Assaying embryotoxicity in the test tube: Current limitations of the embryonic stem cell test (EST) challenging its applicability domain

References

• Adler M, Müller K, Rached E, Dekant W, Mally A. (2009). Modulation of key regulators of mitosis linked to chromosomal instability is an early event in ochratoxin A carcinogenicity. Carcinogenesis 30:711–719.
   PubMed Web of Science ®Google Scholar
• Aidlen JT, Nazarey PP, Kinane TB, Donahoe PK, Schnitzer JJ, Kling DE. (2007). Retinoic acid-mediated differentiation protects against nitrofen-induced apoptosis. Birth Defects Res B Dev Reprod Toxicol 80:406–416.
   PubMedGoogle Scholar
• Alves ALG, Rodrigues MAM, Aguiar AJA, Thomassian A, Nicoletti JLM, Hussni CA, Borges AS. (2001). Effects of beta-aminopropionitrile fumarate and exercise on equine tendon healing: Gross and histological aspects. J Equine Vet Sci 21, 335–340.
   Google Scholar
• Augustine-Rauch K, Zhang CX, Panzica-Kelly JM. (2010). In vitro developmental toxicology assays: A review of the state of the science of rodent and zebrafish whole embryo culture and embryonic stem cell assays. Birth Defects Res C Embryo Today 90:87–98.
   PubMed Web of Science ®Google Scholar
• Bakke OM, Segura J. (1976). The absorption and elimination of metoclopramide in three animal species. J Pharm Pharmacol 28:32–39.
   PubMed Web of Science ®Google Scholar
• Baldacci A, Prost F, Thormann W. (2004). Identification of diphenhydramine metabolites in human urine by capillary electrophoresis-ion trap-mass spectrometry. Electrophoresis 25:1607–1614.
   PubMedGoogle Scholar
• Balls M, Blaauboer BJ, Fentem JH, Bruner L, Combes RD, Ekwall B, Fielder RJ, Guillouzo A, Lewis RW, Lovell DP, Reinhardt CA, Repetto G, Sladowski D, Spielmann H, Zucco F. (1995). Practical aspects of the validation of toxicity test procedures. The report and recommendations of ECVAM workshop 5. Altern Lab Anim 23, 129–147.
   Web of Science ®Google Scholar
• Bassanini S, Hallene K, Battaglia G, Finardi A, Santaguida S, Cipolla M, Janigro D. (2007). Early cerebrovascular and parenchymal events following prenatal exposure to the putative neurotoxin methylazoxymethanol. Neurobiol Dis 26:481–495.
   PubMedGoogle Scholar
• Becker M, Nothwang HG, Friauf E. (2003). Differential expression pattern of chloride transporters NCC, NKCC2, KCC1, KCC3, KCC4, and AE3 in the developing rat auditory brainstem. Cell Tissue Res 312:155–165.
   PubMedGoogle Scholar
• Bejar A, Roujansky P, de Barry J, Gombos G. (1985). Different effect of methylazoxymethanol on mouse cerebellar development depending on the age of injection. Exp Brain Res 57:279–285.
   PubMedGoogle Scholar
• Belpaire FM, Bogaert MG. (1975). Metabolism of papaverine. II. Species differences. Xenobiotica 5:421–429.
   PubMed Web of Science ®Google Scholar
• Belpaire FM, Bogaert MG, Rosseel MT, Anteunis M. (1975). Metabolism of papaverine. I. Identification of metabolites in rat bile. Xenobiotica 5:413–420.
   PubMed Web of Science ®Google Scholar
• Berkner KL. (2005). The vitamin K-dependent carboxylase. Annu Rev Nutr 25:127–149.
   PubMed Web of Science ®Google Scholar
• Bishai R, Mazzotta P, Atanackovic G, Levichek Z, Pole M, Magee LA, Koren G. (2000). Critical appraisal of drug therapy for nausea and vomiting of pregnancy: II. Efficacy and safety of diclectin (doxylamine-B6). Can J Clin Pharmacol 7:138–143.
   PubMedGoogle Scholar
• Blaesse P, Airaksinen MS, Rivera C, Kaila K. (2009). Cation-chloride cotransporters and neuronal function. Neuron 61:820–838.
   PubMed Web of Science ®Google Scholar
• Bose-O’Reilly S, McCarty KM, Steckling N, Lettmeier B. (2010). Mercury exposure and children’s health. Curr Probl Pediatr Adolesc Health Care 40:186–215.
   PubMed Web of Science ®Google Scholar
• Brent R. (2003). Bendectin and birth defects: hopefully, the final chapter. Birth Defects Res Part A Clin Mol Teratol 67:79–87.
   PubMed Web of Science ®Google Scholar
• Brent RL. (1995). Bendectin: review of the medical literature of a comprehensively studied human nonteratogen and the most prevalent tortogen-litigen. Reprod Toxicol 9:337–349.
   PubMed Web of Science ®Google Scholar
• Brewer GJ. (2006). Novel therapeutic approaches to the treatment of Wilson’s disease. Expert Opin Pharmacother 7:317–324.
   PubMed Web of Science ®Google Scholar
• Bridges CC, Zalups RK. (2010). Transport of inorganic mercury and methylmercury in target tissues and organs. J Toxicol Environ Health B Crit Rev 13:385–410.
   PubMed Web of Science ®Google Scholar
• Brielmeier M, Béchet JM, Falk MH, Pawlita M, Polack A, Bornkamm GW. (1998). Improving stable transfection efficiency: antioxidants dramatically improve the outgrowth of clones under dominant marker selection. Nucleic Acids Res 26:2082–2085.
   PubMed Web of Science ®Google Scholar
• Brown BB, Werner HW. (1948). The pharmacologic properties of 2-[alpha-(2-dimethylaminoethoxy)-alpha-methylbenzyl]-pyridine succinate, a new antihistaminic agent. J Lab Clin Med 33:325–331.
   PubMed Web of Science ®Google Scholar
• Brown NA. (2002). Selection of test chemicals for the ECVAM international validation study on in vitro embryotoxicity tests. European Centre for the Validation of Alternative Methods. Altern Lab Anim 30:177–198.
   PubMed Web of Science ®Google Scholar
• Brown TJ, Manson JM. (1986). Further characterization of the distribution and metabolism of nitrofen in the pregnant rat. Teratology 34:129–139.
   PubMedGoogle Scholar
• Bucher JR. (1989). Toxicology and Carcinogenesis Studies of Furosemide (CAS No. 54-31-9) in F344/N Rats and B6C3F1 Mice (Feed Studies). Natl Toxicol Program Tech Rep Ser 356, 1–190.
   PubMedGoogle Scholar
• Buesen R, Genschow E, Slawik B, Visan A, Spielmann H, Luch A, Seiler A. (2009). Embryonic stem cell test remastered: comparison between the validated EST and the new molecular FACS-EST for assessing developmental toxicity in vitro. Toxicol Sci 108:389–400.
   PubMedGoogle Scholar
• Buesen R, Visan A, Genschow E, Slawik B, Spielmann H, Seiler A. (2004). Trends in improving the embryonic stem cell test (EST): an overview. ALTEX 21:15–22.
   PubMedGoogle Scholar
• Carney EW, Kimmel CA. (2007). Interpretation of skeletal variations for human risk assessment: delayed ossification and wavy ribs. Birth Defects Res B Dev Reprod Toxicol 80:473–496.
   PubMedGoogle Scholar
• Carota I, Theilig F, Oppermann M, Kongsuphol P, Rosenauer A, Schreiber R, Jensen BL, Walter S, Kunzelmann K, Castrop H. (2010). Localization and functional characterization of the human NKCC2 isoforms. Acta Physiol (Oxf) 199:327–338.
   PubMedGoogle Scholar
• Casas López JL, Sánchez Pérez JA, Fernández Sevilla JM, Acién Fernández FG, Molina Grima E, Chisti Y. (2003). Production of lovastatin by Aspergillus terreus: effects of the C: N ratio and the principal nutrients on growth and metabolite production. Enzyme Microb Tech 33, 270–277.
   Web of Science ®Google Scholar
• Cattabeni F, Di Luca M. (1997). Developmental models of brain dysfunctions induced by targeted cellular ablations with methylazoxymethanol. Physiol Rev 77:199–215.
   PubMed Web of Science ®Google Scholar
• Cavallotti C, Mancone M, Bruzzone P, Sabbatini M, Mignini F. (2010). Dopamine receptor subtypes in the native human heart. Heart Vessels 25:432–437.
   PubMedGoogle Scholar
• Cecchelli R, Berezowski V, Lundquist S, Culot M, Renftel M, Dehouck MP, Fenart L. (2007). Modelling of the blood-brain barrier in drug discovery and development. Nat Rev Drug Discov 6:650–661.
   PubMed Web of Science ®Google Scholar
• Choi BH. (1986). Methylmercury poisoning of the developing nervous system: I. Pattern of neuronal migration in the cerebral cortex. Neurotoxicology 7:591–600.
   PubMedGoogle Scholar
• Choi BH, Lapham LW, Amin-Zaki L, Saleem T. (1978). Abnormal neuronal migration, deranged cerebral cortical organization, and diffuse white matter astrocytosis of human fetal brain: a major effect of methylmercury poisoning in utero. J Neuropathol Exp Neurol 37:719–733.
   PubMed Web of Science ®Google Scholar
• Cirillo VJ, Tempero KF. (1976). Pharmacology and therapeutic use of antihistamines. Am J Hosp Pharm 33:1200–1207.
   PubMedGoogle Scholar
• Coecke S, Ahr H, Blaauboer BJ, Bremer S, Casati S, Castell J, Combes R, Corvi R, Crespi CL, Cunningham ML, Elaut G, Eletti B, Freidig A, Gennari A, Ghersi-Egea JF, Guillouzo A, Hartung T, Hoet P, Ingelman-Sundberg M, Munn S, Janssens W, Ladstetter B, Leahy D, Long A, Meneguz A, Monshouwer M, Morath S, Nagelkerke F, Pelkonen O, Ponti J, Prieto P, Richert L, Sabbioni E, Schaack B, Steiling W, Testai E, Vericat JA, Worth A. (2006). Metabolism: a bottleneck in in vitro toxicological test development. The report and recommendations of ECVAM workshop 54. Altern Lab Anim 34:49–84.
   PubMed Web of Science ®Google Scholar
• Coulter DA, Huguenard JR, Prince DA. (1989). Characterization of ethosuximide reduction of low-threshold calcium current in thalamic neurons. Ann Neurol 25:582–593.
   PubMed Web of Science ®Google Scholar
• Coutu DL, Wu JH, Monette A, Rivard GE, Blostein MD, Galipeau J. (2008). Periostin, a member of a novel family of vitamin K-dependent proteins, is expressed by mesenchymal stromal cells. J Biol Chem 283:17991–18001.
   PubMed Web of Science ®Google Scholar
• Crabb DW, Matsumoto M, Chang D, You M. (2004). Overview of the role of alcohol dehydrogenase and aldehyde dehydrogenase and their variants in the genesis of alcohol-related pathology. Proc Nutr Soc 63:49–63.
   PubMed Web of Science ®Google Scholar
• Crawford M. (1986). Hoechst tests lead EPA to ban herbicide. Science 234:422.
   PubMedGoogle Scholar
• Culliton BJ. (1983). Merrell Dow stops marketing bendectin. Science 221:37.
   PubMedGoogle Scholar
• Danielsson C, Azarbayjani F, Sköld AC, Sjögren N, Danielsson BR. (2007). Polytherapy with hERG-blocking antiepileptic drugs: increased risk for embryonic cardiac arrhythmia and teratogenicity. Birth Defects Res Part A Clin Mol Teratol 79:595–603.
   PubMedGoogle Scholar
• De Backer MD, Loonen I, Verhasselt P, Neefs JM, Luyten WH. (1998). Structure of the human histamine H1 receptor gene. Biochem J 335 (Pt 3):663–670.
   PubMedGoogle Scholar
• de Jong E, Louisse J, Verwei M, Blaauboer BJ, van de Sandt JJ, Woutersen RA, Rietjens IM, Piersma AH. (2009). Relative developmental toxicity of glycol ether alkoxy acid metabolites in the embryonic stem cell test as compared with the in vivo potency of their parent compounds. Toxicol Sci 110:117–124.
   PubMed Web of Science ®Google Scholar
• Dembinski J, Heyl W, Steidel K, Hermanns B, Hörnchen H, Schröder W. (1997). The Cantrell-sequence: a result of maternal exposure to aminopropionitriles? Am J Perinatol 14:567–571.
   PubMed Web of Science ®Google Scholar
• Derangeon M, Bozon V, Defamie N, Peineau N, Bourmeyster N, Sarrouilhe D, Argibay JA, Hervé JC. (2010). 5-HT4 and 5-HT2 receptors antagonistically influence gap junctional coupling between rat auricular myocytes. J Mol Cell Cardiol 48:220–229.
   PubMedGoogle Scholar
• Desta Z, Wu GM, Morocho AM, Flockhart DA. (2002). The gastroprokinetic and antiemetic drug metoclopramide is a substrate and inhibitor of cytochrome P450 2D6. Drug Metab Dispos 30:336–343.
   PubMed Web of Science ®Google Scholar
• Dorne JL. (2010). Metabolism, variability and risk assessment. Toxicology 268:156–164.
   PubMed Web of Science ®Google Scholar
• Duarte SC, Pena A, Lino CM. (2010). A review on ochratoxin A occurrence and effects of processing of cereal and cereal derived food products. Food Microbiol 27:187–198.
   PubMed Web of Science ®Google Scholar
• Duester G. (1998). Alcohol dehydrogenase as a critical mediator of retinoic acid synthesis from vitamin A in the mouse embryo. J Nutr 128:459S–462S.
   Google Scholar
• Duester G. (2008). Retinoic acid synthesis and signaling during early organogenesis. Cell 134:921–931.
   PubMed Web of Science ®Google Scholar
• Dumuis A, Sebben M, Bockaert J. (1989). The gastrointestinal prokinetic benzamide derivatives are agonists at the non-classical 5-HT receptor (5-HT4) positively coupled to adenylate cyclase in neurons. Naunyn Schmiedebergs Arch Pharmacol 340:403–410.
   PubMed Web of Science ®Google Scholar
• Elhassani SB. (1982). The many faces of methylmercury poisoning. J Toxicol Clin Toxicol 19:875–906.
   PubMed Web of Science ®Google Scholar
• Endo A. (1980). Monacolin K, a new hypocholesterolemic agent that specifically inhibits 3-hydroxy-3-methylglutaryl coenzyme A reductase. J Antibiot 33:334–336.
   PubMedGoogle Scholar
• European Chemicals Agency. New study inaccurate on the number of test animals for REACH. ECHA/PR/09/11. 30-8-2009. Helsinki, Finland, European Chemicals Agency.
   Google Scholar
• Everson RB, Wehr CM, Erexson GL, MacGregor JT. (1988). Association of marginal folate depletion with increased human chromosomal damage in vivo: demonstration by analysis of micronucleated erythrocytes. J Natl Cancer Inst 80:525–529.
   PubMedGoogle Scholar
• Farooqui T, Brooks K, Harrold MW, Miller DD, Wallace LJ, Uretsky NJ. (1994). Interaction of permanently charged metoclopramide analogs with D-2 dopamine receptors. Gen Pharmacol 25:1577–1584.
   PubMedGoogle Scholar
• Finnell RH, Dansky LV. (1991). Parental epilepsy, anticonvulsant drugs, and reproductive outcome: epidemiologic and experimental findings spanning three decades; 1: Animal studies. Reprod Toxicol 5:281–299.
   PubMed Web of Science ®Google Scholar
• Fischer MH, Welker C, Waisman HA. (1972). Generalized growth retardation in rats induced by prenatal exposure to methylazoxymethyl acetate. Teratology 5:223–232.
   PubMedGoogle Scholar
• Fitzgerald WF, Clarkson TW. (1991). Mercury and monomethylmercury: present and future concerns. Environ Health Perspect 96:159–166.
   PubMed Web of Science ®Google Scholar
• Franco B, Meroni G, Parenti G, Levilliers J, Bernard L, Gebbia M, Cox L, Maroteaux P, Sheffield L, Rappold GA, Andria G, Petit C, Ballabio A. (1995). A cluster of sulfatase genes on Xp22.3: mutations in chondrodysplasia punctata (CDPX) and implications for warfarin embryopathy. Cell 81:15–25.
   PubMed Web of Science ®Google Scholar
• Fraser RJ, Bryant L. (2010). Current and future therapeutic prokinetic therapy to improve enteral feed intolerance in the ICU patient. Nutr Clin Pract 25:26–31.
   PubMed Web of Science ®Google Scholar
• Gaylor DW. (2005). Are tumor incidence rates from chronic bioassays telling us what we need to know about carcinogens? Regul Toxicol Pharmacol 41:128–133.
   PubMed Web of Science ®Google Scholar
• Gelineau-van Waes J, Voss KA, Stevens VL, Speer MC, Riley RT. (2009). Maternal fumonisin exposure as a risk factor for neural tube defects. Adv Food Nutr Res 56:145–181.
   PubMedGoogle Scholar
• Genschow E, Spielmann H, Scholz G, Pohl I, Seiler A, Clemann N, Bremer S, Becker K. (2004). Validation of the embryonic stem cell test in the international ECVAM validation study on three in vitro embryotoxicity tests. Altern Lab Anim 32:209–244.
   PubMed Web of Science ®Google Scholar
• Genschow E, Spielmann H, Scholz G, Seiler A, Brown N, Piersma A, Brady M, Clemann N, Huuskonen H, Paillard F, Bremer S, Becker K. (2002). The ECVAM international validation study on in vitro embryotoxicity tests: results of the definitive phase and evaluation of prediction models. European Centre for the Validation of Alternative Methods. Altern Lab Anim 30:151–176.
   PubMed Web of Science ®Google Scholar
• Giavini E, Broccia ML, Prati M, Cova D, Rossini L. (1989). Teratogenicity of dinoseb: role of the diet. Bull Environ Contam Toxicol 43:215–219.
   PubMedGoogle Scholar
• Gibson JE, Rao KS. (1973). Disposition of 2-sec-butyl-4,6-dinitrophenol (dinoseb) in pregnant mice. Food Cosmet Toxicol 11:45–52.
   PubMedGoogle Scholar
• Gilbert SG, Grant-Webster KS. (1995). Neurobehavioral effects of developmental methylmercury exposure. Environ Health Perspect 103 Suppl 6:135–142.
   PubMed Web of Science ®Google Scholar
• Gilboa SM, Strickland MJ, Olshan AF, Werler MM, Correa A; National Birth Defects Prevention Study. (2009). Use of antihistamine medications during early pregnancy and isolated major malformations. Birth Defects Res Part A Clin Mol Teratol 85:137–150.
   PubMed Web of Science ®Google Scholar
• Goldman AS, Yaffe SJ. (1978). Fetal trimethadione syndrome. Teratology 17:103–105.
   PubMedGoogle Scholar
• Goldsmith SR. (2005). Current treatments and novel pharmacologic treatments for hyponatremia in congestive heart failure. Am J Cardiol 95:14B–23B.
   PubMed Web of Science ®Google Scholar
• Goldstein JL, Brown MS. (1990). Regulation of the mevalonate pathway. Nature 343:425–430.
   PubMed Web of Science ®Google Scholar
• González-Reyes S, Martínez L, Tovar JA. (2005). Effects of prenatal vitamins A, E, and C on the hypoplastic hearts of fetal rats with diaphragmatic hernia. J Pediatr Surg 40:1269–1274.
   PubMed Web of Science ®Google Scholar
• Gorgojo Martínez JJ, Almodóvar Ruiz F, Donnay Candil S. (2006). Baseline serum folate level may be a predictive factor of weight loss in a morbid-obesity-management programme. Br J Nutr 96, 956–964.
   PubMedGoogle Scholar
• Greenhough S, Medine CN, Hay DC. (2010). Pluripotent stem cell derived hepatocyte like cells and their potential in toxicity screening. Toxicology 278:250–255.
   PubMed Web of Science ®Google Scholar
• Greer JJ, Allan DW, Babiuk RP, Lemke RP. (2000). Recent advances in understanding the pathogenesis of nitrofen-induced congenital diaphragmatic hernia. Pediatr Pulmonol 29:394–399.
   PubMed Web of Science ®Google Scholar
• Groebe K, Hayess K, Klemm-Manns M, Schwall G, Wozny W, Steemans M, Peters AK, Sastri C, Jaeckel P, Stegmann W, Zengerling H, Schopf R, Poznanovic S, Stummann TC, Seiler A, Spielmann H, Schrattenholz A. (2010). Protein biomarkers for in vitro testing of embryotoxicity. J Proteome Res 9:5727–5738.
   PubMed Web of Science ®Google Scholar
• Haddad RK, Rabe A, Dumas R. (1972). Comparison of effects of methylazoxymethanol acetate on brain development in different species. Fed Proc 31:1520–1523.
   PubMedGoogle Scholar
• Hafizi S, Dahlbäck B. (2006). Gas6 and protein S. Vitamin K-dependent ligands for the Axl receptor tyrosine kinase subfamily. FEBS J 273:5231–5244.
   PubMed Web of Science ®Google Scholar
• Hall JG, Pauli RM, Wilson KM. (1980). Maternal and fetal sequelae of anticoagulation during pregnancy. Am J Med 68:122–140.
   PubMed Web of Science ®Google Scholar
• Halpin RA, Ulm EH, Till AE, Kari PH, Vyas KP, Hunninghake DB, Duggan DE. (1993). Biotransformation of lovastatin. V. Species differences in in vivo metabolite profiles of mouse, rat, dog, and human. Drug Metab Dispos 21:1003–1011.
   PubMed Web of Science ®Google Scholar
• Han X, Lamshöft M, Grobe N, Ren X, Fist AJ, Kutchan TM, Spiteller M, Zenk MH. (2010). The biosynthesis of papaverine proceeds via (S)-reticuline. Phytochemistry 71:1305–1312.
   PubMedGoogle Scholar
• Hansen JM, Contreras KM, Harris C. (2005). Methanol, formaldehyde, and sodium formate exposure in rat and mouse conceptuses: a potential role of the visceral yolk sac in embryotoxicity. Birth Defects Res Part A Clin Mol Teratol 73:72–82.
   PubMedGoogle Scholar
• Hartung T. (2008). Food for thought. on animal tests. ALTEX 25:3–16.
   PubMedGoogle Scholar
• Heath CW Jr. (1966). Cytogenetic observations in vitamin B12 and folate deficiency. Blood 27:800–815.
   PubMed Web of Science ®Google Scholar
• Hendrickx AG, Peterson PE. (1997). Perspectives on the use of the baboon in embryology and teratology research. Hum Reprod Update 3:575–592.
   PubMed Web of Science ®Google Scholar
• Herzel F, Murty AS. (1984). Do carrier solvents enhance the water solubility of hydrophobic compounds? Bull Environ Contam Toxicol 32:53–58.
   PubMedGoogle Scholar
• Hettwer M, Reis-Fernandes MA, Iken M, Ott M, Steinberg P, Nau H. (2010). Metabolic activation capacity by primary hepatocytes expands the applicability of the embryonic stem cell test as alternative to experimental animal testing. Reprod Toxicol 30:113–120.
   PubMed Web of Science ®Google Scholar
• Hirokawa Y, Fujiwara I, Suzuki K, Harada H, Yoshikawa T, Yoshida N, Kato S. (2003). Synthesis and structure-affinity relationships of novel N-(1-ethyl-4-methylhexahydro-1,4-diazepin-6-yl)pyridine-3-carboxamides with potent serotonin 5-HT3 and dopamine D2 receptor antagonistic activity. J Med Chem 46:702–715.
   PubMed Web of Science ®Google Scholar
• Ho KM, Power BM. (2010). Benefits and risks of furosemide in acute kidney injury. Anaesthesia 65:283–293.
   PubMed Web of Science ®Google Scholar
• Höfer T, Gerner I, Gundert-Remy U, Liebsch M, Schulte A, Spielmann H, Vogel R, Wettig K. (2004). Animal testing and alternative approaches for the human health risk assessment under the proposed new European chemicals regulation. Arch Toxicol 78:549–564.
   PubMed Web of Science ®Google Scholar
• Holder CL, Siitonen PH, Slikker W Jr, Branscomb CJ, Korfmacher WA, Thompson HC Jr, Cerniglia CE, Gosnell AB, Lay JO Jr. (1990). Metabolism of doxylamine succinate in Fischer 344 rats. Part III: Conjugated urinary and fecal metabolites. J Anal Toxicol 14:247–251.
   PubMedGoogle Scholar
• Hornstra IK, Birge S, Starcher B, Bailey AJ, Mecham RP, Shapiro SD. (2003). Lysyl oxidase is required for vascular and diaphragmatic development in mice. J Biol Chem 278:14387–14393.
   PubMed Web of Science ®Google Scholar
• Howe AM, Webster WS. (1990). Exposure of the pregnant rat to warfarin and vitamin K1: an animal model of intraventricular hemorrhage in the fetus. Teratology 42:413–420.
   PubMedGoogle Scholar
• Huffman J, Gerber R, Du L. (2010). Recent advancements in the biosynthetic mechanisms for polyketide-derived mycotoxins. Biopolymers 93:764–776.
   PubMed Web of Science ®Google Scholar
• Hurt SS, Smith JM, Hayes AW. (1983). Nitrofen: a review and perspective. Toxicology 29:1–37.
   PubMed Web of Science ®Google Scholar
• ICCVAM. Validation and Regulatory Acceptance of Toxicological Test Methods. NIH PUBLICATION NO: 97–3981. 1997. Research Triangle Park, North Carolina 27709, USA, National Institute of Environmental Health Sciences.
   Google Scholar
• Joly D, Rieu P, Méjean A, Gagnadoux MF, Daudon M, Jungers P. (1999). Treatment of cystinuria. Pediatr Nephrol 13:945–950.
   PubMed Web of Science ®Google Scholar
• Joneja MG, Wiley MJ. (1982). Inhibition of beta-aminopropionitrile (beta APN)-induced skeletal teratogenesis by the flavonoid beta-hydroxyethylrutosides (HR) in hamster fetuses. Teratology 26:59–63.
   PubMedGoogle Scholar
• Jones DR, Moran JH, Miller GP. (2010). Warfarin and UDP-glucuronosyltransferases: writing a new chapter of metabolism. Drug Metab Rev 42:55–61.
   PubMed Web of Science ®Google Scholar
• Joyce DA. (1989). D-penicillamine pharmacokinetics and pharmacodynamics in man. Pharmacol Ther 42:405–427.
   PubMed Web of Science ®Google Scholar
• Jutel M, Akdis M, Akdis CA. (2009). Histamine, histamine receptors and their role in immune pathology. Clin Exp Allergy 39:1786–1800.
   PubMed Web of Science ®Google Scholar
• Kakita A, Wakabayashi K, Su M, Sakamoto M, Ikuta F, Takahashi H. (2000). Distinct pattern of neuronal degeneration in the fetal rat brain induced by consecutive transplacental administration of methylmercury. Brain Res 859:233–239.
   PubMedGoogle Scholar
• Kaminsky LS, Zhang ZY. (1997). Human P450 metabolism of warfarin. Pharmacol Ther 73:67–74.
   PubMed Web of Science ®Google Scholar
• Katagiri R, Kurome M, Teshima Y, Ueta E, Naruse I. (2007). Prevention of ochratoxin A-induced neural tube defects by folic acid in the genetic polydactyly/arhinencephaly mouse, Pdn/Pdn. Congenit Anom (Kyoto) 47:90–96.
   PubMedGoogle Scholar
• Kearney PC, Kaufman DD. (1975). Herbicides: Chemistry, Degredation and Mode of Action., Marcel Dekker, Inc., New York.
   Google Scholar
• Khalifa M, Drolet B, Daleau P, Lefez C, Gilbert M, Plante S, O’Hara GE, Gleeton O, Hamelin BA, Turgeon J. (1999). Block of potassium currents in guinea pig ventricular myocytes and lengthening of cardiac repolarization in man by the histamine H1 receptor antagonist diphenhydramine. J Pharmacol Exp Ther 288:858–865.
   PubMedGoogle Scholar
• Kisby GE, Fry RC, Lasarev MR, Bammler TK, Beyer RP, Churchwell M, Doerge DR, Meira LB, Palmer VS, Ramos-Crawford AL, Ren X, Sullivan RC, Kavanagh TJ, Samson LD, Zarbl H, Spencer PS. (2011). The cycad genotoxin MAM modulates brain cellular pathways involved in neurodegenerative disease and cancer in a DNA damage-linked manner. PLoS ONE 6:e20911.
   Google Scholar
• Kitazawa E, Tamura N, Iwabuchi H, Uchiyama M, Muramatsu S, Takahagi H, Tanaka M. (1993). Biotransformation of pravastatin sodium (I). Mechanisms of enzymic transformation and epimerization of an allylic hydroxy group of pravastatin sodium. Biochem Biophys Res Commun 192:597–602.
   PubMed Web of Science ®Google Scholar
• Kling DE, Cavicchio AJ, Sollinger CA, Schnitzer JJ, Kinane TB, Newburg DS. (2010). Nitrofen induces apoptosis independently of retinaldehyde dehydrogenase (RALDH) inhibition. Birth Defects Res B Dev Reprod Toxicol 89:223–232.
   PubMedGoogle Scholar
• Kling DE, Schnitzer JJ. (2007). Vitamin A deficiency (VAD), teratogenic, and surgical models of congenital diaphragmatic hernia (CDH). Am J Med Genet C Semin Med Genet 145C:139–157.
   PubMedGoogle Scholar
• Knight A. (2007). Animal experiments scrutinised: systematic reviews demonstrate poor human clinical and toxicological utility. ALTEX 24:320–325.
   PubMed Web of Science ®Google Scholar
• Koçtürk S, Oktay G, Güner G, Pekçetin C, Güre A. (2006). Effect of D-penicillamine on rat lung elastin cross-linking during the perinatal period. Cell Biochem Funct 24:167–172.
   PubMedGoogle Scholar
• Krämer BK, Bergler T, Stoelcker B, Waldegger S. (2008). Mechanisms of Disease: the kidney-specific chloride channels ClCKA and ClCKB, the Barttin subunit, and their clinical relevance. Nat Clin Pract Nephrol 4:38–46.
   PubMedGoogle Scholar
• Kristensen M, Juel C. (2010). Potassium-transporting proteins in skeletal muscle: cellular location and fibre-type differences. Acta Physiol (Oxf) 198:105–123.
   PubMedGoogle Scholar
• Kulman JD, Harris JE, Xie L, Davie EW. (2007). Proline-rich Gla protein 2 is a cell-surface vitamin K-dependent protein that binds to the transcriptional coactivator Yes-associated protein. Proc Natl Acad Sci USA 104:8767–8772.
   PubMed Web of Science ®Google Scholar
• Lakics V, Karran EH, Boess FG. (2010). Quantitative comparison of phosphodiesterase mRNA distribution in human brain and peripheral tissues. Neuropharmacology 59:367–374.
   PubMed Web of Science ®Google Scholar
• Lee H, Nagele RG. (1979). Neural tube closure defects caused by papaverine in explanted early chick embryos. Teratology 20:321–331.
   PubMedGoogle Scholar
• Lee JH, Han DH. (1995). Maternal and fetal toxicity of methylmercuric chloride administered to pregnant Fischer 344 rats. J Toxicol Environ Health 45:415–425.
   PubMed Web of Science ®Google Scholar
• Lee MH, Cho YS, Han YM. (2007). Simvastatin suppresses self-renewal of mouse embryonic stem cells by inhibiting RhoA geranylgeranylation. Stem Cells 25:1654–1663.
   PubMed Web of Science ®Google Scholar
• Lengner CJ, Gimelbrant AA, Erwin JA, Cheng AW, Guenther MG, Welstead GG, Alagappan R, Frampton GM, Xu P, Muffat J, Santagata S, Powers D, Barrett CB, Young RA, Lee JT, Jaenisch R, Mitalipova M. (2010). Derivation of pre-X inactivation human embryonic stem cells under physiological oxygen concentrations. Cell 141:872–883.
   PubMed Web of Science ®Google Scholar
• Li T, Chang CY, Jin DY, Lin PJ, Khvorova A, Stafford DW. (2004). Identification of the gene for vitamin K epoxide reductase. Nature 427:541–544.
   PubMed Web of Science ®Google Scholar
• Liochev SI, Fridovich I. (2010). Mechanism of the peroxidase activity of Cu, Zn superoxide dismutase. Free Radic Biol Med 48:1565–1569.
   PubMed Web of Science ®Google Scholar
• LoPachin RM, Barber DS. (2006). Synaptic cysteine sulfhydryl groups as targets of electrophilic neurotoxicants. Toxicol Sci 94:240–255.
   PubMed Web of Science ®Google Scholar
• MacGregor JT, Schlegel R, Wehr CM, Alperin P, Ames BN. (1990). Cytogenetic damage induced by folate deficiency in mice is enhanced by caffeine. Proc Natl Acad Sci USA 87:9962–9965.
   PubMed Web of Science ®Google Scholar
• Manson JM. (1986). Mechanism of nitrofen teratogenesis. Environ Health Perspect 70:137–147.
   PubMed Web of Science ®Google Scholar
• Martini C, Trapani L, Narciso L, Marino M, Trentalance A, Pallottini V. (2009). 3-hydroxy 3-methylglutaryl coenzyme A reductase increase is essential for rat muscle differentiation. J Cell Physiol 220:524–530.
   PubMed Web of Science ®Google Scholar
• Marx-Stoelting P, Adriaens E, Ahr HJ, Bremer S, Garthoff B, Gelbke HP, Piersma A, Pellizzer C, Reuter U, Rogiers V, Schenk B, Schwengberg S, Seiler A, Spielmann H, Steemans M, Stedman DB, Vanparys P, Vericat JA, Verwei M, van der Water F, Weimer M, Schwarz M. (2009). A review of the implementation of the embryonic stem cell test (EST). The report and recommendations of an ECVAM/ReProTect Workshop. Altern Lab Anim 37:313–328.
   PubMed Web of Science ®Google Scholar
• Matok I, Gorodischer R, Koren G, Sheiner E, Wiznitzer A, Levy A. (2009). The safety of metoclopramide use in the first trimester of pregnancy. N Engl J Med 360:2528–2535.
   PubMed Web of Science ®Google Scholar
• Matsumoto M, Fujii S, Hirose A, Ema M. (2010). Prenatal developmental toxicity of gavage or feeding doses of 2-sec-butyl-4,6-dinitrophenol in rats. Reprod Toxicol 29:292–297.
   PubMedGoogle Scholar
• Matsumoto M, Poncipe C, Ema M. (2008). Review of developmental toxicity of nitrophenolic herbicide dinoseb, 2-sec-butyl-4,6-dinitrophenol. Reprod Toxicol 25:327–334.
   PubMedGoogle Scholar
• McBride WG, Hicks LJ. (1987). Acetylcholine and choline levels in rabbit fetuses exposed to anticholinergics. Int J Dev Neurosci 5:117–125.
   PubMedGoogle Scholar
• Mendelsohn C, Lohnes D, Décimo D, Lufkin T, LeMeur M, Chambon P, Mark M. (1994). Function of the retinoic acid receptors (RARs) during development (II). Multiple abnormalities at various stages of organogenesis in RAR double mutants. Development 120:2749–2771.
   PubMed Web of Science ®Google Scholar
• Mensch J, Oyarzabal J, Mackie C, Augustijns P. (2009). In vivo, in vitro and in silico methods for small molecule transfer across the BBB. J Pharm Sci 98:4429–4468.
   PubMed Web of Science ®Google Scholar
• Mey J, Babiuk RP, Clugston R, Zhang W, Greer JJ. (2003). Retinal dehydrogenase-2 is inhibited by compounds that induce congenital diaphragmatic hernias in rodents. Am J Pathol 162:673–679.
   PubMed Web of Science ®Google Scholar
• Minsker DH, MacDonald JS, Robertson RT, Bokelman DL. (1983). Mevalonate supplementation in pregnant rats suppresses the teratogenicity of mevinolinic acid, an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme a reductase. Teratology 28:449–456.
   PubMedGoogle Scholar
• Miskon A, Mahara A, Uyama H, Yamaoka T. (2010). A suspension induction for myocardial differentiation of rat mesenchymal stem cells on various extracellular matrix proteins. Tissue Eng Part C Methods 16:979–987.
   PubMedGoogle Scholar
• Mizuta E, Shirai M, Arakawa K, Hidaka K, Miake J, Ninomiya H, Kato M, Shigemasa C, Shirayoshi Y, Hisatome I, Morisaki T. (2010). Different distribution of Cav3.2 and Cav3.1 transcripts encoding T-type Ca(2+) channels in the embryonic heart of mice. Biomed Res 31:301–305.
   PubMed Web of Science ®Google Scholar
• Molnar J, Fong KS, He QP, Hayashi K, Kim Y, Fong SF, Fogelgren B, Szauter KM, Mink M, Csiszar K. (2003). Structural and functional diversity of lysyl oxidase and the LOX-like proteins. Biochim Biophys Acta 1647:220–224.
   PubMed Web of Science ®Google Scholar
• Moore H, Jentsch JD, Ghajarnia M, Geyer MA, Grace AA. (2006). A neurobehavioral systems analysis of adult rats exposed to methylazoxymethanol acetate on E17: implications for the neuropathology of schizophrenia. Biol Psychiatry 60:253–264.
   PubMed Web of Science ®Google Scholar
• Moraes AP, Schwarz A, Spinosa HS, Florio JC, Bernardi MM. (2004). Maternal exposure to diphenhydramine during the fetal period in rats: effects on physical and neurobehavioral development and on neurochemical parameters. Neurotoxicol Teratol 26:681–692.
   PubMedGoogle Scholar
• Moran D, Rice RW. (1976). Action of papaverine and ionophore A23187 on neurulation. Nature 261:497–499.
   PubMedGoogle Scholar
• Moreland DE. (1999). Biochemical mechanisms of action of herbicides and the impact of biotechnology on the development of herbicides. J Pesticide Sci 24, 299–307.
   Google Scholar
• Morgan RW, Hoffmann GR. (1983). Cycasin and its mutagenic metabolites. Mutat Res 114:19–58.
   PubMedGoogle Scholar
• Morris AJ, Malbon CC. (1999). Physiological regulation of G protein-linked signaling. Physiol Rev 79:1373–1430.
   PubMed Web of Science ®Google Scholar
• Mosmann T. (1983). Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods 65:55–63.
   PubMed Web of Science ®Google Scholar
• Murshed M, Schinke T, McKee MD, Karsenty G. (2004). Extracellular matrix mineralization is regulated locally; different roles of two gla-containing proteins. J Cell Biol 165:625–630.
   PubMed Web of Science ®Google Scholar
• Myint B. (1984). D-penicillamine-induced cleft palate in mice. Teratology 30:333–340.
   PubMedGoogle Scholar
• Nagasawa HT, Shirota FN, Matsumoto H. (1972). Decomposition of methylazoxymethanol, the aglycone of cycasin, in D 2 O. Nature 236:234–235.
   PubMed Web of Science ®Google Scholar
• Nakatsuka T, Fujikake N, Hasebe M, Ikeda H. (1993). Effects of sodium bicarbonate and ammonium chloride on the incidence of furosemide-induced fetal skeletal anomaly, wavy rib, in rats. Teratology 48:139–147.
   PubMedGoogle Scholar
• Napoletano M, Pennino D, Izzo G, de Maria S, Ottaviano R, Ricciardi M, Mancini R, Schiattarella A, Farina E, Metafora S, Cartenì M, Ritieni A, Minucci S, Morelli F. (2010). Ochratoxin A induces craniofacial malformation in mice acting on Dlx5 gene expression. Front Biosci (Elite Ed) 2:133–142.
   PubMedGoogle Scholar
• National Research Council. Toxicity Testing in the 21st Century: A Vision and a Strategy. (2007). Washington, DC, National Academy Press.
   Google Scholar
• Newland MC, Paletz EM, Reed MN. (2008). Methylmercury and nutrition: adult effects of fetal exposure in experimental models. Neurotoxicology 29:783–801.
   PubMedGoogle Scholar
• Noble BR, Babiuk RP, Clugston RD, Underhill TM, Sun H, Kawaguchi R, Walfish PG, Blomhoff R, Gundersen TE, Greer JJ. (2007). Mechanisms of action of the congenital diaphragmatic hernia-inducing teratogen nitrofen. Am J Physiol Lung Cell Mol Physiol 293:L1079–L1087.
   PubMed Web of Science ®Google Scholar
• Notman J, Tan QH, Zedeck MS. (1982). Inhibition of methylazoxymethanol-induced intestinal tumors in the rat by pyrazole with paradoxical effects on skin and kidney. Cancer Res 42:1774–1780.
   PubMed Web of Science ®Google Scholar
• O’Brien E, Dietrich DR. (2005). Ochratoxin A: the continuing enigma. Crit Rev Toxicol 35:33–60.
   PubMed Web of Science ®Google Scholar
• OECD. Final report of the OECD Workshop on Harmonisation of Validation and Acceptance Criteria for Alternative Toxicological Test Methods. 1996. Paris, France, Organisation for Economic Co-operation and Development.
   Google Scholar
• Paquette JA, Kumpf SW, Streck RD, Thomson JJ, Chapin RE, Stedman DB. (2008). Assessment of the Embryonic Stem Cell Test and application and use in the pharmaceutical industry. Birth Defects Res B Dev Reprod Toxicol 83:104–111.
   PubMed Web of Science ®Google Scholar
• Parenti G, Meroni G, Ballabio A. (1997). The sulfatase gene family. Curr Opin Genet Dev 7:386–391.
   PubMed Web of Science ®Google Scholar
• Pasutto F, Sticht H, Hammersen G, Gillessen-Kaesbach G, Fitzpatrick DR, Nürnberg G, Brasch F, Schirmer-Zimmermann H, Tolmie JL, Chitayat D, Houge G, Fernández-Martínez L, Keating S, Mortier G, Hennekam RC, von der Wense A, Slavotinek A, Meinecke P, Bitoun P, Becker C, Nürnberg P, Reis A, Rauch A. (2007). Mutations in STRA6 cause a broad spectrum of malformations including anophthalmia, congenital heart defects, diaphragmatic hernia, alveolar capillary dysplasia, lung hypoplasia, and mental retardation. Am J Hum Genet 80:550–560.
   PubMed Web of Science ®Google Scholar
• Patil RD, Dwivedi P, Sharma AK. (2006). Critical period and minimum single oral dose of ochratoxin A for inducing developmental toxicity in pregnant Wistar rats. Reprod Toxicol 22:679–687.
   PubMed Web of Science ®Google Scholar
• Pazos P, Pellizzer C, Stummann TC, Hareng L, Bremer S. (2010). The test chemical selection procedure of the European Centre for the Validation of Alternative Methods for the EU Project ReProTect. Reprod Toxicol 30:161–199.
   PubMedGoogle Scholar
• Peters AK, Steemans M, Hansen E, Mesens N, Verheyen GR, Vanparys P. (2008a). Evaluation of the embryotoxic potency of compounds in a newly revised high throughput embryonic stem cell test. Toxicol Sci 105:342–350.
   PubMed Web of Science ®Google Scholar
• Peters AK, Wouwer GV, Weyn B, Verheyen GR, Vanparys P, Gompel JV. (2008b). Automated analysis of contractility in the embryonic stem cell test, a novel approach to assess embryotoxicity. Toxicol In Vitro 22:1948–1956.
   PubMed Web of Science ®Google Scholar
• Pfohl-Leszkowicz A. (2009). Ochratoxin A and aristolochic acid involvement in nephropathies and associated urothelial tract tumours. Arh Hig Rada Toksikol 60:465–483.
   PubMed Web of Science ®Google Scholar
• Pinter R, Hogge WA, McPherson E. (2004). Infant with severe penicillamine embryopathy born to a woman with Wilson disease. Am J Med Genet A 128A:294–298.
   PubMedGoogle Scholar
• Preache MM, Gibson JE. (1975). Effects in mice of high and low environmental temperature on the maternal and fetal toxicity of 2-sec-butyl-4,6-dinitrophenol (dinoseb) and on disposition of [14C]-dinoseb(12). Teratology 12:147–156.
   PubMedGoogle Scholar
• Priebe HJ. (2007). Aneurysmal subarachnoid haemorrhage and the anaesthetist. Br J Anaesth 99:102–118.
   PubMed Web of Science ®Google Scholar
• Quion JA, Jones PH. (1994). Clinical pharmacokinetics of pravastatin. Clin Pharmacokinet 27:94–103.
   PubMed Web of Science ®Google Scholar
• Reidy JA, Zhou X, Chen AT. (1983). Folic acid and chromosome breakage. I. Implications for genotoxicity studies. Mutat Res 122:217–221.
   PubMedGoogle Scholar
• Riebeling C, Pirow R, Becker K, Buesen R, Eikel D, Kaltenhäuser J, Meyer F, Nau H, Slawik B, Visan A, Volland J, Spielmann H, Luch A, Seiler A. (2011a). The embryonic stem cell test as tool to assess structure-dependent teratogenicity: the case of valproic acid. Toxicol Sci 120:360–370.
   PubMed Web of Science ®Google Scholar
• Riebeling C, Schlechter K, Buesen R, Spielmann H, Luch A, Seiler A. (2011b). Defined culture medium for stem cell differentiation: applicability of serum-free conditions in the mouse embryonic stem cell test. Toxicol In Vitro 25:914–921.
   PubMedGoogle Scholar
• Ringot D, Chango A, Schneider YJ, Larondelle Y. (2006). Toxicokinetics and toxicodynamics of ochratoxin A, an update. Chem Biol Interact 159:18–46.
   PubMed Web of Science ®Google Scholar
• Rosa FW. (1986). Teratogen update: penicillamine. Teratology 33:127–131.
   PubMedGoogle Scholar
• Rovida C, Hartung T. (2009). Re-evaluation of animal numbers and costs for in vivo tests to accomplish REACH legislation requirements for chemicals - a report by the transatlantic think tank for toxicology (t(4)). ALTEX 26:187–208.
   PubMed Web of Science ®Google Scholar
• Rumora L, Grubisic TZ. (2009). A journey through mitogen-activated protein kinase and ochratoxin A interactions. Arh Hig Rada Toksikol 60:449–456.
   PubMedGoogle Scholar
• Russell JM. (2000). Sodium-potassium-chloride cotransport. Physiol Rev 80:211–276.
   PubMed Web of Science ®Google Scholar
• Sakamoto M, Murata K, Tsuruta K, Miyamoto K, Akagi H. (2010). Retrospective study on temporal and regional variations of methylmercury concentrations in preserved umbilical cords collected from inhabitants of the Minamata area, Japan. Ecotoxicol Environ Saf 73:1144–1149.
   PubMed Web of Science ®Google Scholar
• Sanger GJ. (2009). Translating 5-HT receptor pharmacology. Neurogastroenterol Motil 21:1235–1238.
   PubMed Web of Science ®Google Scholar
• Schaefer L, Ballabio A, Zoghbi HY. (1996). Cloning and characterization of a putative human holocytochrome c-type synthetase gene (HCCS) isolated from the critical region for microphthalmia with linear skin defects (MLS). Genomics 34:166–172.
   PubMedGoogle Scholar
• Schardein JL, Keller KA. (1989). Potential human developmental toxicants and the role of animal testing in their identification and characterization. Crit Rev Toxicol 19:251–339.
   PubMed Web of Science ®Google Scholar
• Schenk B, Weimer M, Bremer S, van der Burg B, Cortvrindt R, Freyberger A, Lazzari G, Pellizzer C, Piersma A, Schäfer WR, Seiler A, Witters H, Schwarz M. (2010). The ReProTect Feasibility Study, a novel comprehensive in vitro approach to detect reproductive toxicants. Reprod Toxicol 30:200–218.
   PubMed Web of Science ®Google Scholar
• Schmidt S, Gonzalez D, Derendorf H. (2010). Significance of protein binding in pharmacokinetics and pharmacodynamics. J Pharm Sci 99:1107–1122.
   PubMed Web of Science ®Google Scholar
• Schneider D, Wink M, Sporer F, Lounibos P. (2002). Cycads: their evolution, toxins, herbivores and insect pollinators. Naturwissenschaften 89:281–294.
   PubMed Web of Science ®Google Scholar
• Scholz G, Genschow E, Pohl I, Bremer S, Paparella M, Raabe H, Southee J, Spielmann H. (1999). Prevalidation of the Embryonic Stem Cell Test (EST)-A New In Vitro Embryotoxicity Test. Toxicol In Vitro 13:675–681.
   PubMed Web of Science ®Google Scholar
• Seiler A, Visan A, Buesen R, Genschow E, Spielmann H. (2004). Improvement of an in vitro stem cell assay for developmental toxicity: the use of molecular endpoints in the embryonic stem cell test. Reprod Toxicol 18:231–240.
   PubMed Web of Science ®Google Scholar
• Seiler AE, Buesen R, Visan A, Spielmann H. (2006). Use of murine embryonic stem cells in embryotoxicity assays: the embryonic stem cell test. Methods Mol Biol 329:371–395.
   PubMedGoogle Scholar
• Seiler AE, Spielmann H. (2011). The validated embryonic stem cell test to predict embryotoxicity in vitro. Nat Protoc 6:961–978.
   PubMed Web of Science ®Google Scholar
• Sharma A, Hamelin BA. (2003). Classic histamine H1 receptor antagonists: a critical review of their metabolic and pharmacokinetic fate from a bird’s eye view. Curr Drug Metab 4:105–129.
   PubMed Web of Science ®Google Scholar
• Sievert HW, Lipton SH, Strong FM. (1960). Quantitative determination of cyanoacetic acid as an enzymic product of beta-aminopropionitrile. Arch Biochem Biophys 86:311–316.
   PubMedGoogle Scholar
• Sinicropi MS, Amantea D, Caruso A, Saturnino C. (2010). Chemical and biological properties of toxic metals and use of chelating agents for the pharmacological treatment of metal poisoning. Arch Toxicol 84:501–520.
   PubMed Web of Science ®Google Scholar
• Siuciak JA, Chapin DS, Harms JF, Lebel LA, McCarthy SA, Chambers L, Shrikhande A, Wong S, Menniti FS, Schmidt CJ. (2006). Inhibition of the striatum-enriched phosphodiesterase PDE10A: a novel approach to the treatment of psychosis. Neuropharmacology 51:386–396.
   PubMed Web of Science ®Google Scholar
• Smedley MJ, Stanisstreet M. (1986). Calcium and neurulation in mammalian embryos. II. Effects of cytoskeletal inhibitors and calcium antagonists on the neural folds of rat embryos. J Embryol Exp Morphol 93:167–178.
   PubMedGoogle Scholar
• Smith MB, Feldman W. (1993). Over-the-counter cold medications. A critical review of clinical trials between 1950 and 1991. JAMA 269:2258–2263.
   PubMed Web of Science ®Google Scholar
• Spielmann H, Pohl I, Döring B, Liebsch M, Moldenhauer F. (1997). The Embryonic Stem cell Test, an in vitro embryotoxicity test using two permanent mouse cell lines: 3T3 fibroblasts and embryonic stem cells. In Vitro Mol Toxicol J Basic Appl Res 10, 119–127.
   Google Scholar
• Stolper G, Klausner M, Sheasgreen J, Hayden P. (2005). Development of an in vitro blood-brain barrier model for brain disposition screening of pharmaceuticals. The Toxicologist 84, 257.
   Google Scholar
• Stummann TC, Hareng L, Bremer S. (2007). Embryotoxicity hazard assessment of methylmercury and chromium using embryonic stem cells. Toxicology 242:130–143.
   PubMedGoogle Scholar
• Suarez-Almazor ME, Spooner C, Belseck E. (2000). Penicillamine for treating rheumatoid arthritis. Cochrane Database Syst Rev (4): CD001460.
   Google Scholar
• Sutherland GR. (1979). Heritable fragile sites on human chromosomes I. Factors affecting expression in lymphocyte culture. Am J Hum Genet 31:125–135.
   PubMed Web of Science ®Google Scholar
• Taglialatela M, Timmerman H, Annunziato L. (2000). Cardiotoxic potential and CNS effects of first-generation antihistamines. Trends Pharmacol Sci 21:52–56.
   PubMed Web of Science ®Google Scholar
• Taguchi N, Rubin ET, Hosokawa A, Choi J, Ying AY, Moretti ME, Koren G, Ito S. (2008). Prenatal exposure to HMG-CoA reductase inhibitors: effects on fetal and neonatal outcomes. Reprod Toxicol 26:175–177.
   PubMed Web of Science ®Google Scholar
• Takahashi N, Chernavvsky DR, Gomez RA, Igarashi P, Gitelman HJ, Smithies O. (2000). Uncompensated polyuria in a mouse model of Bartter’s syndrome. Proc Natl Acad Sci USA 97:5434–5439.
   PubMedGoogle Scholar
• Takai Y, Sasaki T, Matozaki T. (2001). Small GTP-binding proteins. Physiol Rev 81:153–208.
   PubMed Web of Science ®Google Scholar
• Tanaka E, Ishikawa A, Abei M, Kobayashi S. (1996). Trimethadione as a probe drug to estimate hepatic oxidizing capacity in humans. Comp Biochem Physiol C, Pharmacol Toxicol Endocrinol 115:211–216.
   PubMed Web of Science ®Google Scholar
• Tang SS, Trackman PC, Kagan HM. (1983). Reaction of aortic lysyl oxidase with beta-aminopropionitrile. J Biol Chem 258:4331–4338.
   PubMed Web of Science ®Google Scholar
• Tarín JJ, Ten J, Vendrell FJ, Cano A. (1998). Dithiothreitol prevents age-associated decrease in oocyte/conceptus viability in vitro. Hum Reprod 13:381–386.
   Google Scholar
• Theunissen PT, Schulpen SH, van Dartel DA, Hermsen SA, van Schooten FJ, Piersma AH. (2010). An abbreviated protocol for multilineage neural differentiation of murine embryonic stem cells and its perturbation by methyl mercury. Reprod Toxicol 29:383–392.
   PubMed Web of Science ®Google Scholar
• Timmerman H. (1999). Why are non-sedating antihistamines non-sedating? Clin Exp Allergy 29 Suppl 3:13–18.
   PubMedGoogle Scholar
• Tong S, Yao Q, Wan Y, Zhou J, Shu M, Zhong L, Li Y, Zhang Q, Yindai J, Song Z. (2009). Development of functional I f channels in mMSCs after transfection with mHCN4: effects on cell morphology and mechanical activity in vitro. Cardiology 112:114–121.
   PubMedGoogle Scholar
• Tonini M, Cipollina L, Poluzzi E, Crema F, Corazza GR, De Ponti F. (2004). Review article: clinical implications of enteric and central D2 receptor blockade by antidopaminergic gastrointestinal prokinetics. Aliment Pharmacol Ther 19:379–390.
   PubMed Web of Science ®Google Scholar
• Torres Pazmiño DE, Winkler M, Glieder A, Fraaije MW. (2010). Monooxygenases as biocatalysts: Classification, mechanistic aspects and biotechnological applications. J Biotechnol 146:9–24.
   PubMedGoogle Scholar
• Tsujita Y, Kuroda M, Shimada Y, Tanzawa K, Arai M, Kaneko I, Tanaka M, Masuda H, Tarumi C, Watanabe Y. (1986). CS-514, a competitive inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase: tissue-selective inhibition of sterol synthesis and hypolipidemic effect on various animal species. Biochim Biophys Acta 877:50–60.
   PubMed Web of Science ®Google Scholar
• Turpeinen M, Ghiciuc C, Opritoui M, Tursas L, Pelkonen O, Pasanen M. (2007). Predictive value of animal models for human cytochrome P450 (CYP)-mediated metabolism: a comparative study in vitro. Xenobiotica 37:1367–1377.
   PubMed Web of Science ®Google Scholar
• Tyl RW, Price CJ, Marr MC, Kimmel CA. (1988). Developmental toxicity evaluation of Bendectin in CD rats. Teratology 37:539–552.
   PubMedGoogle Scholar
• Uibel F, Mühleisen A, Köhle C, Weimer M, Stummann TC, Bremer S, Schwarz M. (2010). ReProGlo: a new stem cell-based reporter assay aimed to predict embryotoxic potential of drugs and chemicals. Reprod Toxicol 30:103–112.
   PubMed Web of Science ®Google Scholar
• Ullrich SM, Tanton TW, Abdrashitova SA. (2001). Mercury in the aquatic environment: A review of factors affecting methylation. Crit Rev Env Sci Tec 31, 241–293.
   Web of Science ®Google Scholar
• Uriu-Adams JY, Scherr RE, Lanoue L, Keen CL. (2010). Influence of copper on early development: prenatal and postnatal considerations. Biofactors 36:136–152.
   PubMed Web of Science ®Google Scholar
• Vacher H, Mohapatra DP, Trimmer JS. (2008). Localization and targeting of voltage-dependent ion channels in mammalian central neurons. Physiol Rev 88:1407–1447.
   PubMed Web of Science ®Google Scholar
• van Assche CJ, Carles PM. Photosystem-II Inhibiting Chemicals - Molecular Interaction Between Inhibitors and A Common Target. ACS Symposium Series 181, 1-21. 11-2-1982. Washington, DC, USA, American Chemical Society. Biochemical Responses Induced by Herbicides. Moreland DE.
   Google Scholar
• van Dartel DA, Pennings JL, de la Fonteyne LJ, van Herwijnen MH, van Delft JH, van Schooten FJ, Piersma AH. (2010). Monitoring developmental toxicity in the embryonic stem cell test using differential gene expression of differentiation-related genes. Toxicol Sci 116:130–139.
   PubMed Web of Science ®Google Scholar
• van der Valk, Brunner D, De SK, Fex SA, Honegger P, Knudsen LE, Lindl T, Noraberg J, Price A, Scarino ML, Gstraunthaler G. (2010). Optimization of chemically defined cell culture media--Replacing fetal bovine serum in mammalian in vitro methods. Toxicol In Vitro 24, 1053–1063.
   PubMedGoogle Scholar
• van Driel D, Wesseling J, Sauer PJ, Touwen BC, van der Veer E, Heymans HS. (2002). Teratogen update: fetal effects after in utero exposure to coumarins overview of cases, follow-up findings, and pathogenesis. Teratology 66:127–140.
   PubMedGoogle Scholar
• Verwei M, van Burgsteden JA, Krul CA, van de Sandt JJ, Freidig AP. (2006). Prediction of in vivo embryotoxic effect levels with a combination of in vitro studies and PBPK modelling. Toxicol Lett 165:79–87.
   PubMed Web of Science ®Google Scholar
• Viant MR, Pincetich CA, Hinton DE, Tjeerdema RS. (2006). Toxic actions of dinoseb in medaka (Oryzias latipes) embryos as determined by in vivo 31P NMR, HPLC-UV and 1H NMR metabolomics. Aquat Toxicol 76:329–342.
   PubMed Web of Science ®Google Scholar
• Voisin EM, Ruthsatz M, Collins JM, Hoyle PC. (1990). Extrapolation of animal toxicity to humans: interspecies comparisons in drug development. Regul Toxicol Pharmacol 12:107–116.
   PubMed Web of Science ®Google Scholar
• Wallin R, Hutson SM. (2004). Warfarin and the vitamin K-dependent gamma-carboxylation system. Trends Mol Med 10:299–302.
   PubMed Web of Science ®Google Scholar
• Walton K, Dorne JLCM, Renwick AG. (2001). Default factors for interspecies differences in the major routes of xenobiotic elimination. Human Ecol. Risk Assessment 7:181–201.
   Web of Science ®Google Scholar
• Wardrop D, Keeling D. (2008). The story of the discovery of heparin and warfarin. Br J Haematol 141:757–763.
   PubMed Web of Science ®Google Scholar
• Waterman RE. (1979). Scanning electron microscope studies of central nervous system development. Birth Defects Orig Artic Ser 15:55–77.
   PubMedGoogle Scholar
• Watterson K, Sankala H, Milstien S, Spiegel S. (2003). Pleiotropic actions of sphingosine-1-phosphate. Prog Lipid Res 42:344–357.
   PubMedGoogle Scholar
• Whitlow S, Bürgin H, Clemann N. (2007). The embryonic stem cell test for the early selection of pharmaceutical compounds. ALTEX 24:3–7.
   PubMedGoogle Scholar
• Wiley MJ, Joneja MG. (1976). The teratogenic effects of beta-aminopropionitrile in hamsters. Teratology 14:43–52.
   PubMedGoogle Scholar
• Wiley MJ, Joneja MG. (1978). Neural tube lesions in the offspring of hamsters given single oral doses of lathyrogens early in gestation. Acta Anat (Basel) 100:347–353.
   PubMedGoogle Scholar
• Williams DP, Antoine DJ, Butler PJ, Jones R, Randle L, Payne A, Howard M, Gardner I, Blagg J, Park BK. (2007). The metabolism and toxicity of furosemide in the Wistar rat and CD-1 mouse: a chemical and biochemical definition of the toxicophore. J Pharmacol Exp Ther 322:1208–1220.
   PubMed Web of Science ®Google Scholar
• Wilson JG, Roth CB, Warkany J. (1953). An analysis of the syndrome of malformations induced by maternal vitamin A deficiency. Effects of restoration of vitamin A at various times during gestation. Am J Anat 92:189–217.
   PubMedGoogle Scholar
• Yasuda Y, Datu AR, Hirata S, Fujimoto T. (1985). Characteristics of growth and palatal shelf development in ICR mice after exposure to methylmercury. Teratology 32:273–286.
   PubMedGoogle Scholar
• zur Nieden NI, Davis LA, Rancourt DE. (2010). Comparing three novel endpoints for developmental osteotoxicity in the embryonic stem cell test. Toxicol Appl Pharmacol 247:91–97.
   PubMed Web of Science ®Google Scholar