol. 22:58–64.
  • Grasl-Kraupp, B., Huber, W., Timmermann-Trosiener, I., and Schulte-Hermann, R. (1993). Peroxisomal en- zyme induction uncoupled from enhanced DNA synthesis in putative preneoplastic liver foci of rats treated with a single dose of the peroxisome prolif- erator nafenopin. Carcinogenesis 14:2435–2437.
  • Grasl-Kraupp, B., Ruttkay-Nedecky, B., Mullauer, L., Taper, H., Huber, W., Bursch, W., and Schulte- Hermann, R. (1997). Inherent increase of apop- tosis in liver tumors: Implications for carcinogen- esis and tumor regression. Hepatology. 25:906–912.
  • Gray, T.J., Lake, B.G., Beamand, J.A., Foster, J.R., and Gangolli, S.D. (1983). Peroxisome proliferation in primary cultures of rat hepatocytes. Toxicol. Appl. Pharmacol. 67:15–23.
  • Greaves, P., Irisarri, E., and Munro, A.M. 1986. Hep- atic foci of cellular and enzymatic alteration and nodules in rats treated with clofibrate or diethylni- trosamine followed by phenobarbital: Their rate of onset and reversibility. JNCI 76:475–484.
  • Green, T., Mainwaring, G.W., and Foster, J.R. (1997). Trichloroethylene-induced mouse lung tumors: Studies of the mode of action and comparisons between species. Fundam. Appl. Toxicol. 37:125–130.
  • Green, T., and Prout, M.S. (1985). Species dif- ferences in response to trichloroethylene. II. Biotransformation in rats and mice. Toxicol. Appl. Pharmacol. 79:401–411.
  • Griffith, F.D., and Long, J.E. (1980). Animal toxicity stud- ies with ammonium perfluorooctanoate. AM. Ind. Hyg. Assoc. J. 41:576–583.
  • Gugler, R., and Hartlapp, J. (1978). Clofibrate kinetics after single and multiple doses. Clin. Pharmacol. Ther. 24:432–438.
  • Hagmar, L., Akesson, B., Nielsen, J., Andersson, C., Linden, K., Attewell, R., and Moller, T. (1990). Mortality and cancer morbidity in workers ex- posed to low levels of vinyl chloride monomer at a polyvinyl chloride processing plant. Am. J. Ind. Med. 17:553–565.
  • Hahn, S.E., and Goldberg, D.M. (1992). Modulation of lipoprotein production in Hep G2 cells by fenofi- brate and clofibrate. Biochem. Pharmacol. 43:625–633.
  • Handler, J.A., Seed, C.B., Bradford, B.U., and Thurman, R.G. (1992). Induction of peroxisomes by treat- ment with perfluorooctanoate does not increase rates of H2O2 production in intact liver. Toxicol. Lett. 60:61–68.
  • Handler, J.A., and Thurman, R.G. (1988). Catalase- dependent ethanol oxidation in perfused rat liver. Requirement for fatty-acid-stimulated H2O2 production by peroxisomes. Eur. J. Biochem. 176:477–484.
  • Hanefeld, M., Kemmer, C., and Kadner, E. (1983). Rela- tionship between morphological changes and lipid- lowering action of p-chlorphenoxyisobutyric acid (CPIB) on hepatic mitochondria and peroxisomes in man. Atherosclerosis 46:239–246.
  • Hanhijarvi, H., Ophaug, R.H., and Singer, L. (1982). The sex related difference in perfluorooctanoate excre- tion in the rat. Proc. Soc. Exp. Biol. Med. 171:50–55.
  • Hanhijarvi, H., Ylinen, M., Haaranen, T., and Nevalainen, T. (1988). A proposed species difference in the renal excretion of perfluorooctanoic acid in the beagle dog and rat. In: New Developments in Bio- sciences: Their Implications for Laboratory An- imal Science, A.C. Beynen and H. A. Solleveld, eds., pp. 409–412. Martinus Nijhoff, Dordrecht.
  • Hanhijarvu, H., Ylinen, M., Kojo, A., and Kosma, V.-M. (1987) Elimination and toxicity of perfluorooc- tanoic acid during subchronic administration in the Wistar rat. Pharmacol. Toxicol. 61:66–68.
  • Hansen, K.J., Clemen, L.A., Ellefson, M.E., and John- son, H.O. (2001). Compound-specific, quantitative characterization of organic fluorochemicals in bi- ological matrices. Environ. Sci. Tech. 35:766–770.
  • Hardell, L., Ohlson, C.-G., and Fredrikson, M. (1997). Occupational exposure to polyvinyl chloride as a risk factor for testicular cancer evaluated in a case- control study. Int J. Cancer. 73:828–830.
  • Hartig, F., Stegmeier, K., Hebold, G., O¨ zel, M., and Fahimi, H. D. (1982). Study of liver enzymes: Per- oxisome proliferation and tumor rates in rats at the end of carcinogenicity studies with bezafibrate and clofibrate. Ann. NY Acad. Sci. 386:111–135.
  • Hashimoto, T. (1996) Peroxisomal β-oxidation: Enzy- mology and molecular biology. In: Peroxisomes: Biology and Role in Toxicology and Disease, J.K. Reddy, T. Suga, G.P. Mannaerts, P.B. Lazarow, and S. Subramani, eds. Ann. NY Acad. Sci. 804:86–98.
  • Hasmall, S., James, N., Hedley, K., Olsen, K., and Roberts, R. (2001). Mouse hepatocyte response to peroxisome proliferators: Dependency on hepatic nonparenchymal cells and peroxisome proliferator activated receptor alpha (PPAR alpha). Arch. Tox- icol. 75:357–361.
  • Hasmall, S.C., James, N.H., Macdonald, N., Gonzalez, F.J., Peters, J.M., and Roberts, R.A. (2000a). Sup- pression of mouse hepatocyte apoptosis by perox- isome proliferators: Role of PPARα and TNF. Mu- tat. Res. 448:193–200.
  • Hasmall, S.C., James, N.H., Macdonald, N., Soames, A.R., and Roberts, R.A. (2000b). Species differences in response to diethylhexylphthalate: suppression of apoptosis, induction of DNA syn- thesis and peroxisome proliferator activated recep- tor alpha-mediated gene expression Arch. Toxicol. 74:85–91.
  • Hasmall, S.C., James, N.H., Macdonald, N., West, D., Chevalier, S., Cosulich, S.C., and Roberts, R.A. (1999). Suppression of apoptosis and induction of DNA synthesis in vitro by the phthalate plas- ticizers monoethylhexylphthalate (MEHP) and di- isononylphthalate (DINP): A comparison of rat and human hepatocytes in vitro. Arch. Toxicol. 73:451–456.
  • Hasmall, S., Olsen, K., and Roberts, R. (2000c). Role of nonparenchymal cells in the response of rat hepa- tocytes to the peroxisome proliferator nafenopin in vitro. Carcinogenesis. 21:2159–2165.
  • Hasmall, S.C., Pyrah, I.T., Soames, A.R., and Roberts, R.A. (1997). Expression of the immediate-early genes, c-fos, c-jun, and c-myc: A comparison in rats of nongenotoxic hepatocarcinogens with non- carcinogenic liver mitogens. Fundam. Appl. Toxi- col. 40:129–137.
  • Haughom, B., and Spydevold, O. 1992. The mech- anism underlying the hypolipemic effect of perfluorooctanoic acid (PFOA), perfluorooctane sulphonic acid (PFOSA) and clofibricacid. Biochem. Biophys. Acta 1128:65–72.
  • Hegi, M.E., Ulrich, D., Sagelsdorff, P., Richter, C., and Lutz, W.K. (1990). No measurable increase in thymidine glycol or 8-hydroxydeoxyguanosine in liver DNA of rats treated with nafenopin or choline- devoid low-methionine diet. Mutat. Res. 238:325–329.
  • Hertz, R., Bishara-Shieban, J., and Bar-Tana, J. (1995). Mode of action of peroxisome proliferators as hy- polipidemic drugs. Suppression of apolipoprotein C-III. J. Biol. Chem. 270:13470–13475.
  • Hess, R., Staubli, W., and Riess, W. (1965). Na- ture of the hepatomegalic effects produced by ethyl chlorophenoxyisobutyrate (CPIB). Nature 208:856–868.
  • Hihi, A.K., Michalik, L., and Wahli, W. (2002). PPARs: Transcriptional effectors of fatty acids and their derivatives. Cell Mol. Life Sci. 59:790–798.
  • Hildebrand, H., Schmidt, U., Kempka, G., Jacob, R., Ahr, H.J., Ebener, C., Goretzki, P.E., and Bader A. (1999). An in vitro model for peroxisome prolif- eration utilizing primary hepatocytes in sandwich culture. Toxicol. In Vitro. 13:265–273.
  • Hinton, R.H., Mitchell, D.E., Mann, A., Chescoe, D., Price, S.C., Mann, A., Grasso, P., and Bridges, J.W. (1986). Effect of phthalic acid esters on the liver and thyroid. Environ. Health Perspect. 70:195–210.
  • Holden, P., Hasmall, S., James, N., West, D., Brindle, R., Gonzalez, F., Peters, J., and Roberts, R. (2000). Tumour necrosis factor a (TNFa): Role in suppres- sion of apoptosis by peroxisome proliferators. Cell. Mol. Biol. 46:29–39.
  • Holicky, E.L., Hadac, E.M., Ding, X.-Q., and Miller, L.J. (2001). Molecular characterization and organ dis- tribution of type A and B cholecystokinin receptors in cynomolgus monkey. Am. J. Physiol. Gastroin- test. Liver Physiol. 281:G507–G514.
  • Holland, F.J. (1991). Gonadotropin-independent preco- cious puberty. Endocrinol. Metabolism Clin. N. Am. 20:191–210.
  • Hollander, H., and Wiegand, W. (1978). Diclofop methyl—Toxicity and tumorigenicity study in mice during dietary administration for 2 years with interim sacrifice after 88 weeks. Prepared by Pharma Research Toxicology and Pathology, Frankfurt Germany. Unpublished. U.S. EPA MRID 92036058.
  • Hollenberg, A.N., Susulic, V.S., Madura, J.P., Zhang, B., Moller D.E., Tontonoz, P., Sarraf, P., Spiegel-man, B.M., and Lowell, B.B. (1997). Functional antagonism between CCAAT/enhancer binding protein-alpha and peroxisome proliferator- activated receptor-gamma on the leptin promoter. J. Biol. Chem. 272:5283–5290.
  • Holt, S., Roy, G., Mitra, S., Upton, P.B., Bogdanffy, M.S., and Swenberg, J.A. (2000). Deficiency of N-methylpurine-DNA-glycosylase expression in nonparenchymal cells, the target cell for vinyl chlo- ride and vinyl fluoride. Mutat. Res. 460:105–115.
  • Hopman, W., Jansen, J., and Lamers, C. (1984). Plasma cholecystokinin response to oral fat in patients with Billroth I and Billroth II gastrectomy. Ann. Surg. 199:276–280.
  • Horwitz, K.B., Jackson, T.A., Bain, D.L., Richer, J.K., Takimoto, G.S., and Tung, L. (1996). Nuclear receptor coactivators and corepressors. Mol. En- docrinol. 10:1167–1177.
  • Hosokawa, S., Tatematsu, M., Aoki, T., Nakanowatari, J., Igarashi, T., and Ito, N. (1989). Modulation of diethylnitrosamine-initiated placental glutathione S-transferase positive preneoplastic and neoplastic lesions by clofibrate, a hepatic peroxisome prolif- erator. Carcinogenesis 10:2237–2241.
  • Howatson, A.G., and Carter, D.C. (1985). Pancreatic carcinogenesis-enhancement by cholecystokinin in the hamster-nitrosamine model. Br. J. Cancer 51:107–114.
  • Hsu, M.H., Savas, U., Griffin, K.J., and Johnson, E.F. (2001). Identification of peroxisome proliferator- responsive human genes by elevated expression of the peroxisome proliferator-activated receptor al- pha in HepG2 cells. J. Biol. Chem. 276:27950–27958.
  • Huber, W., Grasl-Kraupp, B., Esterbauer, H., and Schulte- Hermann, R. (1991). Role of oxidative stress in age dependent hepatocarcinogenesis by the perox- isome proliferator nafenopin in the rat. Cancer Res. 51:1789–1792.
  • Huber, W.W., Grasl-Kraupp, B., and Schulte-Hermann, R. (1996). Hepatocarcinogenic potential of di(2- ethylhexyl)phthalate in rodents and its implications for human risk. Crit. Rev. Toxicol. 26:365–481.
  • Huhtaniemi, I.T. (1983). Gonadotrophin receptors: Corre- lates with normal and pathological functions of the human ovary and testis. In: Clinical Endocrinology and Metabolism: Receptors in Health and Disease, ed. R.N. Clayton, pp. 117–132. W.B.Saunders, Philadelphia.
  • Hunt, M.C., Lindquist, P.J., Peters, J.M., Gonzalez, F.J., Diczfalusy, U., and Alexson, S.E. (2000). Involve- ment of the peroxisome proliferator-activated re- ceptor alpha in regulating long-chain acyl-CoA thioesterases. J. Lipid Res. 41:814–823.
  • Hunt, M.C., Yang, Y.Z., Eggertsen, G., Carneheim, C.M., Einarsson, C., and Alexson, S. (2001). The peroxi- some proliferator-activated receptor alpha (PPAR- alpha) is involved in bile acid biosynthesis. Inter- national bile acid meeting; Biology of bile acids in health and disease (Proceedings of the Falk Sym- posium 120 held in Den Haag, the Netherlands, Oc- tober 12–23, 2000, G.P. van Berge Henegouwen, ed.), 120, pp. 43–53.
  • Hunt, M.C., Yang, Y.Z., Eggertsen, G., Carneheim, C.M., Gafvels, M., Einarsson, C., and Alexson, S.E. (2000). The peroxisome proliferator-activated receptor alpha (PPARalpha) regulates bile acid biosynthesis. J. Biol. Chem. 275:28947–28953.
  • Hunter, J., Kassam, A., Winrow, C.J., Rachubinski, R.A., and Capone, J.P. (1996). Crosstalk be- tween the thyroid hormone and peroxisome proliferator-activated receptors in regulating per- oxisome proliferator-responsive genes. Mol. Cell. Endocrinol. 116:213–221.
  • Hunter, M.G., Sullivan, M.H., Dix,C.J., Aldred, L.F., and Cooke, B.A. (1982). Stimulation and inhibition by LHRH analogues of cultured rat Leydig cell func- tion and lack of effect on mouse Leydig cells. Mol. Cell Endocrinol. 27:31–44.
  • Huttunen, J.K., Heinonen, O.P., Manninen, V., Koski- nen, P., Hakulinen, T., Teppo, L., Manttari, M., and Frick, M.H. (1994). The Helsinki Heart Study: An 8.5-year safety and mortality follow-up [see com- ments]. J. Intern. Med. 235:31–39.
  • IARC. (1995a). WHO International Agency for Research on Cancer. IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Hu- mans: Dry Cleaning, Some Chlorinated Solvents and Other Industrial Chemicals, Vol. 63.IARC Press, Lyon, France.
  • IARC. (1995b). WHO International Agency for Research on Cancer. IARC Technical Report No. 24. Peroxi- some Proliferation and its Role in Carcinogenesis. IARC Press, Lyon, France.
  • IARC. (1996). WHO International Agency for Research on Cancer. IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans: Some Pharmaceutical Drugs, Vol. 66, pp. 391– 426. IARC Press, Lyon, France.
  • IARC. (1999) WHO International Agency for Research on Cancer. IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans: Some chemicals that cause tumours of the kidney or urinary bladder in rodents and some other sub- stances. IARC Press, Lyon, France. Volume 73, pp. 155–131.
  • IARC. (2000). WHO International Agency for Research on Cancer. IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans: Some Industrial Chemicals, Vol. 77. IARC Press, Lyon, France.
  • Inamoto, H., Ozaki, R., Matsuzaki, T., Wakui, M., Saruta, T., and Osawa, A. (1991). Incidence and mortality patterns of malignancy and factors affecting the risk of malignancy in dialysis patients. Nephron 59:611–617.
  • Iseki, K., Osawa, A., and Fukiyama, K. (1993). Evidence for increased cancer deaths in chronic dialysis pa- tients. Am. J. Kidney Dis. 22:308–313.
  • Isenberg, J.S., Kamendulis, L.M., Ackley, D.C., Smith, J.H., Pugh, G., Lington, A.W., McKee, R.H., and Klaunig, J.E. (2001). Reversibility and persis- tence of di-2-ethylhexyl phthalate (DEHP)- and phenobarbital-induced hepatocellular changes in rodents. Toxicol. Sci. 64:192–199.
  • Isenberg, J.S., Kamendulis, L.M., Smith, J.H., Ackley, D.C., Pugh, G. Jr., Lington, A.W., and Klaunig, J.E. (2000). Effects of di-2-ethylhexyl phthalate (DEHP) on gap-junctional intercellular commu- nication (GJIC), DNA synthesis, and peroxisomal beta oxidation (PBOX) in rat, mouse, and hamster liver. Toxicol. Sci. 56:73–85.
  • Isenberg, J.S., Kolaja, K.L., Ayoubi, S.A., Watkins, J.B. 3rd, and Klaunig, J.E. (1997). Inhibition of WY 14,643-induced hepatic lesion growth in mice by rotenone. Carcinogenesis 18:1511–1519.
  • Issemann, I., and Green, S. (1990). Activation of a mem- ber of the steroid hormone receptor superfamily by peroxisome proliferators. Nature 347:645–650.
  • Issemann, I., Prince, R.A., Tugwood, J.D., and Green, S. (1993). The peroxisome proliferator-activated re- ceptor: retinoidX receptor heterodimer is activated by fatty acids and fibrate hypolipidaemic drugs. J. Mol. Endocrinol. 11:37–47.
  • Iwai, K., Fushiki, T., and Fukuoka, S.-I. (1988). Pancre- atic enzyme secretion mediated by novel peptide: Monitor peptide hypothesis. Pancreas 3:720–728.
  • Izydore, R.A., and Hall, I.H. (1991). Hypolipodemic ac- tivity of aliphatic dicarboxylic acids in rodents. Acta Pharma. Nord. 3:141–146.
  • James, N.H., and Roberts, R.A. (1996). Species differ- ences in response to peroxisome proliferators cor- relate in vitro with induction of DNA synthesis rather than suppression of apoptosis. Carcinogen- esis 17:1623–1632.
  • James, N.H., Soames, A.R., and Roberts, R.A. (1998). Suppression of hepatocyte apoptosis and induc- tion of DNAsynthesis by the rat and mouse hep- atocarcinogen diethylhexylphthalate (DEHP) and the mouse hepatocarcinogen 1,4-dichlorobenzene (DCB). Arch. Toxicol. 72:784–790.
  • Jansen, L., and Jongen, W. (1996). The use of initi- ated cells as a test system for the detection of in- hibitors of gap junctional intercellular communi- cation. Carcinogenesis 17:333–339.
  • Ji, B., Bi, Y., Simeone, D., Mortensen, R.M., and Logsdon, C.D. (2001). Human pancreatic acinar cells lack functional responses to cholecystokinin and gas- trin. Gastroenterology 121:1380–1390.
  • Jin, F.Y., Kamanna, V.S., Chuang, M.Y., Morgan, K., and Kashyap, M.L. (1996). Gemfibrozil stimulates apolipoprotein A-I synthesis and secretion by sta- bilization of mRNA transcripts in human hepato- blastoma cell line (Hep G2). Arterioscler. Thromb. Vasc. Biol. 16:1052–1062.
  • Johnson, F.E., LaRegina, M.C., Martin, S.A., and Bashiti, H.M. (1983). Cholecystokinin inhibits pancreatic and hepatic carcinogenesis. Cancer Detect. Prev. 6:389–402.
  • Johnson, L.R. (1981). Effects of gastrointestinal hor- mones on pancreatic growth. Cancer 47:1640–1645.
  • Johnson, L.R. (1987). Cholesystokinin. In: Physiology of the Gastrointestinal Tract, eds. L.R. Johnson, J. Christensen, M.J. Jackson, G.D. Jacobson, and J.H. Walsh, pp. 195–205. Raven Press, New York.
  • Jung, D., Fried, M., and Kullak-Ublick Gerd, A. (2002). Human apical sodium-dependent bile salt trans- porter gene (SLC10A2) is regulated by the peroxi- some proliferator-activated receptor alpha. J. Biol. Chem. 277:30559–30566.
  • Kaikaus, R.M., Chan, W.K., Lysenko, N., Ray, R., Ortiz de Montellano, P.R., and Bass, N.M. (1993). In- duction of peroxisomal fatty acid beta-oxidation and liver fatty acid-binding protein by peroxi- some proliferators. Mediation via the cytochrome P-450IVA1 omega-hydroxylase pathway. J. Biol. Chem. 268:9593–9603.
  • Kamendulis, L., Isenberg, J., Smith, J., Pugh, G., Lington, A., and Klaunig, J. (2002). Comparative effects of phthalate monoesters on gap junctional intercel- lular communication and peroxisome proliferation in rodent and primate hepatocytes. J. Toxicol. En- viron. Health A 65:569–588.
  • Kantor, A.F., Hoover, R.N., Kinlen, L.J., McMullan, M.R., and Fraumenti, J.F., Jr. (1987). Cancer in pa- tients receiving long-term dialysis treatment. Am. J. Epidemiol. 126:370–376.
  • Kasai, H. (1997). Analysis of a form of oxidative DNA damage, 8-hydroxy-21-deoxyguanosine, as a marker of cellular oxidative stress during carcino- genesis. Mutat. Res. 387:147–163.
  • Kasai, H., Okada, Y., Nishimura, S., Rao, M.S., and Reddy, J.K. (1989). Formation of 8-hydroxyde- oxyguanosine in liver DNA of rats following long- term exposure to a peroxisome proliferator. Cancer Res. 49:2603–2605.
  • Kaufmann, W., Deckardt, K., McKee, R., Butala, J., and Bahnemann, R. (2002). Tumor induction in mouse liver—Di-isononyl phthalate (DINP) acts via per- oxisome proliferation. Regul. Toxicol. Pharmacol. 36:175–183.
  • Kawashima, Y., Uy-Yu, N., and Kozuka, H. (1989). Sex- related difference in the inductions by perfluoro- octanoic acid of peroxisomal β-oxidation, micro- somal 1-acylglycero-phosphocholine acyltrans- ferase and cytosolic long-chain acyl-CoA hydro- lase in rat liver. Biochem. J. 261:595–600.
  • Kazeto, Y., Ijiri, S., Place, A.R., Zohar, Y., and Trant, J.M. (2001). The 51-flanking regions of CYP19A1 and CYP19A2 in zebrafish. Biochem. Biophy. Res. Commun. 288:503–508.
  • Keller, H., Devchand, P.R., Perroud, M., and Wahli, W. (1997). PPAR alpha structure-function rela- tionships derived from species-specific differences in responsiveness to hypolipidemic agents. Biol. Chem. 378:651–655.
  • Kennedy, G.L., Jr., Hall, G.T., Brittelli, M.R., Barnes, J.R., and Chen, H.C. (1986). Inhalation toxicity of am- monium perfluorooctanoate. Food Chem. Toxicol. 24:1325–1329.
  • Kersten, S., Seydoux, J., Peters, J.M., Gonzalez, F.J., Desvergne, B., and Wahli, W. (1999). Peroxi- some proliferator-activated receptor alpha medi- ates the adaptive response to fasting. J. Clin. Invest. 103:1489–1498.
  • Keys, D.A, Wallance, D.G., Kepler, T.B., and Conolly, R.B. (1999). Quantitative evaluation of alternative mechanisms of blood and testes disposition of di(2- ethylhexyl) phthalate and mono(2-ethylhexyl) ph- thalate in rats. Toxicol. Sci. 49:172–185.
  • Khan, S., Teerds, K., and Dorrington, J. (1992). Growth factor requirements for DNA synthesis by Leydig cells from the immature rat. Biol. Reprod. 46:335–341.
  • Klaunig, J., Ruch, R., DeAngelo, A., and Kaylor, W. (1988). Inhibition of mouse hepatocyte intercel- lular communication by phthalate esters. Cancer Lett. 43:65–71.
  • Klaunig, J., Ruch, R., and Lin, E. (1989). Effects of trichloroethylene and its metabolites on rodent hepatocyte intercellular communication. Toxicol. Appl. Pharmacol. 99:454–465.
  • Klaunig, J.E., Xu, Y., Isenberg, J.S., Bachowski, S., Kolaja, K.L., Jiang, J., Stevenson, D.E., and Wal- borg, E.F., Jr. (1998). The role of oxidative stress in chemical carcinogenesis. Environ. Health Per- spect. 106(Suppl. 1): S289–S295.
  • Kliewer, S.A., Sundseth, S.S., Jones, S.A., Brown, P.J., Wisely, G.B., Koble, C.S., Devchand, P., Wahli, W., Willson, T.M., Lenhard, J.M., and Lehmann, J.M. (1997). Fatty acids and eicosanoids regulate gene expression through direct interactions with peroxisome proliferator-activated receptors alpha and gamma. Proc. Natl. Acad. Sci. USA 94:4318–4323.
  • Kluwe, W.M. (1982). The carcinogenicity of dietary di(2 ethylhexyl) phthalate (DEHP) in Fischer 344 rats and B6C3F1 mice. J. Toxicol. Environ. Health 10:797–815.
  • Kluwe, W.M., Huff, J.E., Matthews, H.B., Irwin, R., and Haseman, J.K. (1985). Comparative chronic toxi- cities and carcinogenic potentials of 2-ethylhexyl- containing compounds in rats and mice. Carcino- genesis 6:1577–1583.
  • Koop, I., Koop, H., Gerhardt, C., Schafmayer, A., and Arnold, R. (1989). Do bile acids exert a nega- tive feedback control of cholecystokinin release? Scand. J. Gastroenterol. 24:315–320.
  • Krey, G., Braissant, O., L’Horset, F., Kalkhoven, E., Perroud, M., Parker, M.G., and Wahli, W. (1997). Fatty acids, eicosanoids, and hypolipidemic agents identified as ligands of peroxisome proliferator- activated receptors by coactivator-dependent re- ceptor ligand assay. Mol. Endocrinol. 11:779–791.
  • Krutovskikh, V., Mesnil, M., Mazzoleni, G., and Yamasaki, H. (1995). Inhibition of rat liver gap junction intercellular communication by tumor- promoting agents. In vivo association with aber- rant localization of connexin proteins. Lab. Invest. 72:571–577.
  • Kudo, N., Katakura, M., Sato, Y., and Kawashima, Y. (2002) Sex hormone-regulated renal transport of perfluorooctanoic acid. Chem. Biol. Interact. 139:301–316.
  • Kurata, Y., Kidachi, F., Yokoyama, M., Toyota, N., Tsuchitani, M., and Katoh, M. 91998). Subchronic toxicity of di(2-ethylhexyl)phthalate in common marmosets: Lack of hepatic peroxisome prolifer- ation, testicular atrophy or pancreatic acinar cell hyperplasia. Toxicol. Sci. 42:49–56.
  • Kurosawa, H., Miyasaka, K., and Kitani, K. (1989). In- fluence of bile flow obstruction vs. bile diversion on pancreatic secretion in the conscious rat. Int. J. Pancreat. 4:187–197.
  • Kuslikis, B.I., Vanden Heuvel, J.P., and Peterseon, R.E. (1992). Lack of evidence for perfluorodecanoyl- or perfluorooctanoyl-coenzyme A formation in male and female rats. J. Biochem. Toxicol. 7:25–29.
  • Lake, B.G. (1995a). Mechanisms of hepatocarcinogenic- ity of peroxisome-proliferating drugs and chemi- cals. Annu. Rev. Pharmacol. Toxicol. 35:483–507.
  • Lake, B.G. (1995b). Peroxisome proliferation: Current mechanisms relating to nongenotoxic carcinogen- esis. Toxicol. Lett. 83:673–681.
  • Lake, B.G., Evans, J.G., Cunninghame, M.E., and Price, R.J. (1993). Comparison of the hepatic effects of nafenopin and WY 14,643-14,643 on peroxisome proliferation and cell replication in the rat and Syr- ian hamster. Environ. Health Perspect. 5:241–247.
  • Lake, B.G., Evans, J.G., Gray, T.J., Korosi, S.A., and North, C.J. (1999). Comparative studies on nafenopin-induced hepatic peroxisome prolifera- tion in the rat, Syrian hamster, guinea pig, and mar- moset. Toxicol. Appl. Pharmacol. 99:148–160.
  • Lake, B.G., Gray, T.J.B., Foster, J.R., Stubberfield, C.R., and Gangolli, S.D. (1984a). Comparative stud- ies on di-(2-ethylhexyl) phthalate-induced hepatic peroxisome proliferation in the rat and hamster. Toxicol. Appl. Pharmacol. 72:46–60.
  • Lake, B.G., Gray, T.J., and Gangolli, S.D. (1986). Hepatic effects of phthalate esters and related compounds—In vivo and in vitro correlations. En- viron. Health Perspect. 67:283–290.
  • Lake, B.G., Kozlen, S.L., Evans, J.G., Gray, T.J., Young, P.J., and Gangolli, S.D. (1987). Effect of prolonged administration of clofibric acid and di-(2- ethyl- hexyl)phthalate on hepatic enzyme activities and lipid peroxidation in the rat. Toxicology 44:213–228.
  • Lake, B.G., Phillips, J.C., Linnell, J.C., and Gangolli, S.D. (1977). The in vitro hydrolysis of some phtha- late diesters by hepatic and intestinal preparations from various species. Toxicol. Appl. Pharmacol. 39:239–248.
  • Lake, B.G., Price, R.J., Cunninghame, M.E., and Wal- ters, D.G. (1997a). Comparison of the effects of cinnamyl anthranilate on hepatic peroxisome pro- liferation and cell replication in the rat and mouse. Fundam. Appl. Toxicol. 39:60–66.
  • Lake, B.G., Price, R.J., Cunninghame, M.E., and Walters, D.G. (1997b). Comparison of the effects of di-(2- ethylhexyl)adipate on hepatic peroxisome prolif- eration and cell replication in the rat and mouse. Toxicology 123:217–226.
  • Lake, B.G., Rijcken, W.R.P., Gray, T.J.B., Foster, J.R., and Gangolli, S.D. (1984b). Comparative studies of the hepatic effects of di- and mono-N-octyl phthalates, di-(2-ethylhexyl) phthalate and clofibrate in the rat. Acta. Pharmacol. Toxicol. 54:167–176.
  • Lambe, K.G., Woodyatt, N.J., Macdonald, N., Chevalier, S., and Roberts, R.A. (1999). Species differences in sequence and activity of the peroxisome prolifer- ator response element (PPRE) within the acyl CoA oxidase gene promoter. Toxicol. Lett. 110:119–127.
  • Law, M.R., Thompson, S.G., and Wald, N.J. (1994). As- sessing possible hazards of reducing serum choles- terol Br. Med. J. 308:373–379.
  • Lawrence, J., Li, Y., Chen, S., DeLuca, J.G., Berger, J.P., Umbenhauer, D.R., Moller, D.E., and Zhou, G. (2001a). Differential gene regulation in human ver- sus rodent hepatocytes by PPAR alpha: PPAR alpha fails to induce peroxisome proliferation associated genes in human cells independently of receptor lev- els. J. Biol. Chem. 276:1521–32527.
  • Lawrence, J.W., Wollenberg, G.K., and DeLuca, J.G. (2001b). Tumor necrosis factor alpha is not re- quired for WY 14,643-induced cell proliferation. Carcinogenesis 22:381–386.
  • Ledwith, B.J., Johnson, T.E., Wagner, L.K., Pauley, C.J., Manam, S., Galloway, S.M., and Nichols, W.W. (1996). Growth regulation by peroxisome prolif- erator: Opposing activities in early and late G1. Cancer Res. 56:3257–3264.
  • Ledwith, B.J., Manam, S., Troilo, P., Joslyn, D.J., Gal- loway, S.M., and Nichols, W.W. (1993). Activation of immediate-early gene expression by peroxisome proliferators in vitro. Mol. Carcinogen. 8:20–27.
  • Lee, S.S., Pineau, T., Drago, J., Lee, E.J., Owens, J.W., Kroetz, D.L., Fernandez-Salguero, P.M., Westphal, H., and Gonzalez, F.J. (1995). Targeted disruption of the alpha isoform of the peroxisome proliferator- activated receptor gene in mice results in abolish- ment of the pleiotropic effects of peroxisome pro- liferators. Mol. Cell Biol. 15:3012–3022.
  • Leibold, E., Greim, H., and Schwarz, L. (1994). Inhibi- tion of intercellular communication of rat hepato- cytes by nafenopin: Involvement of protein kinase C. Carcinogenesis 15:1265–1269.
  • Leone, T.C., Weinheimer, C.J., and Kelly, D.P. (1999). A critical role for the peroxisome proliferator- activated receptor alpha (PPARalpha) in the cel- lular fasting response: The PPARalpha-null mouse as a model of fatty acid oxidation disorders. Proc. Natl. Acad. Sci. USA 96:7473–7478.
  • Li, Y., Glauert, H.P., and Spear, B.T. (2000a). Activation of nuclear factor-kappaB by the peroxisome prolifer- ator ciprofibrate in H4IIEC3 rat hepatoma cells and its inhibition by the antioxidants N -acetylcysteine and vitamin E. Biochem. Pharmacol. 59:427–434.
  • Li, Y., Hao, Y., and Owyang, C. (1997). High-affinity CCK-A receptors on the vagus nerve mediate CCK-stimulated pancreatic secretion in rats. Am. J. Physiol. Gastrointest. Liver Physiol. 273:G679–G685.
  • Li, Y., Leung, L.K., Glauert, H.P., and Spear, B.T. (1996). Treatment of rats with the peroxisome proliferator ciprofibrate results in increased liver NF-kappaB activity. Carcinogenesis 17:2305–2309.
  • Li, Y., Tharappel, J.C., Cooper, S., Glenn, M., Glauert, H.P., and Spear, B.T. (2000b). Expression of the hydrogen peroxide-generating enzyme fatty acyl CoA oxidase activates NF-kappaB. DNA Cell Biol. 19:113–120.
  • Lington, A.W., Bird, M.G., Plutnick, R.T., Stubblefield, W.A., and Scala, R.A. (1997). Chronic toxicity and carcinogenic evaluation of diisononyl phthalate in rats. Fundam. Appl. Toxicol. 36:79–89.
  • Lington, A., Kalimi, G., Klaunig, J., and Nikiforov, A. (1996). Value of liver tissue dosimetry data to de- sign and interpret in vitro (hepatocyte) gap junction studies with peroxisomal proliferating agents. Tox- icologist 30:209.
  • Liener, I.E. (1986). Trypsin inhibitors: Concern for human nutrition or not? J. Nutr. 116:920–923.
  • Liu, R.C., Hahn, C., and Hurtt, M.E. (1996a). The direct effect of hepatic peroxisome proliferators on rat Leydig cell function in vitro. Fundam. Appl. Toxi- col. 30:102–108.
  • Liu, R.C.M., Hurtt, M.E., Cook, J.C., and Biegel, L.B. (1996b). Effect of the peroxisome proliferator, am- monium perfluorooctanoate (C8), on hepatic aro- matase activity in adult male Crl: CDBR(CD) rats. Fundam. Appl. Toxicol. 30:220–228.
  • Liu, S.C., Sanfilippo, B., Perroteau, I., Derynck, R., Sa- lomon, D.S., and Kidwell, W.R. (1987). Expression of transforming growth factor alpha (TGF alpha) in differentiated rat mammary tumors: Estrogen in- duction of TGF alpha production. Mol. Endocrinol. 1:683–692.
  • Longnecker, D.S. (1983). Early morphologic markers of carcinogenicity in rat pancreas. In: Application of biological markers to carcinogen testing, eds. H. Milman, and S. Sell, pp. 43–60. Plenum, New York.
  • Longnecker, D.S. (1987). Interface between adaptive and neoplastic growth in the pancreas. Gut 28: 253-258.Longnecker,D.S., and Sumi, C. (1990). Effects of sex steroid hormones on pancreatic cancer in the rat. Int. J. Pancreatol. 7:159–165.
  • Lu, T.T., Makishima, M., Repa, J.J., Schoonjans, K., Kerr, T.A., Auwerx, J., and Mangelsdorf, D.J. (2000). Molecular basis for feedback regulation of bile acid synthesis by nuclear receptors. Mol. Cell. 6:507–515.
  • Mailloux, L.U., Bellucci, A.G., Wilkes, B.M., Napolitano, B., Mossey, R.T., Lesser, M., and Bluestone, P.A. (1991). Mortality in dialysis patients: Analysis of the causes of death. Am. J. Kidney Dis. 18:326–335.
  • Makowska, J.M., Bonner, F.W., and Gibson, G.G. (1990). Hepatic induction potency of hypolipi- daemic drugs in the rat following long-term admin- istration: Influence of different dosing regimens. Xenobiotica 20:1121–1128.
  • Makowska, J.M., Gibson, G.G., and Bonner, F.W. (1992). Species differences in ciprofibrate induction of hepatic cytochrome P450 4A1 and peroxisome pro- liferation. J. Biochem. Toxicol. 7:183–191.
  • Malley, L.A., Carakostas, M., Hansen, J.F., Rusch, G.M., Kelley, D.P., and Trochimowicz, H.J. (1995). Two- year inhalation toxicity study in rats with hydro- chorofluorocarbon 123. Fundam. Appl. Toxicol. 25:101–114.
  • Maloney, E.K., and Waxman, D.J. (1999). Trans- activation of PPARalpha and PPARgamma by structurally diverse environmental chemicals. Tox- icol. Appl. Pharmacol. 161:209–218.
  • Maltoni, C., Lefemine, G., Cotti, G., and Perino, G. (1988). Long-term carcinogenicity bioassays on trichloroethylene administered by inhalation to Sprague-Dawley rats and Swiss and B6C3F1 mice. Ann. NY Acad. Sci. 534:316–342.
  • Mangelsdorf, D.J. (2000). Molecular basis for feedback regulation of bile acid synthesis by nuclear recep- tors. Mol. Cell 6:507–515.
  • Mannaerts, G.P., and van Veldhoven, P.P. (1996) Func- tions and organization of peroxisomal β-oxidation. In: Peroxisomes: Biology and Role in Toxicology and Disease, eds. J.K. Reddy, T. Suga, G.P. Man- naerts, P.B. Lazarow, S. Subramani. Ann. NY Acad. Sci. 804:99–115.
  • Maragoudakis, M.E., and Hankin, H. (1971). On the mode of action of lipid-lowering agents. V. Kinetics of the inhibition in vitro of rat acetyl coenzyme A carboxylase. J. Biol. Chem. 246:348–358.
  • Marrapodi, M., and Chiange, J.Y. (2000). Peroxi- some proliferator-activated receptor alpha (PPA- Ralpha) and agonist inhibit cholesterol 7alpha-hydroxylase gene (CYP7A1) transcription. J. Lipid Res. 41:514–520.
  • Marselos, M., and Tomatis, L. (1993). Diethylstilbestrol. II. Pharmacology, toxicology and carcinogenicity in experimental animals. Eur. J. Cancer 29A:149-155.
  • Marsman, D.S., Cattley, R.C., Conway, J.G., and Popp, J.A. (1988). Relationship of hepatic peroxisome proliferation and replicative DNA synthesis to the hepatocarcinogenicity of the peroxisome prolif- erators di(2-ethylhexyl)phthalate and [4-chloro- 6-(2,3-xylidino)-2-pyrimidinylthio] acetic acid (WY 14,643) in rats. Cancer Res. 48:6739–6744.
  • Marsman, D.S., Goldsworthy, T.L., and Popp, J.A. (1992). Contrasting hepatocytic peroxisome proliferation, lipofuscinaccumulation and cell turnover for the hepatocarcinogens WY 14,643-14,643 and clofib- ric acid. Carcinogenesis 13:1011–1017.
  • Martin, G., Schoonjans, K., Lefebvre, A.M., Staels, B., and Auwerx, J. (1997). Coordinate regulation of the expression of the fatty acid transport pro- tein and acyl-CoA synthetase genes by PPARal- pha and PPARgamma activators. J. Biol. Chem. 272:28210–28217.
  • Matringe, M., Camadro, J.M., Labbe, P., and Scalla, R. (1989). Protoporphyrinogen oxidase inhibition by three peroxidizing herbicides: Oxadiazon, LS 82-556 and M&B 39279. FEBS Lett. 245(1-2): 35–38.
  • Mascaro, C., Acosta, E., Ortiz, J.A., Marrero, P.F., Hegardt, F.G., and Haro, D. (1998). Control of human muscle-type carnitine palmitoyltransferase I gene transcription by peroxisome proliferator- activated receptor. J. Biol. Chem. 273:8560–8563.
  • McGuinness, E.E., Morgan, R.G., Levison, D.A., Frape, D.L., Hopwood, D., and Wormsley, K.G. (1980). The effects of long-term feeding of soya flour on the rat pancreas. Scand. J. Gastroenterol. 15:497–502.
  • McGuinness, E.E., Morgan, R.G.H., and Wormsley, K.G. (1985). Trophic effects on the pancreas of trypsin and bile salt deficiency in the small-intestinal lu- men. Scand. J. Gastroenterol. 20(Suppl. 112):64-67.
  • McGuinness, E.E., Morgan, R.G., and Wormsley, K.G. (1987). Fate of pancreatic nodules induced by raw soya flour in rats. Gut 28(Suppl.):207–212.
  • Meijers, M., van Garderen-Hoetmer, A., Lamers, C.B., Rovati, L.C., Jansen, J.B., and Woutersen, R.A. (1990). Role of cholecystokinin in the development of BOP-induced pancreatic lesions in ham- sters. Carcinogenesis 11:2223–2226.
  • Meikle, A.W., Sanders, S.W., Tolman, K.G., Jennings, D.E., Karol, M.D., and Ringham, G.L. (1994). Ef- fect of lansoprazole on male hormone function. Drug Invest. 8:191–202.
  • Mennear, J.H. (1986). Toxicology and carcinogene- sis studies of tetrachloroethylene (perchloroethy- lene) in F344/N rats and B6C3F1 mice. NTP Technical Report 311 (NIH Publication No. 86- 2567), Research Triangle Park, NC.
  • Mennear, J.H. (1988). Toxicology and carcinogenesis studies of trichloroethylene in four strains of rats. NTP Technical Report 273 (NIH Publication No. 88-2529), Research Triangle Park, NC.
  • Messina, M., and Messina, V. (1991). Increasing use of soyfoods and their potential role in cancer preven- tion. J. Am. Diet. Assoc. 91:836–840.
  • Miller, R.W. (1978). Epidemiology. In: Cancer in China, eds. H.S. Kaplan and P.J. Tsuchitani, pp. 39–57. Alan R. Liss, New York.
  • Mitchell, A.M., Lhuguenot, J.-C., Bridges, J.W., and El- combe, C.R. (1985a). Identification of the proxi- mate peroxisome proliferator(s) derived from di(2- ethylhexyl) phthalate. Toxicol. Appl. Pharmacol. 80:23–32.
  • Mitchell, F.E., Price, S.C., Hinton, R.H., Grasso, P., and Bridges, J.W. (1985b). Time and dose-response study of the effects on rats of the plasticizer di(2- ethylhexyl) phthalate. Toxicol. Appl. Pharmacol. 81:371–392.
  • Miyamoto, T., Kaneko, A., Kakizawa, T., Yajima, H., Kamijo, K., Sekine, R., Hiramatsu, K., Nishii, Y., Hashimoto, T., and Hashizume, K. (1997). Inhibi- tion of peroxisome proliferator signaling pathways by thyroid hormone receptor. Competitive binding to the response element. J. Biol. Chem. 272:7752–7758.
  • Miyata, K.S., McCaw, S.E., Patel, H.V., Rachubinski, R.A., and Capone, J.P. (1996). The orphan nu- clear hormone receptor LXR alpha interacts with the peroxisome proliferator-activated receptor and inhibits peroxisome proliferator signaling. J. Biol. Chem. 271:9189–9192.
  • Mizuguchi, H., Kudo, N., Ohya, T., and Kawashima, Y. (1999). Effects of tiadenol and di-(2- ethylhexyl)phthalate on the metabolism of phos- phatidylcholine and phosphatidylethanol-amine in the liver of rats: Comparison with clofibric acid. Biochem. Pharmacol. 57:869–876.
  • Mizumoto, K., Kitazawa, S., Eguchi, T., Nakajima, A., Tsutsumi, M., Ito, S., Danda, A., and Konishi, Y. (1988). Modulation of N-nitrosobis(2- hydroxypropyl)amine-induced carcinogenesis by clofibrate in hamsters. Carcinogenesis 9:1421–1425.
  • Mochizuki, Y., Furukawa, K., and Sawada, N. (1983). Effect of simultaneous administration of clofibrate with diethylnitrosamine on hepatic tumorigenesis in the rat. Cancer Lett. 19:99–105.
  • Mohamood, A.S., Gyles, P., Balan, K.V., Hollis, V.W., Eckberg, W.R., Asseffa, A., Han, Z., Wyche, J.H., and Anderson, W.A. (1997). Estrogen receptor, growth factor receptor and protooncogene protein activities and possible signal transduction crosstalk in estrogen dependent and independent breast can- cer cell lines. J. Submicrosc. Cytol. Pathol. 29: 1–17.
  • Moody, D.E., and Reddy, J.K. (1978). Hepatic peroxi- some (microbody) proliferation in rats fed plasti- cizers and related compounds. Toxicol. Appl. Phar- macol. 45:497–504.
  • Moody, D.E., Reddy, J.K., Lake, B.G., Popp, J.A., and Reese, D.H. (1991). Peroxisome proliferation and non-genotoxic carcinogenesis: Commentary on a symposium. Fundam. Appl. Toxicol. 16:233–248.
  • Moonka, R., Zhou, W., and Bell, R. (1999). Cholecystokinin-A receptor messenger RNA expression in human pancreatic cancer. J. Gastrointest. Surg. 3:134–140.
  • Morgan, R.G.H., Papadimitriou, J.M., and Crass, R.A. (1990). Potentiation of azaserine by cholestyra- mine in the rat. Int. J. Exp. Pathol. 71:485–491.
  • Motojima, K., Passilly, P., Peters, J.M., Gonzalez, F.J., and Latruffe, N. (1998). Expression of putative fatty acid transporter genes are regulated by per- oxisome proliferator-activated receptor alpha and gamma activators in a tissue- and inducer-specific manner. J. Biol. Chem. 273:16710–16714.
  • Moya-Camarena, S.Y., Vanden Heuvel, J.P., Blanchard, S.G., Leesnitzer, L.A., and Belury, M.A. (1999). Conjugated linoleic acid is a potent naturally oc- curring ligand and activator of PPARalpha. J. Lipid Res. 40:1426–1433.
  • Mukherjee, R., Jow, L., Noonan, D., and McDonnell, D.P. (1994). Human and rat peroxisome prolifera- tor activated receptors (PPARs) demonstrate simi- lar tissue distribution but different responsiveness to PPAR activators. J. Steroid Biochem. Mol. Biol. 51:157–166.
  • Mukherjee, R., Sun, S., Santomenna, L., Miao, B., Walton, H., Liao, B., Locke, K., Zhang, J.-H., Nguyen, S.H., Zhang, L.T., Murphy, K., Ross, H.O., Xia, M.X., Teleha, C, Chen, S-Y., Selling, B., Wynn, R., Burn, T., and Young, P.R. (2002). Ligand and coactivator recruitment pReferences of peroxisome proliferator activated receptor α. J. Steroid Biochem. Mol. Biol. 81:217–225.
  • Nachlas, M.M., and Seligman, A.M. (1949). Evidence for the specificity of esterase and lipase by the use of three chromogenic substrates. J. Biol. Chem. 181:343–355.
  • Nemali, M.R., Usuda, N., Reddy, M.K., Oyasu, K., Hashimoto, T., Osumi, T., Rao, M.S., and Reddy, J.K. (1988). Comparison of constitutive and in- ducible levels of expression of peroxisomal beta- oxidation and catalase genes in liver and extrahep- atic tissues of rat. Cancer Res. 48:5316–5324.
  • Neptun, D.A., Cattley, R.C., and Popp, J.A. (1988). Bile acid profiles and serum enzyme alterations in rats fed the peroxisome proliferator WY 14,643. Clin. Chem. 34 (6):1196(Abstr.)
  • Neve, B.P., Fruchart, J., and Staels, B. (2000). Role of the peroxisome proliferator-activated receptors (PPAR) in atherosclerosis. Biochem. Pharmacol. 60:1245–1250
  • Nicholls, P., and Schonbaum, G.R. (1963). Catalases. In: The Enzymes, eds. P.D. Boyer, H. Lardy, K and Myrbach, Vol. 8, pp. 147–225. Academic Press, New York.
  • Nilakantan, V., Spear, B.T., and Glauert, H.P. (1998). Liver-specific catalase expression in transgenic mice inhibits NF-kappaB activation and DNA synthesis induced by the peroxisome proliferator ciprofibrate. Carcinogenesis 19:631–637.
  • Nilsson, R., Beije, B., Preat, V., Erixon, K., and Ramel, C. (1991). On the mechanism of the hepatocarcino- genicity of peroxisome proliferators. Chem. Biol. Interact. 78:235–250.
  • Nishimori, I., Kamakura, M., Fujikawa-Adachi, K., Nojima, M., Onishi, S., Hollingsworth, M.A., and Harris, A. (1999). Cholecystokinin A and B recep- tor mRNA expression in human pancreas. Pancreas 19:109–113.
  • NTP. (1980). Bioassay of cinnamyl anthranilate for pos- sible carcinogenicity (CAS No. 87-29-6). NTP TR 2196. NTIS PB81–143141. National Toxicology Program, Research Triangle Park, NC.
  • NTP. (1982a). Carcinogenesis bioassay of di(2- ethylhexyl) adipate (CAS No. 103-23-1) in F344 rats and B6C3F1 mice (feed study). NTP TR 212. NTIS PB82-185927. National Toxicology Program, Research Triangle Park, NC.
  • NTP. (1982b). Carcinogenesis bioassay of butyl benzyl phthalate (CAS No. 85-68-7) in F344/N rats and B6C3F1 mice (Feed study). NTP-80-25. NIH Publ. 82-1769). National Toxicology Program, Research Triangle Park, NC.
  • NTP. (1982c). Carcinogenesis bioassay of di(2- ethylhexyl)phthalate in F344 rats and B6C3F1 mice. NTP TR217. National Toxicology Program, Research Triangle Park, NC.
  • NTP. (1990). Carcinogenesis studies of trichloroethylene (without epichlorhydrin) (CAS No. 79-01-6) in F334/N rats and B6C3F1 mice (Gavage studies). NTP TR 243. NTIS PB91-111815. National Toxi- cology Program, Research Triangle Park, NC.
  • NTP. (1993). Compendium of abstracts from long-term cancer studies reported by the National Toxicology Program from 1976–1992. Environ. Health Per- spect. 101(Suppl. 1):1–295.
  • NTP. (1996). 13-Week subchronic dosed-feed toxicity study of dibutyl phthalate in Harlan Sprague- Dawley rats, B6C3F1 mice, and Syrian hamsters (SC940084): Gemfibrozil [SC-R/M/H] (25812-30-0) C93027B. National Toxicology Program, Re- search Triangle Park, NC.
  • NTP. (1997a). Carcinogenesis bioassay of butyl phthalate (CAS no. 85-68-7) in F344/N rats and B6C3F1 mice (Feed studies). NTP TR 458. NIH Publication No. 97-3374. National Toxicology Program, U.S. DHHS, Atlanta, GA.
  • NTP. (1997b). Effect of dietary restriction on toxicol- ogy and carcinogenesis of butyl benzyl phthalate in F344/N rats and B6C3F1 mice. NTP TR 460. NIH Publication No. 97-3376. National Toxicol- ogy Program, U.S. DHHS, Atlanta, GA.
  • NTP. (1997c). Toxicology and carcinogenesis studies of butyl benzyl phthalate (CAS No. 85-68-7) in F344/N rats (Feed studies). TR-458. NTIS Publica- tion No. PB98-131089. National Toxicology Pro- gram, Research Triangle Park, NC.
  • NTP. (1998). Toxicology and carcinogenesis studies of trichloroethylene (CAS No. 79-01-6) in four strains of rats (ACI, August, Marshall, Osborne-Mendel) (Gavage studies). NTP TR 273. NTIS PB88- 218896/AS. National Toxicology Program, Re- search Triangle Park, NC.
  • Nustede, R., Schmidt, W.E., Kohler, H., Folsch, U.R., and Schafmayer, A. (1993). The influence of bile acids on the regulation of exocrine pancreatic secretion and on the plasma concentrations of neurotensin and CCK in dogs. Int. J. Pancreatol. 13:23–30.
  • Oates, P.S., Morgan, G.R., and Light, A.M. (1986). Cell death (apoptosis) during pancreatic involution after raw soya flour. Amer. J. Physiol. 250:G9–G14.
  • Oberhammer, F.A., and Qin, H.M. (1995). Effect of three tumour promoters on the stability of hepatocyte cultures and apoptosis after transforming growth factor-beta1. Carcinogenesis 16:1363–1371.
  • Obourn, J.D., Frame, S.R., Bell, R.H., Jr., Longnecker, D.S., Elliott, G.S., and Cook, J.C. (1997a). Mech- anisms for pancreatic oncogenic effects of the peroxisome proliferator Wyeth-14,643. Toxicol. Appl. Pharmacol. 145:425–436.
  • Obourn, J.D., Frame, S.R., Elliot, G.S., and Cook, J.C. (1997b). Pancreatic oncogenic effects of Wyeth 14,643. Toxicologist 36(1 Part 2):232–233 (Abstr. 1181).
  • Obourn, J.D., Frame, S.R., Chiu, T., Solomon, T.E., and Cook, J.C. (1997c). Evidence that A8947 enhances pancreas growth via a trypsin inhibitor mechanism. Toxicol. Appl. Pharmacol. 146:116–126.
  • O’Connor, J.C., Cook, J.C., Marty, M.S., Davis. L.G., Kaplan, A.M., and Carney, E.W. (2002). Evalu- ation of Tier I screening approaches for detect- ing endocrine-active compounds (EACs). Crit. Rev. Toxicol. 32:521–549.
  • Oesterle, D., and Deml, E. (1988). Promoting activity of di(2-ethylhexyl) phthalate in rat liver foci bioassay. J. Cancer. Res. Clin. Oncol. 114:133–136.
  • Ohlson, C.G., and Hardell, L. (2000). Testicular cancer and occupational exposures with a focus on xe- noestrogens in polyvinyl chloride plastics. Chemo- sphere 40:1277–1282.
  • Ohmura, T., Katyal, S.L., Locker, J., Ledda-Columbano, G.M., and Shinozuka, H. (1997). Induction of cel- lular DNA synthesis in the pancreas and kidneys of rats by peroxisome proliferators, 9-cis retinoic acid and 3,31,5-triiodo-L-thyronine. Cancer Res. 57:795–798.
  • Ohta, H., Guan, K., Tawail, T., Liddle, R.A., and Green, G.M. (1990). Regulation of plasma cholecys- tokinin levels by bile and bile acids in the rat. Gas- troenterology 90:819–825.
  • Oliver, M.F., Heady, J.A., Morris, J.N., and Cooper, J. (1978). A cooperative trial in the primary preven- tion of ischemic heart disease using clofibrate. Br. Heart J. 40:1069–1118.
  • Olsen, G.W., Burris, J.M., Burlew, M.M., and Man- del, J.H. (2000). Plasma cholecystokinin and hep- atic enzymes, cholesterol and lipoproteins in am- monium perfluorooctanoate production workers. Drug Chem. Toxicol. 23:603–620.
  • Olsen, G.W., Gilliland, F.D., Burlew, M.M., Burris, J.M., Mandel, J.S., and Mandel, J.H. (1998). An epi- demiologic investigation of reproductive hormones in men with occupational exposure to perfluorooc- tanoic acid. J. Occup. Environ. Med. 40:614–622.
  • Ophaug, R.H., and Singer, L. (1980). Metabolic handling of perfluorooctanoic acid in rats. Proc. Soc. Exp. Biol. Med. 163:19–23.
  • Owyang, C. (1996). Physiological mechanisms of chole- cystokinin action on pancreatic secretion. Am. J. Physiol. 269:G1–G7.
  • Ozasa, H., Miyazawa, S., Furuta, S., Osumi, T., and Hashimoto, T. (1985). Induction of peroxisomal beta-oxidation enzymes in primary cultured rat hepatocytes by clofibric acid. J. Biochem. (Tokyo) 97:1273–1278.
  • Palmer, C.N., Hsu, M.H., Griffin, K.J., Raucy, J.L., and Johnson, E.F. (1998). Peroxisome proliferator ac- tivated receptor-alpha expression in human liver. Mol. Pharmacol. 53:14–22.
  • Parzefall, W., Erber, E., Sedivy, R., and Schulte-Hermann, R. (1991). Testing for induction of DNA syn- thesis in human hepatocyte primary cultures by rat liver tumor promoters. Cancer Res. 51:1143–1147.
  • Parzefall, W., Berger, W., Kainzbauer, E., Teufelhofer, O., Schulte-Hermann, R., and Thurman, R.G. (2001). Peroxisome proliferators do not increase DNA syn- thesis in purified rat hepatocytes. Carcinogenesis 22:519–523.
  • PDR. (1995a). Eulexin (Flutamide). Physician’s Desk Reference, 11th ed., pp. 2253–2254. Medical Eco- nomics Data, Oradell, NJ.
  • PDR. (1995b). Lupron. (Leuprolide). Physician’s Desk Reference, 11th ed., pp. 2503–2505. Medical Eco- nomics Data, Oradell, NJ.
  • PDR. (1995c). Proscar×R (Finasteride). Physician’s Desk Reference, 11th ed., pp. 1625–1628. Medical Eco- nomics Data, Oradell, NJ.
  • PDR. (1995d). Supprelin. (Histrelin). Physician’s Desk Reference, 11th ed., pp. 2000–2002. Medical Eco- nomics Data, Oradell, NJ.
  • PDR. (1995e). Synarel. (Nafarelin). Physician’s Desk Ref- erence, 11th ed., pp. 2486–2487. Medical Eco- nomics Data, Oradell, NJ.
  • PDR. 2002. Tricor (fenofibrate). Physician’s Desk Ref- erence, 18th edition, pp. 513–516. Medical Eco- nomics Data, Oradell, NJ.
  • Perrone, C.E., Shao, L., and Williams, G.M. (1998). Effect of rodent hepatocarcinogenic peroxisome proliferators on fatty acyl-CoA oxidase, DNA synthesis, and apoptosis in cultured human and rat hepatocytes. Toxicol. Appl. Pharmacol. 150: 277–86.
  • Perrone, C.E., and Williams, G.M. (1998). Rodent hepato- carcinogenic peroxisome proliferators induce pro- liferation of rat hepatocytes in primary mixed cul- tures with rat liver epithelial cells. Cancer Lett. 123:27–33.
  • Peters, J.M., Aoyama, T., Cattley, R.C., Nobumitsu, U., Hashimoto, T., and Gonzalez, F.J. (1998). Role of peroxisome proliferator-activated receptor alpha in altered cell cycle regulation in mouse liver. Car- cinogenesis 19:1989–1994.
  • Peters, J.M., Cattley, R.C., and Gonzalez, F.J. (1997a). Role of PPAR alpha in the mechanism of action of the nongenotoxic carcinogen and peroxisome proliferator WY 14,643. Carcinogenesis 18:2029–2033.
  • Peters, J.M., Hennuyer, N., Staels, B., Fruchart, J.C., Fievet, C., Gonzales, F.J., and Auwerx, J. (1997b). Alterations in lipoprotein metabolism in per- oxisome proliferator-activated receptor alpha- deficient mice. J. Biol. Chem. 272:27307–27312.
  • Peters, J, Rusyn, I., Rose, M., Gonzalez, F., and Thurman, R. (2000). Peroxisome proliferator-activated re- ceptor alpha is restricted to hepatic parenchymal cells, not Kupffer cells: Implications for the mech- anism of action of peroxisome proliferators in hep- atocarcinogenesis. Carcinogenesis 21:823–826.
  • Peters, J.M., and Vanden Heuvel, J.P. (2002). Peroxi- some, peroxisome proliferators and peroxisome- proliferator activated receptors (PPARs). In: Cellular and Molecular Toxicology, eds. J.P. Van- dern Heuvel, G.H. Perdew, W.B. Mattes, and
  • W.F. Greenlee, pp. 133–158. Elsevier Science, Amsterdam.
  • Pineau, T., Hudgins, W.R., Liu, L., Chen, L.C., Sher, T., Gonzalez, F.J., and Samid, D. (1996). Activation of a human peroxisome proliferator-activated re- ceptor by the antitumor agent phenylacetate and its analogs. Biochem. Pharmacol. 52:659–667.
  • Posnick, L.M., and Samson, L.D. (1999). Imbalanced base excision repair increases spontaneous muta- tion and alkylation sensitivity in Escherichia coli. J. Bacteriol. 181:6763–6771.
  • Post, S.M., Duez, H., Gervois, P.P., Staels, B., Kuipers, F., and Princen, H.M.G. (2001). Fi- brates suppress bile acid synthesis via peroxisome proliferator-activated receptor-α-mediated down- regulation of cholesterol 7α-hydroxylase and sterol 27-hydroxylase expression. Arterioscler. Thromb. Vasc. Biol. 21:1840–1845.
  • Pour, P.M., Lawson, T., Helgeson, S., Donnelly, T., and Stepan, K. (1988). Effect of cholecystokinin on pancreatic carcinogenesis in the hamster model. Carcinogenesis 9:597–601.
  • Povoski, S.P., Zhou, W., Longnecker, D.S., Roebuck, B.D., and Bell, R.H., Jr. (1993). Stimulation of growth of azaserine-induced putative preneoplastic lesions in rat pancreas is mediated specifically by way of cholecystokinin-A receptors. Cancer Res. 53:3925–3929.
  • Prahalada, S., Majka, J.A.,Soper, K.A., Nett, T.M., Bag- don, W.J., Peter, C.P., Burek, J.D., MacDonald, J.S., and van Zweiten, M.J. (1994). Leydig cell hy- perplasia and adenoma in mice treated with finas- teride, a 5α-reductase inhibitor: A possible mech- anism Fundam. Appl. Toxicol. 22:211–219.
  • Prentice, D.E., Siegel, R.A., Donatsch, P., Qureshi, S., and Ettlin, R.A. (1992). Mesulergine induced Leydig cell tumours, a syndrome involving the pituitary-testicular axis of the rat. Arch. Toxicol. 15(Suppl.):197–204.
  • Prentice, D.E., and Meikle, A.W. (1995). A review of the drug-induced Leydig cell hyperplasia and neopla- sia in the rat and some comparisons with man. Hum. Exp. Toxicol. 14:562–572.
  • Price, S.C. (1991). Studies on morphological and bio- chemical changes in the livers of rats treated for 14 Days with oxidiazon. Robens Institute of Health and Safety, Surrey, England. Report dated January 9, 1991 (unpublished). U.S. EPA MRID Number 42310001, Research Triangle Park, NC.
  • Prout, M.S., Provan, W.M., and Green, T. (1985). Species differences in response to trichloroethylene. I. Pharmacokinetics in rats and mice. Toxicol. Appl. Pharmacol. 79:389–400.
  • Pugh, G. Jr., Isenberg, J.S., Kamendulis, L.M., Ackley, D.C., Clare, L.J., Brown, R., Lignton, A.W., Smith, J.H., and Klaunig, J.E. (2000). Effects of di- isononyl phthalate, di-2-ethylhexyl phthalate, and clofibrate in cynomolgus monkeys. Toxicol. Sci. 56:181–188.
  • Puigserver, P., Wu, Z., Park, C.W., Graves, R., Wright, M., and Spiegelman, B.M. (1998). A cold-inducible coactivator of nuclear receptors linked to adaptive thermogenesis. Cell. 92:829–839.
  • Qu, B., Li, Q., Wong, K.P., Tan, T.M., and Halliwell, B. (2001). Mechanism of clofibrate hepatotoxic- ity: Mitochondrial damage and oxidative stress in hepatocytes. Free Radical. Biol. Med. 31:659–669.
  • Qualls, C.W., Hoivik, D.J., Santostefano, M.J., Brown, H.R., Anderson, S.P., Ott, R.J., Oliver, B.R., Mudd, P.N., Mirabile, R.C., Kimbrough, C.L., and Millet, R.T. (2003). Fibrates induce peroxisomal and mi- tochondrial proliferation in cynomolgus monkeys without causing cell cycle alterations or oxidative stress. Toxicologist 72(S-1):198, Abstr. 961.
  • Randerath, E., Randerath, K., Reddy, R., Danna, T.F., Rao, M.S., and Reddy, J.K. (1991). Induction of rat liver DNA alterations by chronic administra- tion of peroxisome proliferators as detected by 32P- postlabeling. Mutat. Res. 247:65–76.
  • Rao, K.N., Epley, M.J., Elm, M.S., Brady, E.P., Chan- dar, N., and Eagon, P.K. (1994). Di-(2-ethylhexyl) phthalate (DEHP) and clofibrate induced liver hy- perplasia. Role of early changes in hepatocarcino- genicity. Toxicologist 14:301 [Abstr. 164].
  • Rao, M.S., Dwivedi, R.S., Subbarno, V., and Reddy, J.K. (1988). Induction of peroxisome proliferation and hepatic tumours in C57BL/6N mice by ciprofi- brate, a hypolipidaemic compound. Br. J. Cancer 58:46–51.
  • Rao, M.S., Lalwani, N.D., Watanabe, T.K., and Reddy, J.K. (1984). Inhibitory effect of antioxidants ethoxyquin and 2(3)-tert-butyl-4- hydroxyanisole on hepatic tumorigenesis in rats fed ciprofibrate, a peroxisome proliferator. Cancer Res. 44:1072–1076.
  • Reddy, J.K., and Chu, R. (1996). Peroxisome proliferator- induced pleiotropic responses: Pursuit of a phe- nomenon. In: Peroxisomes: Biology and Role in Toxicology and Disease. eds. J.K. Reddy, T. Suga, G.P. Mannaerts, P.B. Lazarow, and S. Subramani. Ann. NY Acad. Sci. 804:176–201.
  • Reddy, J.K., Goel, S.K., Nemali, M.R., Carrino, J.J., Laffler, T.G., Reddy, M.K., Sperbeck, S.J., Osumi, T., Hashimoto, T., Lalwani, N.D., et al. (1986a). Transcriptional regulation of peroxisomal fatty acyl-CoA oxidase and enoyl-CoA hydratase/3- hydroxyacyl-CoA dehydrogenase in rat liver by peroxisome proliferators. Proc. Natl. Acad. Sci. USA 83:1747–1751.
  • Reddy, J.K., and Lalwani, N.D. (1983). Carcinogene- sis by hepatic peroxisome proliferators. Evalua- tion of the risk of hypolipidemic drugs and indus- trial plasticizers to humans. Crit. Rev. Toxicol. 12: 1–58.
  • Reddy, J.K., Lalwani, N.D., Qureshi, S.A., Reddy, M.K., and Moehle, C.M. (1984). Induction of hepatic per- oxisome proliferation in nonrodent species, includ- ing primates. Am. J. Pathol. 114:171–183.
  • Reddy, J.K., Lalwani, N.D., Reddy, M.K., and Qureshi, S.A. (1982). Excessive accumulation of autoflu- orescent lipofuscin in the liver during hepatocar- cinogenesis by methylclofenapate and other hy- polipidemic peroxisome proliferators. Cancer Res. 42:259–266.
  • Reddy, J.K., and Qureshi, S.A. (1979). Tumorigenicity of the hypolipidaemic peroxsiome proliferator ethyl- α-p-chlorophenoxyisobutyrate (clofibrate) in rats. Brit. J. Cancer 40:476–482.
  • Reddy, J.K., and Rao, M.S. (1989). Oxidative DNA dam- age caused by persistent peroxisome prolifera- tion: Its role in hepatocarcinogenesis. Mutat. Res. 214:63–68.
  • Reddy, J.K., and Rao, M.S. (1997a). Transplantable pan- creatic carcinoma of the rat. Science 198:78–80.
  • Reddy, J.K., and Rao, M.S. (1997b). Malignant tumors in rats fed nafenopin, a hepatic peroxisome prolifer- ator. JNCI 59:1645–1650.
  • Reddy, J.K., Rao, S., and Moody, D.E. (1976). Hepatocel- lular carcinomas in acatalesemic mice treated with nafenopin, a hypolipidemic peroxisome prolifera- tor. Cancer Res. 36:1211–1217.
  • Reddy, J.K., Reddy, M.K., Usman, M.I., Lalwani, N.D., and Rao, M.S. (1986b). Comparison of hepatic peroxisome proliferation effect and its implication for hepatocarcinogenicity phthalate esters, di(2- ethylhexyl) phthalate, and di(2-ethylhexyl) adipate with a hypolipidemic drug. Environ. Health Per- spect. 65:317–327.
  • Ren, B., Thelen, A.P., Peters, J.M., Gonzalez, F.J., and Jump, D.B. (1997). Polyunsaturated fatty acid suppression of hepatic fatty acid synthase and S14 gene expression does not require peroxisome proliferator-activated receptor alpha. J. Biol. Chem. 272:26827–26832.
  • Rhodes, C., Orton, T.C., Pratt, I.S., Batten, P.L., Bratt, H., Jackson, S.J., and Elcombe, C.R. (1986). Com- parative pharmacokinetics and subacute toxicity of di(2-ethylhexyl) phthalate (DEHP) in rats and mar- mosets. Extrapolation of effects in rodents to man. Environ. Health. Perspect. 65:299–308.
  • Richert, L., Price, S., Chesne, C., Maita, K., and Carmichael, N. (1996). Comparison of the induc- tion of hepatic peroxisome proliferation by the her- bicide Oxadiazon in vivo in rats, mice, and dogs and in vitro in rat and human hepatocytes. Toxicol. Appl. Pharmacol. 141:35–43.
  • Ricote, M., Li, A.C., Willson, T.M., Kelly, C.J., and Glass, C.K. (1998). The peroxisome proliferator- activated receptor-gamma is a negative regulator of macrophage activation. Nature. 391:79–82.
  • Rittmaster, R.S., Lemay, A., Zwicker, H., Capizzi, T.P., Winch, S., Moore, E., and Gormley, G.J. (1992). Effect of finasteride, a 5-alpha reductase inhibitor, on serum gonadotropins in normal men. J. Clin. Endocrinol. Metab. 75:484–488
  • Roberts, R., and Kimber, I. (1999). Cytokines and nongenotoxic hepatocarcinogenesis. Carcinogen- esis 20:1397–1401.
  • Roberts, R., and Moffat, G. (2001). Biology and tox- icology of PPAR alpha ligands—The hypolipi- daemic peroxisome proliferators. Comments Toxi- col. 7:259–274.
  • Roberts, R.A., Soames, A.R., Gill, J.H., James, N.H., andWheeldon,E.B. (1995).Non-genotoxic hepatocarcinogens stimulate DNA synthesis and their withdrawal induces apoptosis, but in differ- ent discrete hepatocyte populations. Carcinogene- sis 16:1693–1698.
  • Rodriguez, C., Noe, V., Cabrero, A., Ciudad, C.J., and Laguana, J.C. (2000). Differences in the formation of PPARalpha-RXR/acoPPRE complexes between responsive and nonresponsive species upon fibrate administration. Mol. Pharmacol. 58:185–193.
  • Roduit, R., Morin, J., Masse, F., Segall, L., Roche, E., Newgard, C.B., Assimacopoulos-Jeannet, F., and Prentki, M. (2000). Glucose down-regulates the ex- pression of the peroxisome-proliferator activated receptor-alpha gene in pancreatic beta-cell. J. Biol. Chem. 275:35799–35806.
  • Roebuck, B.D., Kaplita, P.V., Edwards, B.R., and Praissman, M. (1987). Effects of dietary fats and soybean protein on azaserine-induced pancreatic carcinogenesis and plasma cholecystokinin in the rat. Cancer Res. 47:1333–1338.
  • Roglans, N., Bellido, A., Rodriguez, C., Cabrero, A., Novell, F., Ros, E., Zambon, D., and Laguna, J.C. (2002). Fibrate treatment does not modify the ex- pression of acyl coenzyme A oxidase in human liver. Clin. Pharmacol. Ther. 72(6):692–701.
  • Rolfe, M., James, N.H., and Roberts, R.A. (1997). Tumour necrosis factor alpha (TNF-alpha) suppreses apop- tosis and induces S-phase in rodent hepatocytes: A mediator of the hepatocarcinogenicity of per- oxisome proliferators? Carcinogenesis 18:2277–2280.
  • Rose, M.L., Germolec, D., Arteel, G.H., Schoonhoven, R., and Thurman, R.G. (1997a). Dietary glycine com- pletely prevents the increase in hepatotcyte repli- cation caused by the PP, Wyeth 14,643. Chem. Res. Toxicol. 10:1198–1204.
  • Rose, M.L., Germolec, D., Schoonhoven, R., and Thur- man, R.G. (1997b). Kupffer cells are causally re- sponsible for the mitogenic effect of peroxisome proliferators. Carcinogenesis 18:1453–1456.
  • Rose, M.L., Rivera, C.A., Bradford, B.U., Graves, L.M., Cattley, R.C., Schoonhoven, R., Swenberg, J.A., and Thurman, R.G. (1999). Kupffer cell oxidant production is central to the mechanism of peroxi- some proliferators. Carcinogenesis 20:27–33.
  • Rose, M.L., Rusyn, I., Bojes, H.K., Belyea, J., Cattley, R.C., and Thurman, R.G. (2000). Role of Kupf- fer cells and oxidants in signaling peroxisome proliferator-induced hepatocyte proliferation. Mu- tat. Res. 448:179–192.
  • Rosenthal, S.M., Grumbach, M.M., and Kaplan, S. (1983). Gonadotropin-independent familial sexual precocity with premature Leydig cell and germinal cell maturation (familial testotoxicosis): Effects of a potent luteinizing hormone-releasing factor ag- onist and medroxyprogesterone acetate therapy in four cases. J. Clin. Endocrinol. Metab. 57:571–579.
  • Roze, C., Cuchet, P., Souchard, M., Vaille, C., and Debray, C. (1977). The effects of tiadenol, cofibrate and clofibride on bile composition in the rat. Eur. J. Pharmacol. 43:57–64
  • Rusyn, I., Denissenko, M.F., Wong, V.A., Butterworth, B.E., Cunningham, M.L., Upton, P.B., Thurman, R.G., and Swenberg, J.A. (2000a). Expression of base excision repair enzymes in rat and mouse liver is induced by peroxisome proliferators and is de- pendent upon carcinogenic potency. Carcinogene- sis 21:2141–2145.
  • Rusyn, I., Kadiiska, M.B., Dikalova, A., Kono, H., Yin, M., Tsuchiya, K., Mason, R.P., Peters, J.M., Gonzalez, F.J., Segal, B.H., Holland, S.M., and Thurman, R.G. (2001). Phthalates rapidly increase production of reactive oxygen species in vivo: Roleof Kupffer cells. Mol. Pharmacol. 59:744–750.
  • Rusyn, I., Rose, M.L., Bojes, H.K., and Thurman, R.G. (2000b). Novel role of oxidants in the molecular mechanism of action of peroxisome proliferators. Antioxid. Redox. Signal. 2:607–621.
  • Rusyn, I., Tsukamoto, H., and Thurman, R.G. (1998). WY 14,643 rapidly activates nuclear factor kappaB in Kupffer cells before hepatocytes. Carcinogenesis 19:1217–1222.
  • Sakai, M., Matsushima-Hibiya, Y., Nishizawa, M., and Nishi, S. (1995). Suppression of rat glutathione transferase P expression by peroxisome prolifer- ators: Interaction between Jun and peroxisome proliferator-activated receptor alpha. Cancer Res. 55:5370–5376.
  • Saku, K., Gartside, P.S., Hynd, B.A., and Kashyap, M.L. (1985). Mechanism of action of gemfibrozil on lipoprotein metabolism. J. Clin. Invest. 75:1702–1712.
  • Santilli, A.A., Scotese, A.C., and Tomarelli, R.M. (1974). A potent antihypercholesterolemic agent: (4- chloro-6-(2,3-xylidino)-2-pyrimidinylthio) acetic acid (Wy-14643). Experentia (Basel) 30:1110–1111.
  • Sapone,A.,Peters,J.M.,Sakai,S.,Tomita,S., Papiha, S.S., Dai, R., Friedman, F.K., and Gonzalez, F.J. (2000). The human peroxisome proliferator-activated receptor alpha gene: Identi- fication and functional characterization of two nat- ural allelic variants. Pharmacogenetics 10:321–333.
  • Sausen, P.J., Lee, D.C., Rose, M.L., and Cattley, R.C. (1995). Elevated 8-hydroxydeoxyguanosine in hepatic DNA of rats following exposure to peroxisome proliferators: Relationship to mito- chondrial alterations. Carcinogenesis 16:1795–1801.
  • Schardein, J.L. (1980). Studies of the components of an oral contraceptive agent in albino rats. I. Estrogenic component. J. Toxicol. Environ. Health 6:885–894.
  • Schardein, J.L., Kaump, D.H., Woosley, E.T., and Jellema, M.M. (1970). Long-term toxicologic and tumori- genesis studies on an oral contraceptive agent in albino rats. Toxicol. Appl. Pharmacol. 16:10–23.
  • Schedewie, H.K., Reiter, E.O., Beitins, I.Z., Seyed, S., Wooten, V.D., Jimenez, J.F., Aiman, E.J., DeVane, G.W., Redman, J.F., and Elders, M.J. (1981). Tes- ticular Leydig cell hyperplasia as a cause of famil- ial sexual precocity. J. Clin. Endocrinol. Metab. 52:271–278.
  • Schmezer, P., Pool, B., Klein, R., Komitowski, D., and Schmal, D. (1988). Various short-term assays and two long-term studies with the plasticizer di(2- ethylhexyl) phthalate in the Syrian golden hamster. Carcinogenesis. 9:37–43.
  • Schmid, P., and Schlatter, C. (1985). Excretion and metabolism of di(2-ethylhexyl)-phthalate in man. Xenobiotica 15:251–256.
  • Schoonjans, K., Peinado-Onsurbe, J., Lefebvre, A.M., Heyman, R.A., Briggs, M., Deeb, S., Staels, B., and Auwerx, J. (1996a). PPARalpha and PPARgamma activators direct a distinct tissue-specific transcrip- tional response via a PPRE in the lipoprotein lipase gene. EMBO J. 15:5336–5348.
  • Schoonjans, K., Staels, B., and Auwerx, J. (1996b). The peroxisome proliferator activated receptors (PPARs) and their effects on lipid metabolism and adipocyte differentiation. Biochim. Biophys. Acta 1302:93–109.
  • Schoonjans, K., Watanabe, M., Suzuki, H., Mahfoudi, A., Krey, G., Wahli, W., Grimaldi, P., Staels, B., Ya- mamoto, T., and Auwerx, J. (1995). Induction of the acyl-coenzyme A synthetase gene by fibrates and fatty acids is mediated by a peroxisome prolif- erator response element in the C promoter. J. Biol. Chem. 270:19269–19276.
  • Schulte-Hermann, R., Grasl-Kraupp, B., and Bursch, W. (1995). Apoptosis and Hepatocarcinogenesis. In: Liver Regeneration and Carcinogenesis, pp. 141-178. Academic Press, New York.
  • Schultz, R., Yan, W., Toppari, J., Volkl, A., Gustafs- son, J.A., and Pelto-Huikko, M. (1999). Expres- sion of peroxisome proliferator-activated receptor alpha messenger ribonucleic acid and protein in human and rat testis. Endocrinology 140:2968–2975.
  • Scotto, C., Keller, J.-M., Schohn, H., and Dauca, M. (1995). Comparative effects of clofibrate on per- oxisomal enzymes of human (Hep EBNA2) and rat (FaO) hepatoma cell lines. Eur. J. Cell Biol. 66:375–381.
  • Shearer, B.G., and Hoekstra, W.J. (2003). Recent ad- vances in peroxisome proliferator-activated recep- tor science. Curr. Med. Chem. 10:267–280.
  • Shenker, A., Laue, L., Kosugi, S., Merendino, J.J., Jr, Minegichi, T., Cutler, G.B., Jr. (1993). A consti- tutively activating mutation of the luteinizing hor- mone receptor in familial male precocious puberty. Nature 365:652–654.
  • Sher, T., Yi, H.F., McBride, O.W., and Gonzalez, F.J. (1993). cDNA cloning, chromosomal mapping, and functional characterization of the human per- oxisome proliferator activated receptor. Biochem- istry. 32:5598–5604.
  • Shirasu, Y. (1987a). Oxadiazon—24 Month Chronic Toxi- city and Carcinogenicity Study in Wistar Rats. Un- published report, U.S. EPA MRID 40993401. In- stitute of Environmental Toxicology, Tokyo.
  • Shirasu, Y. (1987b). Oxadiazon—23 Month Chronic Tox- icity and Carcinogenicity Study in ICR-JCL Mice. Unpublished report, U.S. EPA MRID 40993301. Institute of Environmental Toxicology, Tokyo.
  • Short, R.D., Robinson, E.C., Lington, A.W., and Chin, A.E. (1987). Metabolic and peroxisome prolifera- tion studies with di(2-ethylhexyl)phthalate in rats and monkeys. Toxicol. Ind. Health 3:185–194.
  • Sibinski, L.J. (1987). Two Year Oral (Diet) Toxic- ity/Carcinogenicity Study of Fluorochemical FC- 143 in Rats. Riker Laboratories, Inc./3M Co.
  • Simard, J., Luthy, I., Guay, J., Belanger, A., and Labrie, F. (1986). Characteristices of interaction of the an- tiandrogen flutamide with the androgen receptor in various target tissues. Mol. Cell. Endocrinol. 44:261–270.
  • Simpson, B.J., Wu, F.C., and Sharpe, R.M. 1987. Iso- lation of human Leydig cells which are highly re- sponsive to human chorionic gonadotropin. J. Clin. Endocrinol. Metab. 65:415–422.
  • Smith, J., Isenberg, J., Pugh, G., Kamendulis, L., Ackley, D., Lington, A., and Klaunig, J. (2000). Compara- tive in vivo hepatic effects of di-isononyl phtha- late (DINP) and related C7-C11 dialkyl phtha- lates on gap junctional intercellular communica- tion (GJIC), peroxisomal beta-oxidation (PBOX) and DNA synthesis in rat and mouse liver. Toxicol. Sci. 54:312–321.
  • Smith, J.P., Liu, G., Soundararajan, V., McLaughlin, P.J., and Zagon, I.S. (1994). Identification and charac- terization of CCK-B/gastrin receptors in human pancreatic cancer cell lines. Am. J. Physiol. Regul. Integrat. Comp. Physiol. 266:R277–R283.
  • Smith-Oliver, T., and Butterworth, B.E. (1987). Cor- relation of the carcinogenic potential of di(2- ethylhexyl) phthalate (DEHP) with induced hyper- plasia rather than with genotoxic activity. Mutat. Res. 188:21–28.
  • Soliman, M.S., Cunningham, M.L., Morrow, J.D., Roberts, L.J., and Badr, M.Z. (1997). Evidence against peroxisome proliferation-induced hepatic oxidative damage. Biochem. Pharmacol. 53:1369–1374.
  • Soudah, H.C., Lu, X., Hasler, W.L., and Owyang, C. (1992) Cholesystokinin at physiological levels evokes pancreatic enzyme secretion via a cholin- ergic pathway Am. J. Physiol. 263:G102–G107.
  • Stace, N.H., Palmer, T.J., Vaja, S., and Dowling, R.H. (1987). Long-term pancreaticobiliary diversion stimulates hyperplastic and adenomatous nodules in the rat pancreas: A new model for spontaneous tumour formation. Gut 28(Suppl):265–268.
  • Staels, B., and Auwerx, J. (1992). Perturbation of de- velopmental gene expression in rat liver by fib- ric acid derivatives: Lipoprotein lipase and alpha- fetoprotein as models. Development 115:1035–1043.
  • Staels, B., Koenig, W., Habib, A., Merval, R., Lebret, M., Torra, I.P., Delerive, P., Fadel, A., Chinetti, G., Fruchart, J.C., Najib, J., Maclouf, J., and Tedgui, A. (1998). Activation of human aortic smooth- muscle cells is inhibited by PPARalpha but not by PPARgamma activators. Nature 393:790–793.
  • Staels, B., Schoonjans, K., Fruchart, J.C., and Auwerx, J. (1997). The effects of fibrates and thiazolidine- diones on plasma triglyceride metabolism are me- diated by distinct peroxisome proliferator activated receptors (PPARs). Biochimie 79:95–99.
  • Staels, B., van Tol, A., Andreu, T., and Auwerx, J. (1992). Fibrates influence the expression of genes involved in lipoprotein metabolism in a tissue- selective manner in the rat. Arterioscler. Thromb. 12:286–294.
  • Staels, B., Vu-Dac, N., Kosykh, V.A., Saladin, R., Fruchart, J.C., Dallongeville, J., and Auwerx, J. (1995). Fibrates downregulate apolipoprotein C-III expression independent of induction of peroxiso- mal acyl coenzyme A oxidase. A potential mech- anism for the hypolipidemic action of fibrates. J. Clin. Invest. 95:705–712.
  • Stanko, R.T., Sekas, G., Isaacson, I.A., Clarke, M.R., Bil- liar, T.R., and Paul, H.S. (1995). Pyruvate inhibits clofibrate-induced hepatic peroxisomal prolifera- tion and free radical production in rats. Metabolism 44:166–171.
  • Stott, W.T. (1988). Chemically induced proliferation of peroxisomes: Implications to risk assessment. Regul. Toxicol. Pharmacol. 8:125–159.
  • Stott, W.T., and Hawkins, N.C. (1993). Risk assessment of chemicals inducing peroxisome proliferation. In Peroxisomes: Biology and Importance in Toxicol- ogy and Medicine, eds. G. Gibson and B. Lake, pp. 695–721. Taylor and Francis, London.
  • Sugden, M.C., Bulmer, K., Augustine, D., and Holness, M.J. (2001). Selective modification of pyruvate de- hydrogenase kinase isoform expression in rat pan- creatic islets elicited by starvation and activation of peroxisome proliferator-activated receptor-alpha: Implications for glucose-stimulated insulin secre- tion. Diabetes 50:2729–2736.
  • Svoboda, D.J., and Azarnoff, D.L. (1979). Tumors in male rats fed ethyl chlorophenoxyisobutyrate, a hypoli- demic drug. Cancer Res. 39:3419–3428.
  • Takagi, A., Sai, K., Umemura, T., Hasegawa, R., and Kurokawa, Y. (1990a). Relationship be- tween hepatic peroxisome proliferation and 8- hydroxydeoxyguanosine formation in liver DNA of rats following long-term exposure to three per- oxisome proliferators: Di(2-ethylhexyl) phthalate, aluminium clofibrate and simfibrate. Cancer Lett. 53:33–38.
  • Takagi, A., Sai, K., Umemura, T., Hasegawa, R., and Kurokawa, Y. (1990b). Significant increase of 8- hydroxydeoxyguanosine in liver DNA of rats fol- lowing short-term exposure to the peroxisome proliferators di(2-ethylhexyl)phthalate and di(2- ethylhexyl)adipate. Jpn. J. Cancer Res. 81:213–215.
  • Tam, S.P. (1991). Effects of gemfibrozil and ketocona- zole on human apolipoprotein AI, B and E levels in two hepatoma cell lines, HepG2 and Hep3B. Atherosclerosis 91:51–61.
  • Tamura, H., Iida, T., Watanabe, T., and Suga, T. (1991). Lack of induction of hepatic DNA damage on long- term administration of peroxisome proliferators in male F-344 rats. Toxicology 69:55–62.
  • Tharappel, J.C., Cunningham, M.L., Spear, B.T., and Glauert, H.P. (2001). Differential activation of hepatic NF-kappaB in rats and hamsters by the peroxisome proliferators WY 14,643, gem- fibrozil, and dibutyl phthalate. Toxicol. Sci. 62: 20–27.
  • Thiess, A.M., Korte, A., and Fleig, H. (1978). Chro- mosomenuntersuchungen Bei Mitarbeitern Ex- position Gegenuber Di-2-Anthylhexylphthalate (DOP). Zbl. Arbsitsmed. 12:351–355.
  • Thorp, J.M. (1962). Experimental evaluation of an orally active combination of androsterone with ethyl chlorophenoxyisobutyrate. Lancet i:1323–1326.
  • Toda, K., Takeda, K., Akira, S., Saibara, T., Okada, T., Onishi, S., and Shizuta, Y. (2001). Alterations in hepatic expression of fatty-acid metabolizing en- zymes in ArKO mice and their reversal by the treat- ment with 17beta-estradiol or a peroxisome prolif- erator. J. Steroid Biochem. Mol. Biol. 79:11–17.
  • Tolon, R.M., Castillo, A.I., and Aranda, A. (1998). Activation of the prolactin gene by peroxisome proliferator-activated receptor-alpha appears to be DNA binding-independent. J. Biol. Chem. 273:26652–26661.
  • Tomaszewski, K.E., Agarwal, D.K., and Melnick, R.L. (1986). In vitro steady-state levels of hydrogen per- oxide after exposure of male F344 rats and female B6C3F1 mice to hepatic peroxisome proliferators. Carcinogenesis. 7:1871–1876.
  • Toriumi, Y., Samuel, I., Wilcockson, D.P., Turkleson, C.M., Solomon, T.E., and Joehl, R. (1993). In- creased circulating cholecystokinin in obstruction- induced acute pancreatitis. J. Surg. Res. 54:132–135.
  • Treuter, E., Albrektsen, T., Johansson, L., Leers, J., and Gustafsson, J.A. (1998). A regulatory role for RIP140 in nuclear receptor activation. Mol. En- docrinol. 12:864–881.
  • Trosko, J., Chang, C., and Madmukar, B. (1990). In vitro analysis of modulators of intercellular communi- cation: Implications for biologically based risk as- sessment models for chemical exposure. Toxicol. In Vitro 4:635–643.
  • Tsurudome, Y., Hirano, T., Yamato, H., Tanaka, I., Sagai, M., Hirano, H., Nagata, N., Itoh, H., and Kasai, H. (1999). Changes in levels of 8-hydroxyguanine in DNA, its repair and OGG1 mRNA in rat lungs after intratracheal administration of diesel exhaust particles. Carcinogenesis 20:1573–1576.
  • Tucker, M.J., and Orton, T.C. (1995). Comparative Tox- icology of Hypolipidaemic Fibrates. Taylor and Francis, Bristol, PA.
  • Tugwood, J.D., Aldridge, T.C., Lambe, K.G., Mac- donald, N., and Woodyatt, N.J. (1996). Peroxi- some proliferator-activated receptors: Structures and function. Ann. NY Acad. Sci. 804:252–265.
  • Tugwood, J.D., Holden, P.R., James, N.H., Prince, R.A., and Roberts, R.A. (1998). A PPAR alpha cDNA cloned from guinea pig liver encodes a protein with similar properties to the mouse PPAR alpha: Im- plications for species differences in response to peroxisome proliferators. Arch. Toxicol. 72:169–177.
  • Turek, F.W., and Desjardins, C. (1979). Development of Leydig cell tumors and onset of changes in the re- productive and endocrine system of aging Fischer 344 rats. JNCI 63:969–975.
  • Ubel, F.A., Sorenson, S.D., and Roach, D.E. (1980). Health status of plant workers exposed to fluorochemicals—A preliminary report. Am. Ind. Hyg. Assoc. J. 41:584–589.
  • Upham, B., Deocampo, N., Wurl, B., and Trosko, J. (1998). Inhibition of gap junctional intercellular communication by perfluorinated fatty acids is de- pendent on the chain length of the fluorinated tail. Int. J. Cancer 78:491–495.
  • Upham, B., Kang, K., Cho, H., and Trosko, J. (1997). Hy- drogen peroxide inhibits gap junctional intercellu- lar communication in glutathione sufficient but not glutathione deficient cells. Carcinogenesis 18:37–42.
  • U.S.EnvironmentalProtectionAgency. (2000a). Lactofen—Toxicology evalution. March 2. (http://www.epa.gov/oppsrrd1/reregistration/lactofen/ minitox%20chapter.pdf)
  • U.S. Environmental Protection Agency. (2000b). Evaluation of the carcinogenic potential of diclofop-methyl (second review). Final Re- port May 24. (http://www.epa.gov/pesticides/ reregistration/diclofop-methyl/carc.pdf)
  • Vanden Heuvel, J., Kuslikis, B.,Van Refelghem, M., and Peterson, R. (1991). Tissue distribution, metabolism, and elimination of perfluorooctanoic acid in male and female rats. J. Biochem. Toxicol. 6:83–92.
  • Vanden Heuvel, J.P., Sterchele, P.F., Nesbit, D.J., and Pe- terson, R.E. (1993). Coordinate induction of acyl- CoA binding protein, fatty acid binding protein and peroxisomal beta-oxidation by peroxisome proliferators. Biochim. Biophys. Acta 1177:183–190.
  • Varanasi, U., Chu, R., Huang, Q., Castellon, R., Yeldandi, A.V., and Reddy, J.K. (1996). Identification of a peroxisome proliferator-responsive element up- stream of the human peroxisomal fatty acyl coen- zyme A oxidase gene. J. Biol. Chem. 271:2147–2155.
  • Viguier-Martinez, M.C., Hochereau de Reviers, M.T., Barenton, B., and Perreau, C. (1983a). Endocrino- logical and histological changes induced by flutamide treatment on the hypothalamo- hypophyseal testicular axis of the adult male rat and their incidence on fertility. Acta En- docrinol. 104:246–252.
  • Viguier-Martinez, M.C., Hochereau de Reviers, M.T., Barenton, B., and Perreau, C. (1983b). Effect of a non-steroidal antiandrogen, flutamide, on the hypothalamo-pituitary axis, genital tract and testis in growing male rats: Endocrinoloigcal and histological data. Acta Endocrinol. 104:299–306.
  • Vohl, M.C., Lepage, P., Gaudet, D., Brewer, C.G., Betard, C., Perron, P., Houde, G., Cellier, C., Faith, J.M., Despres, J.P., Morgan, K., and Hudson, T.J. (2000). Molecular scanning of the human PPARa gene. As- sociation of the l162v mutation with hyperapobe- talipoproteinemia. J. Lipid Res. 41:945–952.
  • Von Daeniken, A., Lutz, W.K., Jaeckh, R., and Schlat- ter, C. (1984). Investigation of the potential for binding of di(2-ethylhexyl)phthalate (DEHP) and di (2-ethylhexyl)adipate (DEHA) to liver DNA in vivo. Toxicol. Appl. Pharmacol. 73:373–387.
  • Vu-Dac, N., Chopin-Delannoy, S., Gervois, P., Bonnelye, E., Martin, G., Fruchart, J.C., Laudet, V., and Staels, B. (1998). The nuclear receptors perox- isome proliferator-activated receptor alpha and Rev-erbalpha mediate the species-specific regula- tion of apolipoprotein A-I expression by fibrates. J. Biol. Chem. 273:25713–25720.
  • Vu-Dac, N., Schoonjans, K., Laine, B., Fruchart, J.C., Auwerx, J., and Staels, B. (1994). Negative regu- lation of the human apolipoprotein A-I promoter by fibrates can be attenuated by the interaction of the peroxisome proliferator-activated receptor with its response element. J. Biol. Chem. 269:31012–31018.
  • Vu-Dac, N., Schoonjans, K., Kosykh, V., Dallongeville, J., Fruchart, J.C., Staels, B., and Auwerx, J. (1995). Fibrates increase human apolipoprotein A-II expression through activation of the peroxi- some proliferator-activated receptor. J. Clin. Invest. 96:741–750.
  • Wahli, W., Braissant, O., and Desvergne, B. (1995). Peroxisome proliferator activated receptors: Tran- scriptional regulators of adipogenesis, lipid metabolism and more. Chem. Biol. 2:261–266.
  • Walgren, J.E., Kurtz, D.T., and McMillan, J.M. (2000). Expression of PPAR (alpha) in human hepatocytes and activation by trichloroacetate and dichloroac- etate. Res. Commun. Mol. Pathol. Pharmacol. 108:116–132.
  • Walker, U.J., and Nogues, V. (1994). Changes induced by treatment with aromatase inhibitors in testicular Leydig cells of rats and dogs. Exp. Toxicol. Pathol. 46:211–213.
  • Ward, J.M., Diwan, B.A., Ohshima, M., Hu, H., Schuller, H.M., and Rice, J.M. (1986). Tumor-initiating and promoting activities of di(2-ethylhexyl) phthalate in vivo and in vitro. <i>Environ. Health Perspect. 65:279–291.
  • Ward, J.M., Hagiwara, A., Anderson, L.M., Lindsey, K., and Diwan, B.A. (1988).The chronic hepatic or renal toxicity of di(2-ethylhexyl) phthalate, ac- etaminophen, sodium barbital, and phenobarbital in male B6C3F1 mice: Autoradiographic,immuno- histochemical, and biochemical evidence for levels of DNA synthesis not associated with carcinogene- sis or tumor promotion. Toxicol. Appl. Pharmacol. 96:494–506.
  • Ward, J.M., Peters, J.M., Perella, C.M., and Gonzalez, F.J. (1998). Receptor and non-receptor mediated organ-specific toxicity of di(2-ethylhexyl) phtha- late (DEHP) in peroxisome proliferator-activated receptor a-null mice. Toxicol. Path. 26:240–246.
  • Ward, J.M., Creasia, D., Lynch, P., and Riggs, C. (1983). Dissimilar patterns of promotion by di(2- ethylhexyl) phthalate and phenobarbital of hepato- cellular neoplasia initiated by diethylnitrosamine in B6C3F1 mice. Carcinogenesis 4:1021–1029.
  • Watanabe, T., Horie, S., Yamada, J., Isaji, M., Nishigaki, T., Naito, J., and Suga, T. (1989). Species differ- ences in the effects of bezafibrate, a hypolipidemic agent, on hepatic peroxisome-associated enzymes. Biochem. Pharmacol. 38:367–371.
  • Weinberg, D.S., Ruggeri, B., Barber, M.T., Biswas, S., Miknyocki, S., and Waldman, S.A. (1997). Chole- cystokinin A and B receptors are differentially ex- pressed in normal pancreas and pancreatic adeno- carcinoma. J. Clin. Invest. 100:597–603.
  • West, D., James, N., Holden, P., Brindle, R., Rolfe, M., and Roberts, R. (1999). Role for tumour necrosis factor a (TNFa) receptor 1 (TNFR1) and interleukin 1 receptor (IL1R) in the suppression of apoptosis by peroxisome proliferators. Hepatology 30:1417–1424.
  • White, R.D., Carter, D.E., Earnest, D., and Mueller, J. (1980). Absorption and metabolism of three phtha- late diesters by the rat small intestine. Food Cosmet. Toxicol. 18:383–386.
  • White, R.D., Carter, D.E., Earnest, D., and Mueller, J. (1983). The effect of intestinal esterase inhibition on the in vivo absorption and toxicity of di-n-butyl phthalate. Food Chem. Toxicol. 21:99–101.
  • Williams, G.M., and Perrone, C. (1995). Mechanism- based risk assessment of peroxisome proliferating rodent hepatocarcinogens. In: Peroxisomes: Biol- ogy and Role in Toxicology and Disease, eds. J.K. Reddy, T. Suga, and G.P. Mannaerts, Ann. NY Acad. Sci. 804:554–572.
  • Willson, T.M., Brown, P.J., Sternbach, D.D., and Henke, B.R. (2000). The PPARs: From orphan receptors to drug discovery. J. Med. Chem. 43:527–550.
  • Wood, R.D., Mitchell, M., Sgouros, J., and Lindahl, T. (2001). Human DNA repair genes. Science 291:1284–1289.
  • Woodyatt, N.J., Lambe, K.G., Myers, K.A., Tugwood, J.D., and Roberts, R.A. (1999). The peroxisome proliferator (PP) response element upstream of the human acyl CoA oxidase gene is inactive among a sample human population: Significance for species differences in response to PPs. Carcinogenesis. 20:369–372.
  • Wurch, T., Junquero, D., Delhon, A., and Pauwels, P.J. (2002). Pharmacological analysis of wild-type al- pha, gamma and delta subtypes of the human per- oxisome proliferator-activated receptor. Naunyn- Schmied. Arch. Pharmacol. 365:133–140.
  • Wyllie, A.H. (1993). Apoptosis (The Frank Rose Memo- rial Lecture). Br. J. Cancer 67:205–208.
  • Xu, H.E., Lambert, M.H., Montana, V.G., Plunket, K.D., Moore, L.B., Collins, J.L., Oplinger, J.A., Kliewer, S.A., Gampe, R.T., Jr., McKee, D.D., et al. (2001). Structural determinants of ligand binding selectiv- ity between the peroxisome proliferator-activated receptors. Proc. Natl. Acad. Sci. USA 98:13919–13924.
  • Yamakawa-Kobayashi, K., Ishiguro, H., Arinami, T., Miyazaki, R., and Hamaguchi, H. (2002). A Val227Ala polymorphism in the peroxisome pro- liferator activated receptor alpha (PPARalpha) gene is associated with variations in serum lipid levels. J. Med. Genet. 39:189–191.
  • Yamasaki, H. (1990). Commentary: Gap junctional inter- cellular communication and carcinogenesis. Car- cinogenesis 11:1051–1058.
  • Yan, Z.H., Karam, W.G., Staudinger, J.L., Medvedev, A., Ghanayem, B.I., and Jetten, A.M. (1998). Regulation of peroxisome proliferator-activated receptor alpha-induced transactivation by the nuclear orphan receptor TAK1/TR4. J. Biol. Chem. 273:10948–10957.
  • Yang, Q., Xie, Y., Alexson, S.E.H., Nelson, B.D., and DePierre, J.W. (2002). Involvement of the peroxisome proliferator-activated receptor alpha in the immunomodulation caused by peroxisome prolif- erators in mice. Biochem. Pharmacol. 63:1893–900.
  • Yeldandi, A.V., Rao, M.S., and Reddy, J.K. (2000). Hydrogen peroxide generation in peroxisome proliferator-induced oncogenesis. Mutat. Res. 448:159–177.
  • Ylinen, M., Hanhijarvi, H., Jaakonaho, J., and Peura, P. (1989). Stimulation by oestradiol of the urinary ex- cretion of perfluorooctanoic acid in the male rat. Pharmacol. Toxicol. 65:274–277.
  • Yoo, H.Y., Chang, M.S., and Rho, H.M. (1999). In- duction of the rat Cu/Zn superoxide dismu- tase gene through the peroxisome proliferator- responsive element by arachidonic acid. Gene 234: 87–91.
  • Yu, S., Cao, W.Q., Kashireddy, P., Meyer, K., Jia, Y., Hughes, D.E., Tan, Y., Feng, J., Yeldandi, A.V., Rao, M.S., Costa, R.H., Gonzalez, F.J., and Reddy, J.K. (2001). Human peroxisome proliferator- activated receptor α (PPARα)supports the in- duction of peroxisome proliferation in PPARα deficient mouse liver. J. Biol. Chem. 276:42485–42491.
  • Yuan, C.X., Ito, M., Fondell, J.D., Fu, Z.Y., and Roeder, R.G. (1998). The TRAP220 component of a thy- roid hormone receptor-associated protein (TRAP) coactivator complex interacts directly with nuclear receptors in a ligand-dependent fashion. Proc. Natl. Acad. Sci. USA 95:7939–7944.
  • Zhang, X.K., Wills, K.N., Husmann, M., Hermann, T., and Pfahl, M. (1991). Novel pathway for thyroid hormone receptor action through interaction with jun and fos oncogene activities. Mol. Cell Biol. 11:6016–6025.
  • Zhu, Y., Kan, L., Qi, C., Kanwar, Y.S., Yeldandi, A.V., Rao, M.S., and Reddy, J.K. (2000). Isolation and characterization of peroxisome proliferator- activated receptor (PPAR) interacting protein (PRIP) as a coactivator for PPAR. J. Biol. Chem. 275:13510–1351.
  • Zhu, Y., Qi, C., Calandra, C., Rao, M.S., and Reddy, J.K. (1996). Cloning and identification of mouse steroid receptor coactivator-1 (mSRC-1), as a coactiva- tor of peroxisome proliferator-activated receptor gamma. Gene Expr. 6:185–195.
  • Zhu, Y., Qi, C., Jain, S., Rao, M.S., and Reddy, J.K. (1997). Isolation and characterization of PBP, a protein that interacts with peroxisome proliferator-activated re- ceptor. J. Biol. Chem. 272:25500–25506.

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.