Paternal exposure to testis cancer chemotherapeutics alters sperm fertilizing capacity and affects gene expression in the eight-cell stage rat embryo

Abstract

Treatment of testicular cancer includes the coadministration of bleomycin, etoposide and cis-platinum (BEP); however, along with its therapeutic benefit, BEP exposure results in extensive reproductive chemotoxic effects, including alterations to sperm chromatin integrity. As an intact paternal genome is essential for successful fertilization and embryogenesis, we assessed the effect of paternal exposure to BEP on sperm fertilization capacity and the resulting consequences on early embryonic gene expression. Adult male Brown Norway rats received a 9-week treatment with BEP or saline and then were sacrificed immediately or subject to a 9-week recovery period. HSP90AA1, HSP90B1 and PDIA3, involved in spermatozoa-egg interactions, were overexpressed in BEP-exposed spermatozoa after the 9-week treatment period; overexpression was also observed in spermatozoa from BEP-treated rats after 9 weeks of recovery. These proteins were localized to the plasma membrane of the sperm head; this localization may facilitate their role in spermatozoa-egg interactions as the highest staining intensities were observed in capacitated spermatozoa. The fertilization potential of spermatozoa was determined by in vitro fertilization with oocytes from unexposed naturally cycling female rats. Interestingly, the fertilization potential of spermatozoa following a 9-week recovery period from BEP treatment was significantly enhanced compared with controls. Moreover, stem cell transcription factors, involved in the regulation of a plethora of early embryonic events, were upregulated by more than twofold in eight-cell stage embryos sired by BEP recovery males compared with controls; this suggests that there are potential deleterious effects on embryo development well after termination of BEP exposure.

Carnitine partially improves oxidative stress, acrosome integrity, and reproductive competence in doxorubicin‐treated rats

“…Finally, there are two subjects that must be emphasized here: (i) The exposure to chemotherapeutic drugs may cause adverse effects on the progeny (Hales et al ., ); and (ii) an intact paternal genome is essential for successful fertilization and embryogenesis (Maselli et al ., ). In the present research, the quality and viability of early embryos were not evaluated, but the results of reproductive capacity showed that doxorubicin increased the embryonic loss in comparison to control rats; nevertheless, carnitine administered alone or previously to doxorubicin did not significantly cause any harmful alteration in the reproductive parameters covered by our studies, but it improved some of them.…”

Lutein Attenuates Cyclosporin-induced Testicular Impairment in Male Rats through Modulation of Androgenic Hormones and Enzymes

“…In this study, alteration in sperm acrosomal integrity in cyclosporinetreated group suggests a reduction in the spermatozoa's fertilization capacity of the rats. The ability of lutein to normalize the altered ALP, ACP, sialic acid content as well as sperm acrosomal integrity however, suggests improvement in acrosomal integrity, decreased cellular stress and enhanced spermatogenesis (Maselli et al, 2014).…”

Identification and Validation of Yak (Bos grunniens) Frozen–Thawed Sperm Proteins Associated with Capacitation and the Acrosome Reaction

“…Here, AR sperm exhibited a drop in HSP90AA1 protein levels. HSP90AA1 is a ubiquitously expressed chaperone protein that aids in protein transport, assembly, and folding, , localizing to the flagellum and head of sperm cells. , HSP90AA1 is an important regulator of diverse cellular processes including ROS scavenging, apoptosis, ATP metabolism, and sperm motility . These different activities may shape the role played by HSP90AA1 in the setting of sperm AR induction.…”