443
Views
66
CrossRef citations to date
0
Altmetric
Review

The mechanisms of cyclophosphamide-induced testicular toxicity and the protective agents

, , &
Pages 525-536 | Received 01 Sep 2016, Accepted 23 Dec 2016, Published online: 29 Dec 2016

References

  • Ahmed AR, Hombal SM. Cyclophosphamide (Cytoxan): a review on relevant pharmacology and clinical uses. J Am Acad Dermatol. 1984;11:1115–1126.
  • Vernet P, Aitken R, Drevet J. Antioxidant strategies in the epididymis. Mol Cell Endocrinol. 2004;216:31–39.
  • Aguilar-Mahecha A, Hales BF, Robaire B. Acute cyclophosphamide exposure has germ cell specific effects on the expression of stress response genes during rat spermatogenesis. Mol Reprod Dev. 2001;60:302–311.
  • Trasler JM, Hales B, Robaire B. A time-course study of chronic paternal cyclophosphamide treatment in rats: effects on pregnancy outcome and the male reproductive and hematologic systems. Biol Reprod. 1987;37:317–326.
  • Trasler JM, Hermo L, Robaire B. Morphological changes in the testis and epididymis of rats treated with cyclophosphamide: a quantitative approach. Biol Reprod. 1988;38:463–479.
  • Trasler JM, Robaire B. Effects of cyclophosphamide on selected cytosolic and mitochondrial enzymes in the epididymis of the rat. J Androl. 1988;9:142–152.
  • Hoorweg-Nijman JJ, Delemarre-Van De Waal HA, De Waal FC, et al. Cyclophosphamide-induced disturbance of gonadotropin secretion manifesting testicular damage. Acta Endocrinol. 1992;126:143–148.
  • Aguilar-Mahecha A, Hales BF, Robaire B. Chronic cyclophosphamide treatment alters the expression of stress response genes in rat male germ cells. Biol Reprod. 2002;66:1024–1032.
  • Kehrer JP, Biswal SS. The molecular effects of acrolein. Toxicol Sci. 2000;57:6–15.
  • Roy J, Pallepati P, Bettaieb A, et al. Acrolein induces a cellular stress response and triggers mitochondrial apoptosis in A549 cells. ‎Chem Biol Interact. 2009;181:154–167.
  • Adams JD, Klaidman LK. Acrolein-induced oxygen radical formation. ‎Free Radic Biol Med. 1993;15:187–193.
  • Vernet P, Aitken RJ, Drevet JR. Antioxidant strategies in the epididymis. Mol Cell Endocrinol. 2004;216:31–39.
  • Abd EI Tawab AM, Shahin NN, AbdelMohsen MM. Protective effect of Satureja montana extract on cyclophosphamide-induced testicular injury in rats. Chem Biol Interact. 2014;224:196–205.
  • Connolly KJ, Edelmann RJ, Cooke ID, et al. The impact of infertility on psychological functioning. J Psychosom Res. 1992;36:459–468.
  • Meistrich ML, Shetty G. Hormonal suppression for fertility preservation in males and females. Reproduction. 2008;136:691–701.
  • Rezvanfar MA, Rezvanfar MA, Shahverdi AR, et al. Protection of cisplatin-induced spermatotoxicity, DNA damage and chromatin abnormality by selenium nano-particles. Toxicol Appl Pharmacol. 2013;266:356–365.
  • Elangovan N, Chiou T-J, Tzeng W-F, et al. Cyclophosphamide treatment causes impairment of sperm and its fertilizing ability in mice. Toxicology. 2006;222:60–70.
  • Jana K, Jana S, Samanta PK. Effects of chronic exposure to sodium arsenite on hypothalamo-pituitary-testicular activities in adult rats: possible an estrogenic mode of action. Reprod Biol Endocrinol. 2006;4:9.
  • Selvakumar E, Prahalathan C, Mythili Y, et al. Beneficial effects of dl-alpha-lipoic acid on cyclophosphamide-induced oxidative stress in mitochondrial fractions of rat testis. Chem Biol Interact. 2005;152:59–66.
  • De Lamirande E, Gagnon C. Reactive oxygen species and human spermatozoa. II. Depletion of adenosine triphosphate plays an important role in the inhibition of sperm motility. J Androl. 1992;13:379–386.
  • Ghosh D, Das UB, Ghosh S, et al. Testicular gametogenic and steroidogenic activities in cyclophosphamide treated rat: a correlative study with testicular oxidative stress. Drug Chem Toxicol. 2002;25:281–292.
  • Das UB, Mallick M, Debnath JM. Protective effect of ascorbic acid on cyclophosphamide-induced testicular gametogenic and androgenic disorders in male rats. Asian J Androl. 2002;4:201–207.
  • Aitken RJ, Roman SD. Antioxidant systems and oxidative stress in the testes. Oxid Med Cell Longev. 2008;1:15–24.
  • Badade ZG, Samant PM. Role of oxidative stress in male infertility. J Biomed Sci Res. 2011;3:385–391.
  • Agarwal A, Virk G, Ong C, et al. Effect of oxidative stress on male reproduction. World J Mens Health. 2014;32:1–17.
  • Ma Q. Role of Nrf2 in oxidative stress and toxicity. Annu Rev Pharmacol Toxicol. 2013;53:401–426.
  • Türk G, Çeribaşi AO, Sakin F. Antiperoxidative and anti-apoptotic effects of lycopene and ellagic acid on cyclophosphamide-induced testicular lipid peroxidation and apoptosis. Reprod Fertil Dev. 2010;22:587–596.
  • Dinkova-Kostova AT, Abramov AY. The emerging role of Nrf2 in mitochondrial function. ‎Free Radic Biol Med. 2015;88:179–188.
  • Ucar M, Korkmaz A, Reiter RJ. Melatonin alleviates lung damage induced by the chemical warfare agent nitrogen mustard. Toxicol Lett. 2007;173:124–131.
  • Motawi TMK, Sadik NAH, Refaat A. Cytoprotective effects of DL-alpha-lipoic acid or squalene on cyclophosphamide-induced oxidative injury: an experimental study on rat myocardium, testicles and urinary bladder. Food Chem Toxicol. 2010;48:2326–2336.
  • De Montellano PR. Cytochrome P450-activated prodrugs. Future Med Chem. 2013;5:213–228.
  • Westlind A, Malmebo S, Johansson I, et al. Cloning and tissue distribution of a novel human cytochrome p450 of the CYP3A subfamily, CYP3A43. Biochem Biophys Res Commun. 2001;281:1349–1355.
  • Liu F, Li XL, Lin T, et al. The cyclophosphamide metabolite, acrolein, induces cytoskeletal changes and oxidative stress in Sertoli cells. Mol Biol Rep. 2012;39:493–500.
  • James D, Adams J. Acrolein-induced oxigen radical formation. Free Radic Biol Med. 1993;15:187–193.
  • Crook TR, Souhami RL, Mclean AEM. Cytotoxicity, DNAcross-linking, and single strand breaks induced by activated cyclophosphamide specificity and acrolein in human leukemia cells. Cancer Res. 1986;46:5029–5034.
  • Codrington AM, Hales BF, Robaire B. Exposure of male rats to cyclophosphamide alters the chromatin structure and basic proteome in spermatozoa. Hum Reprod. 2007;22:1431–1442.
  • Aguilar-Mahecha A, Hales BF, Robaire B. Expression of stress response genes in germ cells during spermatogenesis. Biol Reprod. 2001;65:119–127.
  • Codrington AM, Hales BF, Robaire B. Spermiogenic germ cell phase-specific DNA damage following cyclophosphamide exposure. J Androl. 2004;25:354–362.
  • Cagnol S, Chambard JC. ERK and cell death: mechanisms of ERK-induced cell death-apoptosis, autophagy and senescence. Febs J. 2010;277:2–21.
  • Dix DJ, Allen JW, Collins BW, et al. Targeted gene disruption of Hsp70-2 results in failed meiosis, germ cell apoptosis, and male infertility. Proc Natl Acad Sci. 1996;93:3264–3268.
  • Feng HL, Sandlow JI, Sparks AET. Decreased expression of the heat shock protein hsp70-2 is associated with the pathogenesis of male infertility. Fertil Steril. 2001;76:1136–1139.
  • Pegg AE, Shantz LM, Coleman CS. Ornithine decarboxylase: structure, function and translational regulation. Biochem Soc Trans. 1994;22:846–852.
  • Vanella A, Pinturo R, Vasta M, et al. Polyamine levels in human semen of unfertile patients: effect of S-adenosylmethionine. Acta Eur Fertil. 1978;9:99–103.
  • Rubinstein S, Breitbart H. Role of spermine in mammalian sperm capacitation and acrosome reaction. Biochem J. 1991;278:25–28.
  • Trompeter R, Evans P, Barratt T. Gonadal function in boys with steroid-responsive nephrotic syndrome treated with cyclophosphamide for short periods. Lancet. 1981;317:1177–1179.
  • Kenney LB, Laufer MR, Grant FD, et al. High risk of infertility and long term gonadal damage in males treated with high dose cyclophosphamide for sarcoma during childhood. Cancer. 2001;91:613–621.
  • Lentz RD, Bergstein J, Steffes MW, et al. Postpubertal evaluation of gonadal function following cyclophosphamide therapy before and during puberty. J Pediatr. 1977;91:385–394.
  • Fukutani K, Ishida H, Shinohara M, et al. Suppression of spermatogenesis in patients with Behçet’s disease treated with cyclophosphamide and colchicine. Fertil Steril. 1981;36:76–80.
  • Sieniawski M, Reineke T, Nogova L, et al. Fertility in male patients with advanced Hodgkin lymphoma treated with BEACOPP: a report of the German Hodgkin Study Group (GHSG). Blood. 2008;111:71–76.
  • Jalali AS, Hasanzadeh S, Malekinejad H. Achillea millefolium inflorescence aqueous extract ameliorates cyclophosphamide-induced toxicity in rat testis: stereological evidences. Chinese Journal of Natural Medicines. 2012;10:247–254.
  • Rezvanfar M, Sadrkhanlou R, Ahmadi A, et al. Protection of cyclophosphamide-induced toxicity in reproductive tract histology, sperm characteristics, and DNA damage by an herbal source; evidence for role of free-radical toxic stress. Hum Exp Toxicol. 2008;27:901–910.
  • Zanchi M, Manfredini V, Brum DDS, et al. Green tea infusion improves cyclophosphamide-induced damage on male mice reproductive system. Toxicol Rep. 2015;2:252–260.
  • Hosseini A, Pakdel FG, Ahmadi A, et al. Beneficial effects of american ginseng on epididymal sperm analyses in cyclophosphamide treated rats. Cell J. 2012;14:116–121.
  • Oh MS, Chang MS, Park W, et al. Yukmijihwang-tang protects against cyclophosphamide-induced reproductive toxicity. Reprod Toxicol. 2007;24:365–370.
  • Zhao H, Jin B, Zhang X, et al. Yangjing capsule ameliorates spermatogenesis in male mice exposed to cyclophosphamide. Evid Based Complement Alternat Med. 2015;2015:1–8.
  • Rahman SA, Dawood NF, Basha SS, et al. Protective effect of black seed Nigella sativa (l.). Against cyclophosphamide-induced toxicity on reproductive and acrosomal function in mice. Middle East J Sci Res. 2013;17:955–964.
  • Nayak G, Vadinkar A, Nair S, et al. Sperm abnormalities induced by pre-pubertal exposure to cyclophosphamide are effectively mitigated by Moringa oleifera leaf extract. Andrologia. 2016;48:125–136.
  • Selvakumar E, Prahalathan C, Sudharsan PT, et al. Chemoprotective effect of lipoic acid against cyclophosphamide-induced changes in the rat sperm. Toxicology. 2006;217:71–78.
  • Ghosh D, Das UB, Misro M. Protective role of α-tocopherol-succinate (provitamin-E) in cyclophosphamide induced testicular gametogenic and steroidogenic disorders: a correlative approach to oxidative stress. Free Radic Res. 2002;36:1209–1218.
  • Tripathi DN, Jena GB. Astaxanthin inhibits cytotoxic and genotoxic effects of cyclophosphamide in mice germ cells. Toxicology. 2008;248:96–103.
  • Ilbey YO, Ozbek E, Simsek A, et al. Potential chemoprotective effect of melatonin in cyclophosphamide- and cisplatin-induced testicular damage in rats. Fertil Steril. 2009;92:1124–1132.
  • Li J, Hu Y, Zhang Q, et al. Strontium fructose 1, 6-diphosphate alleviate cyclophosphamide-induced oligozoospermia by improving antioxidant and inhibiting testicular apoptosis via FAS/FASL pathway. Andrologia. 2015;47:995–1003.
  • Bakhtiary Z, Shahrooz R, Ahmadi A, et al. Protective effects of ethyl pyruvate on sperm quality in cyclophosphamide treated mice. Iran J Reprod Med. 2015;13:291–296.
  • Abarikwu SO, Otuechere CA, Ekor M, et al. Rutin ameliorates cyclophosphamide-induced reproductive toxicity in male rats. Toxicol Int. 2012;19:207–214.
  • Maremanda KP, Khan S, Jena G. Zinc protects cyclophosphamide-induced testicular damage in rat: involvement of metallothionein, tesmin and Nrf2. Biochem Biophys Res Commun. 2014;445:591–596.
  • Carmely A, Meirow D, Peretz A, et al. Protective effect of the immunomodulator AS101 against cyclophosphamide-induced testicular damage in mice. Hum Reprod. 2009;24:1322–1329.
  • Zhu B, Zheng Y-F, Zhang Y, et al. Protective effect of L-carnitine in cyclophosphamide-induced germ cell apoptosis. J Zhejiang Univ Sci B. 2015;16:780–787.
  • Abdollahi M, Salehnia A, Mortazavi SH, et al. Antioxidant, antidiabetic, antihyperlipidemic,reproduction stimulatory properties and safety of essential oil of Satureja khuzestanica in rat in vivo: a toxicopharmacological study. Med Sci Monit. 2003;9:331–335.
  • Haeri S, Minaie B, Amin G, et al. Effect of Satureja khuzestanica essential oil on male rat fertility. Fitoterapia. 2006;77:495–499.
  • Han D, Handelman G, Packer L, et al. Lipoic acid increases de novo synthesis of cellular glutathione by improving cystine utilization. Biofactors. 1997;6:321–338.
  • Navari-Izzo F, Quartacci MF, Sgherri C. Lipoic acid: a unique antioxidant in the detoxification of activated oxygen species. Plant Physiol Biochem. 2002;40:463–470.
  • Senthilkumar S, Yogeeta SK, Subashini R, et al. Attenuation of cyclophosphamide induced toxicity by squalene in experimental rats. Chem Biol Interact. 2006;160:252–260.
  • Kohno Y, Egawa Y, Itoh S, et al. Kinetic study of quenching reaction of singlet oxygen and scavenging reaction of free radical by squalene in n-butanol. Chem Biol Interact. 1995;1256:52–56.
  • Gerhardt K. Mother’s gut arms offspring. Biol Reprod. 2016;95:1–12.
  • Moloudizargari M, Aghajanshakeri S, Javaherypour S. A current update on the phytopharmacological aspects of Achillea millefolium. J Pharm Biomed Sci. 2014;4:310–317.
  • Dev Rudrama R, Yadamma K, Reddy KD. Protective effects of curcumin in cyclophosphamide induced sperm head abnormalities in male mice. Int J Pharm Bio Sci. 2013;4:1131–1137.
  • Huazhonga L, Guangb W, Jinlongb W, et al. Amelioratory effects of sepia ink polysaccharides on partial internal organs injuried by cyclophosphamide. Chinese J Mod Appl Pharm. 2012;2:2.
  • Le XY, Luo P, Gu YP, et al. Interventional effects of squid ink polysaccharides on cyclophosphamide-associated testicular damage in mice. Bratisl Lek Listy. 2014;116:334–339.
  • Le X, Luo P, Gu Y, et al. Squid ink polysaccharide reduces cyclophosphamide-induced testicular damage via Nrf2/ARE activation pathway in mice. Iran J Basic Med Sci. 2015;18:827.
  • Itoh H, Hiraoka N, Higuchi G, et al. Contractile actions of endothelin-1 in isolated helical strips from rat pulmonary artery: potentiation of serotonin-induced contraction. J Cardiovasc Pharmacol. 1992;20:1–6.
  • Ahmed LA, E L-Maraghy SA, Rizk SM. Role of the KATP channel in the protective effect of nicorandil on cyclophosphamide-induced lung and testicular toxicity in rats. Sci Rep. 2015;5:14043.

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.