Study on the effect of maternal administration of oxaliplatin on offspring testes using unbiased design-based stereology

Oxaliplatin (Ox) is widely used for the treatment of various tumors. Since Ox prevents DNA replication and transcription, it may affect organs with rapid cell divisions such as the testes. Although its use during pregnancy has been reported, no information regarding its effects on the testes of the offspring is not available yet. Thirty-two mice were randomly divided into four groups. The control group (1) was administered intraperitoneally 0.2 ml of saline three times a week for the 21 days of pre-pregnancy, pregnancy and lactation. Experimental groups 2, 3 and 4 received 3 mg/kg of oxaliplatin three times a week for 21 days during pre-pregnancy, pregnancy and lactation, respectively. The left testis was removed from male offspring 30 and 60 days after birth. The volume of the testes, seminiferous tubules and interstitial tissue, the surface area and height of the seminiferous epithelium, as well as the length and diameter of seminiferous tubules, were analyzed by means of stereology. Results showed a decrease in the evaluated parameters in experimental groups, in comparison with the control group. Due to the ameliorating effect of Ox on offspring testes, cautiousness is needed during maternal administration in order to preserve the fertility of male offspring.

___

  • Aitken, R. J., Roman, S. D., 2008. Antioxidant systems and oxidative stress in the testes. Oxid. Med. Cell. Longev. 1, 15-24. Alian O, Azmi A, Mohammad R., 2012. Network insights on oxaliplatin anti-cancer mechanisms. J. Transl. Med. 1, 26.
  • Azu, O. O., Naidu, E. C., Naidu, J. S., Masia, T., Nzemande, N. F., Chuturgoon, A., Singh, S., 2014. Testicular histomorphologic and stereological alterations following short-term treatment with highly active antiretroviral drugs (HAART) in an experimental animal model. Andrology. 2, 772–779.
  • Ateşşahin, A., Karahan, I., Türk, G., Gür, S., Yilmaz, S., Ceribaşi, A. O., 2006. Protective role of lycopene on cisplatin-induced changes in sperm characteristics, testicular damage and oxidative stress in rats. Reprod. Toxicol. 21 (1), 42-47.
  • Bang, Y.J, Kim, Y. W., Yang, H. K., Chung, H. C., Park, Y. K., Lee, K. H., Lee, K. W., Kim, Y. H., Noh, S. I., Cho, J. Y., Mok, Y. J., Kim, Y. H., Ji, J., Yeh, T. S., Button, P., Sirzén, F., Noh, S. H., 2012. Adjuvant capecitabine and oxaliplatin for gastric cancer after D2 gastrectomy (CLASSIC): a phase 3 open-label, randomized controlled trial. Lancet. 379, 315-321
  • Bano, N., Najam, R., Qazi, F., Mateen, A., 2016. Clinical Features of Oxaliplatin induced hypersensitivity reactions and therapeutic approaches. Asian. Pac. J. Cancer. Pre. 17, 1637-1641.
  • Bogliolo, S., Cassani, C., Gardella, B., Musacchi, V., Babilonti, L., Venturini, P. L., Ferrero, S., Spinillo, A., 2015. Oxaliplatin for the treatment of ovarian cancer. Expert. Opin. Investig. Drugs. 24, 1275-1286.
  • Chater, S., Amara, S., Moussata, D., Bozec, A., Omezzine, A., Romestaing, P., Chapet, O., Gerard, J. P., Mornex, F., Benahmed, M., Mauduit, C., 2007. Differential effects of ionizing radiation and platinum-derivative chemotherapy on apoptotic pathways in testicular germ cells. Int. J. Radiat. Biol. 83, 269-278.
  • Choi, J. S., Oh, J. H., Park, H. J., Choi, M. S., Park, S. M., Kang, S. J., Oh, M. J., Kim, S. J., Hwang, S. Y., Yoon, S., 2011. miRNA regulation of cytotoxic effects in mouse Sertoli cells exposed to nonylphenol. Reprod. Biol. Endocrinol. 9, 126.
  • Dehghani, F., Hassanpour, A., Poost-Pasand, A., Noorafshan, A., Karbalay-Doust, S., 2013. Protective effects of L-carnitine and homogenized testis tissue on the testis and sperm parameters of busulfan-induced infertile male rats. Iran. J. Reprod. Med. 11, 693-704.
  • Demontoux, L., Derangère, V., Pilot, T., Thinselin, C., Chevriaux , A., Chalmin, F., Bouyer, F., Ghiringhelli, F., Rébé, C., 2019. Hypotonic stress enhances colon cancer cell death induced by platinum derivatives and immunologically improves antitumor efficacy of intraperitoneal chemotherapy. Int. J. Cancer. 145, 3101-3111.
  • de Souza Predes, F., Diamante, M.A., Dolder, H., 2010. Testis response to low doses of cadmium in Wistar rats. Int. J. Clin. Exp. Patho. 91, 125-131.
  • Franca, L. R., Russell, L. D., 1998. The testes of domestic animals. In: Male Reproduction. A Multidisciplinary Overview, Madrid: Churchill Livingstone.
  • Gensheimer, M., Jones, C. A., Graves, C. R., Merchant, N. B., Lockhart, A. C., 2009. Administration of oxaliplatin to a pregnant woman with rectal cancer. Cancer. Chemoth. Pharm. 63, 371-373.
  • Geohagen, B. C., Weiser, D. A., Loeb, D. M., Nordstroem, L. U., LoPachin, R. M., 2020. Enolate-forming compounds provide protection from platinum neurotoxicity. Chem. Biol. Interact. 317, 108961.
  • Gong, Y., Wua, J., Huangc, Y., Shena, S., Hana, X., 2009. Nonylphenol induces apoptosis in rat testicular Sertoli cells via endoplasmic reticulum stress. Toxicol. Lett. 186, 84-95.
  • Gundersen, H. J., Bagger, P., Bendtsen, T. F., Evans, S. M., Korbo, L., Marcussen, N., Møller, A., Nielsen, K., Nyengaard, J. R., Pakkenberg, B., et al., 1988. The new stereological tools: disector, fractionator, nucleator and point sampled intercepts and their use in pathological research and diagnosis. APMIS. 96, 857–881.
  • Güvenç, M. G., Dizdar, D., Dizdar, S. K., Okutur, S. K., Demir, G., 2016. Sudden hearing loss due to oxaliplatin use in a patient with colon cancer. J. Chemother. 28, 341-342.
  • Hoff, P. M., Saad, E. D., Costa, F., Coutinho, A. K., Caponero, R., Prolla, G., Gansl, R. C., 2012. Literature review and practical aspects on the management of oxaliplatin-associated toxicity. Clin. Colorectal. Cancer. 11, 93-100.
  • Jamieson, E. R., Lippard, S. J., 1999. Structure, Recognition, and Processing of Cisplatin-DNA Adducts. Chem. Rev. 99, 2467-2498.
  • Jedlinska-Krakowska, M., Bomba, G., Jakubowski, K., Rotkiewicz, T., Jana, B., Penkowski, A., 2006. Impact of Oxidative Stress and Supplementation with Vitamins E and C on Testes Morphology in Rats. J. Reprod. Develop. 52, 203-209.
  • Kanate, A. S., Auber, M. L., Higa, G. M., 2009. Priorities and uncertainties of administering chemotherapy in a pregnant woman with newly diagnosed colorectal cancer. J. Oncol. Pharm. pract. 15, 5-8.
  • Kovačevič, K., Budefeld, T., Majdič, G., 2006. Reduced seminiferous tubule diameter in Mice neonatally exposed to perfume. Slov. Vet. Res. 43, 177-183.
  • Le Bihan-Benjamin C, Hoog-Labouret N, Lefeuvre D, Carré-Pigeon F, Bousquet PJ., 2018. Fertility preservation and cancer: How many persons are concerned? Eur. J. Obstet. Gynecol. Reprod. Biol. 225:232-235.
  • Levi, M., Shalgi, R., Brenner, B., Perl, G., Purim, O., Amit, L., Stemmer, S. M., Ben-Aharon, I., 2015. The impact of oxaliplatin on the gonads: from bedside to the bench. Mol. Hum. Reprod. 21, 885-893.
  • Liew, S. H., Meachem, S. J., Hedger, M. P., 2007. A stereological analysis of the response of spermatogenesis to an acute inflammatory episode in adult rats. J. Androl. 28, 176-185.
  • Lirdi, L. C., Stumpp, T., Sasso-Cerri, E., Miraglia, S. M., 2008. Amifostine protective effect on cisplatin-treated rat testis. Anat. Rec. (Hoboken). 291, 797-808.
  • Makoshi, Z., Perrott, C., Al-Khatani, K., Al-Mohaisen, F., 2015. Chemotherapeutic treatment of colorectal cancer in pregnancy: case report. J. Med. Case. Rep. 9, 140.
  • Mohammadnejad, D., Abedelahi, A., soleimani-rad, J., Mohammadi-roshandeh, A., rashtbar, M., Azami, A., 2012. Degenerative Effect of Cisplatin on Testicular Germinal Epithelium. Adv. Pharm. Bull. 2, 173-177.
  • Moskovitz, M., Wollner, M., Haim, N., 2015. Oxaliplatin-Induced Pulmonary Toxicity in Gastrointestinal Malignancies: Two Case Reports and Review of the Literature. Case. Rep. Oncol. Med. 2015, 341064.
  • Niakani, A., Farrokhi, F., Hasanzadeh, S., 2013. Decapeptyl ameliorates cyclosphamide-induced reproductive toxicity in male Balb/C mice: histomorphometric, sterelogic and hormonal evidences. Iran. J. Reprod. Med. 11, 791-800.
  • Noorafshan, A., Karbalay-Doust, S., Valizadeh, A., Aliabadi, E., 2011. Ameliorative effects of curcumin on the structural parameters of seminiferous tubules and Leydig cells in metronidazole-treated mice: a stereological approach. Exp. Toxicol. Pathol. 63, 627-633.
  • Noorafshan, A., 2014. Stereology as a valuable tool in the toolbox of testicular research. Ann. Anat. 196, 57-66.
  • Nyengaard, J. R., 1999. Stereologic methods and their application in kidney research. J. Am. Soc. Nephrol. 10, 1100–1123.
  • Perde-Schrepler, M., Fischer-Fodor, E., Virag, P., Brie, I., Cenariu, M., Pop, C., Valcan, A., Gurzau, E., Maniu, A., 2020. The expression of copper transporters associated with the ototoxicity induced by platinum-based chemotherapeutic agents. Hear. Res. 388, 107893.
  • Pereira, M. R. F., Aleixo, J. F., Cavalcanti, L. F., Costa, N. O., Vieira, M. L., Ceravolo, G. S., Moreira, E. G., Gerardin, D. C. C., 2020. Can maternal exposure to paracetamol impair reproductive parameters of male rat offspring? Reprod. Toxicol. 93, 68-74.
  • Scagliotti, G.V., Kortsik, C., Dark, G.G., Price, A., Manegold, C., Rosell, R., O'Brien, M., Peterson, P.M., Castellano, D., Selvaggi, G., Novello, S., Blatter, J., Kayitalire, L., Crino, L., Paz-Ares, L., 2005. Pemetrexed combined with oxaliplatin or carboplatin as first-line treatment in advanced non-small cell lung cancer: a multicenter, randomized, phase II trial. Clin. Cancer. Res. 11, 690–696.
  • Seethalakshmi, L., Flores, C., Kinkead, T., Carboni, A. A., Malhotra, R. K., Menon, M., 1992. Effects of subchronic treatment with cis-platinum on testicular function, fertility, pregnancy outcome, and progeny. Int. J. Androl. 13, 65-74.
  • Selter, J., Huang, Y., Grossman Becht, L. C., Palmerola, K. L., Williams, S. Z., Forman, E., Ananth, C. V., Hur, C., Neugut, A. I., Hershman, D. L., Wright, J. D., 2019. Use of fertility preservation services in female reproductive-aged cancer patients. Am. J. Obstet. Gynecol. 221, 328.e1-328.e16.
  • Shi, J., Sun, J., Liu, C., Chai, Z., Wang, N., Zhang, H, Cheng, S., 2019. All-trans-retinoic acid (ATRA) plus oxaliplatin plus 5-fluorouracil/leucovorin (FOLFOX) versus FOLFOX alone as palliative chemotherapy in patients with advanced hepatocellular carcinoma and extrahepatic metastasis: study protocol for a randomized controlled trial. Trials. 20, 245.
  • Silva, R. C., Britto, D. M. C., de Fátima Pereira, W., Brito-Melo, G. E. A., Machado, C. T., Pedreira, M. M., 2018. Effect of short- and medium-term toxicity of doxorubicin on spermatogenesis in adult Wistar rats. Reprod. Biol. 18, 169–176.
  • Sinha-Hikim, A. P., Bartke, A., Russell, L., 1989. Morphometric studies on hamster testis in gonadally active and inactive states: light microscopic findings. Biol. Reprod. 39, 1225-1237.
  • Smart, E., Lopes, F., Rice, S., Nagy, B., Anderson, R. A., Mitchell, R. T., Spears, N., 2018. Chemotherapy drugs cyclophosphamide, cisplatin and doxorubicin induce germ cell loss in an in vitro model of the prepubertal testis. Sci. Rep. 8, 1773.
  • Spanos, C.P., Mamopoulos, A., Tsapas, A., Syrakos, T., Kiskinis, D. (2008). Female fertility and colorectal cancer. Int. J. Colorectal. Dis. 23, 735-743.
  • Springfeld, C., Jäger, D., Büchler, M. W., Strobel, O., Hackert, T., Palmer, D. H., Neoptolemos, J. P., 2019. Chemotherapy for pancreatic cancer. Presse. Med. 48, 159-174.
  • Théroux-Rancourt, G., Voggeneder, K., Tholen, D., 2019. Shape matters: the pitfalls of analyzing mesophyll anatomy. New. Phytol. 225, 2239-2242.
  • Varghese, A. C., du Plessis, S. S., Agarwal, A., 2008. Effect of endocrine disrupting chemicals on sertoli cell function. Reproduc. Bio. Med. 17, 866–880.
  • Wafai, L., Taher, M., Jovanovska, V., Bornstein, J. C., Dass, C. R., Nurgali, K. (2013). Effects of oxaliplatin on mouse myenteric neurons and colonic motility. Front. Neurosci. 7, 30.
  • Yang, Z. W., Guo, Y., Lin, L., Wang, X. H., Tong, J. S., Zhang, G. Y., 2004. Quantitative (stereological) study of incomplete spermatogenic suppression induced by testosterone undecanoate injection in rats. Asian. J. Androl. 6, 291-297.
  • Zou, Y., Biao, L., Xu, F., Liu, R., Liu, Z., Fu, Y., 2016. Structural study on the interactions of oxaliplatin and linear DNA. Scanning. 38, 880-888.
  • Zhou, D., Wang, H., Zhang, J., Gao, X., Zhao, W., Zheng, Y., 2010. Di-n-butyl phthalate (DBP) exposure induces oxidative damage in testes of adult rats. Syst. Biol. Reprod. Med. 56, 413–419.
  • Zhang, L. D., Li, C. H., Chong, T., Gao, M., Yin, J., Fu, D. L., Dang, Q., Wang, Z. M., 2014. Prepubertal exposure to genistein alleviates di-(2-ethylhexyl) phthalate induced testicular oxidative stress in adult rats. Biomed. Res. Int. 2014, 598630.