Maternal supplementation of α-lipoic acid attenuates prenatal cytarabine exposure-induced oxidative stress, steroidogenesis suppression and testicular damage in F1 male rat fetus

Abstract

Abstract Background Cytarabine (Ara-C) is an anticancer drug, which is considered as the mainstay in the treatment of hematological malignancies, known to cause various teratogenic effects. Alpha-lipoic acid (ALA) is a natural antioxidant and its supplementation proved to improve pregnancy outcomes in several pathological conditions. We aimed at exploring the benefits of maternal supplementation of ALA against in-utero Ara-C exposure-induced testicular toxicity in rat fetuses. Methods Pregnant rats (dams) received normal saline (control group), ALA 200 mg/kg (ALA group), Ara-C 12.5 mg/kg (Ara-C 12.5 group), Ara-C 25 mg/kg (Ara-C 25 group), and Ara-C 25 mg/kg + ALA 200 mg/kg (protection group) from gestational day (GD)8 to GD21. Ara-C and ALA were administered via the intraperitoneal and oral routes, respectively. The day of parturition was considered as postnatal day (PND)1. On PND1, all the live male pups were collected. The maternal parameters evaluated include (a) food intake, (b) bodyweight, and (c) oxidative stress (OS) markers. The fetal parameters evaluated include (a) bodyweight, (b) anogenital distances (AGD), (c) testicular weight (d) testicular testosterone levels (e) testicular histopathology, and (f) morphometrical parameters. Results A significant and dose-dependent decrease in maternal food intake, weight gain, and an increase in oxidative stress (OS) were observed in the pregnant rats of the Ara-C groups as compared to pregnant rats of the control group. Further, a significant and dose-dependent (a) reduction in bodyweight, AGD, testicular weight, and testosterone levels, (b) increase in OS, and (c) structural and morphometrical anomalies in fetal testes were observed in fetuses of Ara-C groups as compared to fetuses of the control rats. These deleterious effects observed in the Ara-C groups were found to be diminished in the pregnant rats and fetuses of the Protection group as compared to the pregnant rats and fetuses of the Ara-C 25 group. Conclusions From the results of this study, we conclude that the maternal supplementation of ALA may ameliorate the Ara-C exposure-induced impairment in prenatal development and function of the testes in the rat fetuses. However, future experimental and clinical studies are warranted to explore the possible mechanisms involved in the protection offered by maternal supplementation of ALA against Ara-C induced testicular toxicity. Graphical Abstract