Abstract
Chemotherapy is associated with male infertility. Cisplatin (cis-diamminedichloro-platinum (II) (CDDP) as a chemotherapy medication used to treat a number of cancers has been reported to most likely induce testicular toxicity. Administration of antioxidants, such as pentoxifylline (PTX) may reduce some Adverse Drug Reactions (ADRs) of CDDR Therefore, this study investigated the potentially protective effects of PTX on CDDP-induced testicular toxicity in adult male rats. For this purpose, 42 male rats were randomly divided into 7 groups. The rats were orally preheated with PTX at the 3 doses of 75, 150, and 300 mg/kg once a day for 14 successive days. On the 14th day of the study, they were intraperitoneally (IP) administered with a single dose of CDDP (7 mg/kg). Finally, the sperm/testis parameters, serum levels of reproductive hormones, including testosterone, Luteinizing Hormone (LH), and Follicle Stimulating Hormone (FSH) as the pivotal endocrine factors controlling testicular functions, and histopathological changes of testis tissue were examined. Pretreatment with the two doses of 75 and 150 mg/kg PTX indicated significant increases in the sperm count and motility induced by CDDP administration. The right and significantly left testis weights were decreased following the treatment with 300 mg/kg of PTX plus CDDP. However, 75 mg/kg of PTX plus CDDP showed the best near-to-normal histopathological features. The results demonstrated that PTX alone enhanced some parameters, such as the sperm count, while reducing other parameters, including sperm fast motility and germ layer thickness. Furthermore, despite testosterone or LH levels, the mean serum FSH level was significantly augmented by the doses of 75 and 150 mg/ kg. It was concluded that PTX administration cannot reduce CDDP-induced testicular toxicity even at high doses (e.g., 300 mg/kg), while it seemed to partially intensify CDDP toxicity effects at a dose of 75 mg/kg. Thus, further research is required in this regard.
Article PDF
Similar content being viewed by others
Avoid common mistakes on your manuscript.
References
Ebisch, I.M., Thomas, C.M., Peters, W.H., Braat, D.D. and Steegers-Theunissen, R.P. (2007) The importance of folate, zinc and antioxidants in the pathogenesis and prevention of subfertility. Hum. Reprod. Update, 13, 163–174.
Aryanpur, M., Tarahomi, M., Sharifi, H., Heydari, G., Hessami, Z., Akhoundi, M. and Masjedi, M.R. (2011) Comparison of spermatozoa quality in male smokers and nonsmokers of Iranian infertile couples. Int. J. Fertil. Steril., 5, 152–157.
Baker, M.A. and Aitken, R.J. (2004) The importance of redox regulated pathways in sperm cell biology. Mol. Cell. Endocrinol., 216, 47–54.
Amin, A. and Hamza, A.A. (2006) Effects of roselle and ginger on cisplatin-induced reproductive toxicity in rats. Asian J. Androl., 8, 607–612.
Martenies, S.E. and Perry, M.J. (2013) Environmental and occupational pesticide exposure and human sperm parameters: a systematic review. Toxicology, 307, 66–73.
Howell, S.J. and Shalet, S.M. (2005) Spermatogenesis after cancer treatment, damage and recovery. J. Natl. Cancer Inst. Monogr., (34), 12–17.
Mosher, W.D. and Pratt, W.F. (1991) Fecundity and infertility in the United States, incidence and trends. Fertil. Steril., 56, 192–193.
Schill, W.B. (1979) Recent progress in pharmacological therapy of male subfertility-a review. Andrologia, 11, 77–107.
Chirino, Y.I., Hernández-Pando, R. and Pedraza-Chaverri, J. (2004) Peroxynitrite decomposition catalyst ameliorates renal damage and protein nitration in cisplatin-induced nephrotoxicity in rats. BMC Pharmacol., 4, 20.
Colpi, G.M., Contalbi, G.F., Nerva, F., Sagone, P. and Piediferro, G. (2004) Testicular function following chemo-radiotherapy. Eur. J. Obstet. Gynecol. Reprod. Biol., 113, S2–S6.
Atessahin, A., Yilmaz, S., Karahan, I., Ceribasi, A.O. and Karaoglu, A. (2005) Effects of lycopene against cisplatin-induced nephrotoxicity and oxidative stress in rats. Toxicology, 212, 116–123.
Bhat, S.G., Nie, Z. and Ramkumar, V. (1999) Cisplatin up-regulates adenosine A(1) receptors in rat testes. Eur. J. Pharmacol., 382, 35–43.
Ozols, R.F., Deisseroth, A.B., Javadpour, N., Barlock, A., Messerschmidt, G.L. and Young, RC. (1983) Treatment of poor prognosis nonseminomatous testicular cancer with a “high-dose” platinum combination chemotherapy regimen. Cancer, 51, 1803–1807.
Stadnicki, S.W., Fleischman, R.W., Schaeppi, U. and Merriam, P. (1975) Cis-dichlorodiammineplatinum (II) (NSC-119875), hearing loss and other toxic effects in rhesus monkeys. Cancer Chemother. Rep., 59, 467–480.
Fung, C. and Vaughn, D.J. (2011) Complications associated with chemotherapy in testicular cancer management. Nat. Rev. Urol., 8, 213–222.
Hooser, S.B., van Dijk-Knijnenburg, W.C., Waalkens-Berendsen, I.D., Smits-van Prooije, A.E., Snoeij, N.J., Baan, R.A. and Fichtinger-Schepman, A.M. (2000) Cisplatin-DNA adducts formation in rat spermatozoa and its effects on fetal development. Cancer Lett., 151, 71–80.
Ward, A. and Clissold, S.P. (1987) Pentoxifylline. A review of its pharmacodynamic and pharmacokinetic properties, and its therapeutic efficacy. Drugs, 34, 50–97.
Noyan, T., Onem, O., Ramazan Sekeroğlu, M., Köseoğlu, B., Dülger, H., Bayram, I., Yalçinkaya, A.S. and Bakan, V. (2003) Effects of erythropoietin and pentoxifylline on the oxidant and antioxidant systems in the experimental short bowel syndrome. Cell Biochem. Fund., 21, 49–54.
Mandell, G.L. (1988) ARDS, neutrophils and pentoxifylline. Am. Rev. Respir. Dis., 138, 1103–1105.
Tesarik, J., Mendoza, C. and Carreras, A. (1992) Effects of phosphodiesterase inhibitors, caffeine and pentoxifylline, on spontaneous and stimulus-induced acrosome reactions inhuman sperm. Fertil. Steril., 58, 1185–1190.
Garbers, D.L., Lust, W.D., First, N.L. and Lardy H.A. (1971) Effect of phosphodiesterase inhibitors and cyclic nucleotides on sperm respiration and motility. Biochemistry, 10, 1825–1831.
Porter, J.M., Cutler, B.C., Lee, B.Y., Reich, T., Reichle, F.A., Scogin, J.T. and Strandness, DE. (1982) Pentoxifylline efficacy in the treatment of intermittent claudication, multicenter controlled double-blind trial with objective assessment of chronic occlusive arterial disease patients. Am. Heart J., 104, 66–72.
Oliva, A., Dotta, A. and Multigner, L. (2009) Pentoxifylline and antioxidants improve sperm quality in male patients with varicocele. Fertil. Steril., 91, 1536–1539.
Maxwell, D.T., Jacobson, J.D., King, A. and Chan, P.J. (2002) Effect of pentoxifylline on tumor suppressor and proto-oncogene apoptosis in sperm. J. Assist. Reprod. Genet., 19, 279–283.
Terriou, P., Hans, E., Giorgetti, C., Spach, J.L., Salzmann, J., Urrutia, V. and Roulier, R. (2000) Pentoxifylline initiates motility in spontaneously immotile epididymal and testicular spermatozoa and allows normal fertilization, pregnancy, and birth after intracytoplasmic sperm injection. J. Assist. Reprod. Genet., 17, 194–199.
Faka, B., Api, M., Fiçicioğlu, C., Gürbüz, A. and Oral, O. (1994) Pentoxifylline in male-factor infertility, its therapeutic efficacy after oral administration. Acta Eur. Fertil, 25, 351–353.
Noyan, T., Yalcinkaya, A.S., Sekeroglu, M.R., Dulger, H. and Balaharoglu, R. (2004) Antioxidant effects of pentoxifylline and melatonin in the alloxane-induced diabetic mice. Turk. J. Biochem., 29, 268–272.
Alizadeh, N., Abbasi, M., Abolhassani, F., Amidi, F., Mahmoudi, R., Hoshino, Y., Sato, E. and Ragerdikashani, I. (2010) Effects of aminoguanidine on infertile varicocelized rats: A functional and morphological study. Daru, 18, 51–56.
Nikseresht, M., Fallahzadeh, A.R., Toori, M.A. and Mahmoudi, R. (2015) Effects of pomegranate seed oil on the fertilization potency of rat’s sperm. J. Clin. Diagn. Res., 9, FF01–4.
Ilbey, Y.O., Ozbek, E., Simsek, A., Otunctemur, A., Cekmen, M. and Somay, A. (2009) Potential chemoprotective effect of melatonin in cyclophosphamide- and cisplatin-induced testicular damage in rats. Fertil. Steril., 92, 1124–1132.
Nassar, A., Omara, H.M., Sary, A.E.K.H., Ahmed, E. and Ragab, S.M.M. (2012) Vitamin C., N, N-diphenyl-p-phenylenediamine and L-cysteine ameliorate the pathological and oxidative Stress-induced by cisplatin in the lidneys of male rats. J. Free Radie. Antioxid, 138, 112–121.
Ahmed, E.A., Omar, H.M., Abdelghaffar, S.K., Ragb, S.M. and Nasser, A.Y. (2011) The antioxidant activity of vitamin C., DPPD and L-cysteine against Cisplatin-induced testicular oxidative damage in rats. Food Chem. Toxicol., 49, 1115–1121.
Ravi, R., Somani, S.M. and Rybak, L.P. (1995) Mechanisms of cisplatin ototoxicity: antioxidant system. Pharmacol. Toxicol., 76, 386–394.
Iwasaki, A. and Gagnon, C. (1992) Formation of reactive oxygen species in spermatozoa of infertile patients. Fertil. Steril., 57, 409–416.
Sanocka, D. and Kurpisz, M. (2004) Reactive oxygen species and sperm cells. Reprod. Biol. Endocrinol, 2, 12.
Sikka, S.C. (1996) Oxidative stress and role of antioxidant in normal and abnormal sperm function. Front. Biosci., 1, e78–e86.
Turk, G., Atessahin, A., Sonmez, M., Ceribasi, A.O. and Yuce, A. (2008) Improvement of cisplatin-induced injuries to sperm quality, the oxidant-antioxidant system, and the histologic structure of the rat testis by ellagic acid. Fertil. Steril., 89, 1474–1481.
Atessahin, A., Karahan, I., Turk, G., Gur, S., Yilmaz, S. and Ceribasi, A.O. (2006) Protective role of lycopene on cisplatin-induced changes in sperm characteristics, testicular damage and oxidative stress in rats. Reprod. Toxicol., 21, 42–47.
Tremellen, K. (2008) Oxidative stress and male infertility-a clinical perspective. Hum. Reprod. Update, 14, 243–258.
Minaei, M.B., Barbarestani, M., Nekoonam, S., Abdolvahabi, M.A., Takzare, N., Asadi, M.H., Hedayatpour, A. and Amidi, F. (2012) Effect of Trolox addition to cryopreservation media on human sperm motility. Iran J. Reprod. Med., 10, 99–104.
Narayana, K., Al-Bader, M., Mousa, A. and Khan, K.M. (2012) Molecular effects of chemotherapeutic drugs and their modulation by antioxidants in the testis. Eur. J. Pharmacol., 674, 207–216.
Conklin, K.A. (2000) Dietary antioxidants during cancer chemotherapy: impact on chemotherapeutic effectiveness and development on side effects. Nutr. Cancer, 37, 1–18.
Pérez-Rojas, J.M., Cruz, C., García-López, P., Sánchez-González, D.J., Martínez-Martínez, C.M., Ceballos, G., Espinosa, M., Meléndez-Zajgla, J. and Pedraza-Chaverri, J. (2009) Renoprotection by alpha-mangostin is related to the attenuation in renal oxidative/nitrosative stress induced by cisplatin nephrotoxicity. Free Radical. Res., 43, 1122–1132.
Sánchez, P.Y., Morales, B.R., García-Cuellar, C.M., Lopez, M.R., Calderon, O.M., Pedraza, C.J. and Chirino, Y.I. (2010) The alpha mangostin prevention on cisplatin-induced apoptotic death in LLC-PK1 cells is associated to an inhibition of ROS production and p53 induction. Chem. Biol. Interact., 188, 144–150.
Yousef, M.I., Saad, A.A. and El-Shennawy, L.K. (2009) Protective effect of grape seed proanthocyanidin extract against oxidative stress induced by cisplatin in rats. Food Chem. Toxicol., 47, 1176–1183.
Saad, A.A., Yousef, M.I. and El-Shennawy, L.K. (2009) Cisplatin induced damag in kidney genomic DNA and nephrotoxicity in male rats: the protective effect of grape seed proanthocyanidin extract. Food Chem. Toxicol., 47, 1499–1506.
Jariyawat, S., Kigpituck, P., Suksen, K., Chuncharunce, A., Chaovanalikit, A. and Piyachaturawat, P. (2009) Protection against cisplatin-induced nephrotoxicity in mice by Curcuma comosa Roxb, ethanol extract. J. Nat. Med., 63, 430–436.
Iraz, M., Ozerol, E., Gulec, M., Tasdemir, S., Idiz, N., Fadillioglu, E., Naziroglu, M. and Akyol, O. (2006) Protective effect of caffeic acid phenethyl ester (CAPE) administration on cisplatin-induced oxidative damage toliver in rat. Cell Biochem. Funct., 24, 357–361.
Choudhury, R.C. and Jagdale, M.B. (2002) Vitamin E protection from potentiation of the cytogenetic toxicity of cisplatin in Swiss mice. J. Chemother., 14, 397–405.
Narayana, K., Verghese, S. and Jacob, S.S. (2009) I-Ascorbic acid partially protects two cycles of cisplatin chemotherapy-induced testis damage and oligo-astheno-teratospermia in a mouse model. Exp. Toxicol. Pathol., 61, 553–563.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
This is an Open-Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (https://doi.org/creativecommons.org/licenses/by/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
About this article
Cite this article
Fallahzadeh, A.R., Rezaei, Z., Rahimi, H.R. et al. Evaluation of the Effect of Pentoxifylline on Cisplatin-Induced Testicular Toxicity in Rats. Toxicol Res. 33, 255–263 (2017). https://doi.org/10.5487/TR.2017.33.3.255
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.5487/TR.2017.33.3.255