Sodium orthovanadate alleviates lethal effect of total-body irradiation in mice without impairing recovery of male reproductive function.

Sodium orthovanadate (vanadate), a potent inhibitor of p53, has been shown in earlier work to alleviate total-body irradiation (TBI)-induced hematopoietic syndrome. However, as p53 plays a crucial role in normal spermatogenesis, its suppression may raise concerns about potential adverse effects on male reproductive function. In this study, we investigated whether vanadate exacerbates impairment of male fertility when administered for hematopoietic protection under TBI conditions. Trp53 wild-type male ICR mice received a single intraperitoneal injection of vanadate or vehicle, followed by exposure to 6 Gy-TBI, corresponding to a testicular dose of 4.8 Gy. This radiation dose is sufficient to induce hematopoietic syndrome and temporary infertility. Spermatogenic function was assessed by analyzing testicular haploid cell populations and sperm morphology. Fertility recovery was evaluated through mating tests with virgin females, and transgenerational outcomes were assessed by analyzing litter size, fetal body weight, and implantation numbers. Our findings demonstrate that vanadate effectively rescued survival of irradiated animals under conditions known to induce the hematopoietic syndrome, without adversely affecting spermatogenesis. On the contrary, vanadate appeared to promote recovery from temporary infertility, likely through partial suppression of p53 accumulation and Bbc3 expression. This effect was more pronounced in Trp53 heterozygous mice, particularly in those irradiated at a young age. Importantly, the offspring derived from vanadate treated males with recovered fertility exhibited normal development, at least in terms of morphology. Taken together, vanadate confers hematopoietic protection under TBI without compromising, and possibly even supporting, male reproductive recovery. These findings suggest its potential for clinical use with low risk to male fertility.