Cyclophosphamide Induced Testicular Toxicity Mechanisms aAnd Ameliorative Agents
489 / 82
Authors
-
Matam SriDeepthi
1College of Veterinary Science, Rajendranagar, PVNR Telangana Veterinary University, Rajendranagar, Hyderabad
-
Kondampati Kasturi Devi
College of Veterinary Science, Warangal PVNR Telangana Veterinary University, Rajendranagar, Hyderabad
-
Matukuamli Usha rani
College of Veterinary Science, Warangal PVNR Telangana Veterinary University, Rajendranagar, Hyderabad
-
Boinepally Ramya
College of Veterinary Science, Warangal PVNR Telangana Veterinary University, Rajendranagar, Hyderabad
-
Beesam Srinu
College of Veterinary Science, Warangal PVNR Telangana Veterinary University, Rajendranagar, Hyderabad
Keywords:
Cyclophosphamide, Testicular toxicity, Oxidative stress, AntioxidantsAbstract
Cyclophosphamide is an alkylating agent that is widely known for its anticancer and immunosuppressive properties used in various cancerous and autoimmune diseases. Acrolein and phosphoramide mustard, are its toxic metabolites, majorly involved in toxic effects such as induction of oxidative stress that can induce oxidative damage in tissues. The free radicles thus produced are implicated in gonad toxicity, hepatic and kidney disorders, hemorrhagic cystitisetc. Clinical efficacy of cyclophosphamide is restricted because of its toxicity. The reproductive system due to presence of rapidly dividing cells is highly vulnerable to cyclophosphamide toxicity. Especially male subjects treated with cyclophosphamide demonstrated severe alterations in testis and epididymis as well as disturbed gonadotropin and reproductive hormone levels. Several studies suggested the usage of medicinal plants with antioxidant properties along with cyclophosphamide could protect against its organ toxicity. Supplementation of the dietary antioxidant’s during chemotherapy can reduce the drug induced toxic side effects and can further improvise the response to therapy.
Downloads
References
1. Abarikwu, S. O., Otuechere C. A., Ekor M., Monwuba K., and Osobu D. (2012) Rutin Ameliorates Cyclophosphamide-induced Reproductive Toxicity in Male Rats. Toxicol Int, May-Aug; 19(2): 207–214.
2. Aguilar-Mahecha A., Hales B.F., and Robaire B. (2001) Acute cyclophosphamide exposure has germ cell specific effects on the expression of stress response genes during rat spermatogenesis. Mol Reprod Dev, 60:302–311.
3. Anderson, D. (2005) Male-mediated developmental toxicity. Toxicol Appl Pharmacol, 207(2): 506-513.
4. Aung, H.H., Wang, C.Z., FishbeinM. Ni, A., S.R. Mehendale, J.T., Xie, A.Y. Shoyama, and Yuan, C.S., (2007) Crocin from Crocus sativus possesses significant anti-proliferation effects on human colorectal cancer cells.Exp Oncol. 29: 175–180.
5. Chan, W.-K., Tan, L., Chan, K.-G., Lee, L.-H., and Goh, B.-H. (2016). Nerolidol: A sesquiterpene alcohol with multi-faceted pharmacological and biological activities. Molecules, 21(5):529. https://doi.org/10.3390/molecules21050529
6. ConnollyKevin J., Robert J. Edelmann, Ian D. Cooke, and Jill Robson. (1992) The impact of infertility on psychological functioning. J PsychosomRes, 36(5):459-468.
7. Das, U.B., Mallick, M., Debnath, J.M., and Ghosh,D. (2002) Protective effect of ascorbic acid on cyclophosphamide-induced testicular gametogenic and androgenic disorders in male rats. Asian J Androl, 4:201–207.
8. Dinkova-Kostova, A.T., and Abramov, A.Y. (2015) The emerging role of Nrf2 in mitochondrial function.Free Radic Biol Med, 88:179–188.
9. Elangovan, N., Chiou, T.J., Tzeng, W.F., and Chu, S.T. (2006) Cyclophosphamide treatment causes impairment of sperm and its fertilizing ability in mice. Toxicology. 1;222(1-2):60-70. doi: 10.1016/j.tox.2006.01.027.
10. El-Naggar, S. A., Alm-Eldeen, A. A., Germoush, M. O., El-Boray, K, F., and Elgebaly, H. A. (2015) Ameliorative effect of propolis against cyclophosphamide-induced toxicity in mice. Pharm Biol, 53 (2): 235-241.
11. Fahey, J.W., Stephenson, K.K., Dinkova-Kostova, A.T., Egner, P.A., Kensler, T.W., and Talalay, P., (2005) Chlorophyll, chlorophyllin and related tetrapyrroles are significant inducers of mammalian phase 2 cytoprotective genes. Carcinogenesis, 26, 1247–1255
12. Han, D., Handelman, G., Marcocci, L., Sen, C. K., Roy, S., Kobuchi, H., Tritschler, H. J., Flohé, L., and Packer, L. (1997) Lipoic acid increases de novo synthesis of cellular glutathione by improving cystine utilization. Biofactors, 6:321–338
13. Harwansh, R. K., Mukherjee, K., Bhadra, S., Kar, A., Bahadur, S., and Mitra, A.(2014) Cytochrome P450 inhibitory potential and RP-HPLC standardization of trikatu—a rasayana from Indian ayurveda. J Ethnopharmacol.153 (3):674–681.
14. Hix, L.M., Frey, D.A., McLaws, M.D., Osterlie, M., Lockwood, S.F., and Bertram, J.S., (2005) Inhibition of chemically-induced neoplastic transformation by a novel tetrasodium diphosphate astaxanthin derivative. Carcinogenesis26:1634–1641.
15. Hoorweg-Nijman, J.J., Delemarre-Van De Waal, H.A., and De Waal, F.C., (1992) Cyclophosphamide-induced disturbance of gonadotropin secretion manifesting testicular damage. Acta endocrinologica,26:143–148
16. Hosseini, A., Zare, S., Borzouei, Z., and Pakdel, F, G.,(2018) Cyclophosphamide-induced testicular toxicity ameliorate by American ginseng treatment: An experimental study. Int J Reprod Biomed, 16 (11): 711
17. Hosseinzadeh, H. T., Ziaee, A. Sadeghi.(2008) The effect of saffron, Crocus sativus stigma,extract and its constituents, safranal and crocin on sexual behaviors in normal malerats. Phytomed Plus. 15:491–495
18. Hussein, G., Goto, H., Oda, S., Sankawa, U., Matsumoto, K., and Watanabe, H., (2006) Antihypertensive potential and mechanism of action of astaxanthin: III. Antioxidant and histopathological effects in spontaneously hypertensive rats. Biol Pharm Bull. 29: 684–688
19. Hussein, G., Nakagawa, T., Goto, H., Shimada, Y., Matsumoto, K., Sankawa, U., and Watanabe, H., (2007) Astaxanthin ameliorates features of metabolic syndrome in SHR/NDmcr-cp. Life Sciences. 80:522–529
20. Iqubal, A., Syed, M.A., Haque, M.M., Najmi, A.K., Ali, J., and Haque, S.E. (2020) Ameliorative effect of nerolidol on cyclophosphamide-induced gonadal toxicity in Swiss Albino mice: Biochemical-, histological- and immunohistochemical-based evidences. Andrologia. 52:e13535. https://doi.org/10.1111/and.13535
21. James,D., and Adams, J. (1993) Acrolein-induced oxigen radical formation. Free Radical Biology and Medicine.15:187–193
22. Kaur, P., Kaur, G., and Bansal, M.P. (2006) Tertiary-butyl hydroperoxide induced oxidative stress and male reproductive activity in mice: Role of transcription factor NF-kappaB and testicular antioxidant enzymes. Reproductive Toxicology. 22:479–484
23. Kehrer, J.P. and Biswal,S.S. (2000) The molecular effects of acrolein.Toxicological Sciences.57:6–15
24. Kurihara, H., Koda, H., Asami, S., Kiso, Y., and Tanaka, T., (2002) Contribution of the antioxidative property of astaxanthin to its protective effect on the promotion of cancer metastasis in mice treated with restraint stress. Life Sciences. 70:2509–2520.
25. Lai, J.P., Jiang, Y., He, X.W., Huang, J.C., and Chen, F. (2004) Separation and determination of astaxanthin from microalgal and yeast samples by molecularly imprinted microspheres. J Chromatogr B Analyt Technol Biomed Life Sci. 5;804(1):25-30.
26. Ma Q. (2013) Role of Nrf2 in oxidative stress and toxicity. Annu Rev PharmacolToxicol.53:401–426
27. Meistrich, M.L.and Shetty, G. (2008) Hormonal suppression for fertility preservation in males and females. Reproduction, Dec;136(6):691-701
28. Naito, Y., Uchiyama, K., Aoi, W., Hasegawa, G., Nakamura, N., Yoshida, N., Maoka, T., Takahashi, J., and Yoshikawa, T., (2004) Prevention of diabetic nephropathy by treatment with astaxanthin in diabetic db/db mice. Biofactors,20: 49–59.
29. Nakamura, Y., Ishimitsu, S., and Tonogai Y. (2000) Effects of quercetin and rutin on serum and hepatic lipid concentrations, fecal steroid excretion and serum antioxidant properties. Journal of Health Sciences, 46:229–40
30. Potnuri, A.G., Allakonda, L., and Lahkar, M. (2018) Crocin attenuates cyclophosphamide induced testicular toxicity by preserving glutathione redox system. Biomed Pharmacother101:174-180.
31. Rice-Evans C. (2001) Flavonoid antioxidants. Current Medicinal Chemistry, 8:797-807
32. Sapanidou, V., Taitzoglou, I., Tsakmakidis, I., Kourtzelis, D., Fletouris, A., Theodoridis, I., Zervos, M., and Tsantarliotou (2015) Antioxidant effect of crocin on bovine sperm quality and in vitro fertilization.Theriogenology84:1273–1282.
33. Selvakumar, E., Prahalathan, C., Mythili, Y., and Varalakshmi, P. (2005) Beneficial effects of DL-alpha-lipoic acid on cyclophosphamide-induced oxidative stress in mitochondrial fractions of rat testis. Chem Biol Interact, 152(1), 59–66.
34. Sunila, E.S, and Kuttan, G. (2004) Immunomodulatory and antitumor activity of Piper longum Linn. and piperine. J Ethnopharmacol.90(2-3):339-46.
35. Sunila, E.S., and Kuttan G. (2005) Protective effect of Piper longum fruit ethanolic extract on radiation induced damages in mice: a preliminary study. Fitoterapia. 76(7-8):649-55.
36. Tawab Abd El A, M., Shahin, N.N., and AbdelMohsen, M.M. (2014) Protective effect of Saturejamontana extract on cyclophosphamide-induced testicular injury in rats. Chem Biol Interact, 224:196–205
37. Trasler, J.M., Hales, B., and Robaire, B. (1987) A time-course study of chronic paternal cyclophosphamide treatment in rats: effects on pregnancy outcome and the male reproductive and hematologic systems. Biology Reproduction. 37:317–326
38. Trasler, J.M., Hermo, L., and Robaire, B. (1988) Morphological changes in the testis and epididymis of rats treated with cyclophosphamide: a quantitative approach. Biology Reproduction, 38:463–479
39. Tripathi, D. N., and Jena, G. B. (2008) Astaxanthin inhibits cytotoxic and genotoxic effects of cyclophosphamide in mice germ cells.Toxicology, 248(2-3):96–103.
40. Türk G, Çeribaşi AO, and Sakin F. (2010) Antiperoxidative and anti-apoptotic effects of lycopene and ellagic acid on cyclophosphamide-induced testicular lipid peroxidation and apoptosis. Reproduction Fertility and Development. 22:587–596
41. Ucar M, Korkmaz A, and Reiter RJ. (2007) Melatonin alleviates lung damage induced by the chemical warfare agent nitrogen mustard. Toxicology Letters. 173:124–131
42. Vahdati Hassani, F., V. Naseri, B.M., Razavi, S., Mehri, K., Abnous, H., and Hosseinzadeh. (2014) Antidepressant effects of crocin and its effects on transcript and protein levels ofCREB, BDNF, and VGF in rat hippocampus, Daru, 22(1), 16
43. Wakade, A. S., Shah, A. S., Kulkarni, M. P., and Juvekar, A. R. (2008) Protective effect of Piper longum L. on oxidative stress induced injury and cellular abnormality in adriamycin induced cardiotoxicity in rats. Indian J Exp Biol. 46 (7), 528–533
44. Westlind A, Malmebo S, and Johansson I (2001) Cloning and tissue distribution of a novel human cytochrome p450 of the CYP3A subfamily, CYP3A43. BiochemBiophys Res Commun281:1349–1355
45. Yadav V, Krishnan A, Zahiruddin S,Ahmad S and Vohora D (2023) Amelioration of cyclophosphamideinduced DNA damage, oxidative stress, and hepato- and neurotoxicity by Piper longum extract in rats: The role of γH2AX and 8-OHdG.Frontiers Pharmacology. 14:1147823
46. Zahin, M., Khan, M. S., Abul Qais, F., Abulreesh, H. H., and Ahmad, I. (2018) Antioxidant properties and anti-mutagenic potential of Piper Cubeba fruit extract and molecular docking of certain bioactive compounds. Drug and Chemical Toxicology. 41 (3), 358–367.
47. Zanchi, M.M., Manfredini, V., Brum, D.D.S., Vargas, L.M., Spiazzi, C.C., Soares, M.B., Izaguirry, A.P., and Santos, F.W. (2014) Green tea infusion improves cyclophosphamide-induced damage on male mice reproductive system. Toxicology Reports. 2:252-260.
48. Zini A, and Schlegel PN. (1996) Catalase mRNA expression in the male rat reproductive tract. Journal of Andrology. 17:473–480.
Downloads
Published
Versions
- 2025-12-29 (2)
- 2024-02-23 (1)