CBD-rich oil nanoemulsion mitigates long-term testicular and endocrine toxicity induced by prenatal valproic acid exposure in rats.

Valproic acid is a widely used antiepileptic drug and a recognized model of developmental reproductive toxicity, as exposure during critical periods of testicular development can lead to persistent endocrine and reproductive dysfunction in adulthood. Cannabidiol (CBD) has therapeutic potential in several pathological conditions but exhibits low oral bioavailability due to its lipophilic nature. This study evaluated whether chronic treatment with a CBD-rich corn oil nanoemulsion could attenuate long-term testicular and endocrine alterations induced by prenatal valproic acid exposure in rats. CBD-rich nanoemulsions were prepared and physicochemically characterized. On gestational day 12.5, pregnant rats received a single intraperitoneal dose of valproic acid (500 mg/kg). In adulthood, male offspring from valproic acid-exposed dams were treated orally with CBD nanoemulsions at doses of 1 or 2 mg/animal, administered twice daily. After euthanasia, testes were collected for morphometric, biochemical, and hormonal analyses. Prenatal exposure to valproic acid induced persistent testicular alterations, including reduced Leydig cell number, decreased serum testosterone levels, reduced seminiferous epithelium height, and increased seminiferous tubule diameter. Increased activities of superoxide dismutase and glutathione S-transferase suggested an adaptive antioxidant response. These findings are consistent with long-term testicular and endocrine dysfunction following developmental exposure to an endocrine-disrupting drug. Importantly, treatment with the CBD-rich nanoemulsion reversed the morphometric, hormonal, and oxidative alterations induced by valproic acid. Overall, these results indicate that nanoformulated CBD may mitigate long-term reproductive toxicity induced by prenatal valproic acid exposure, highlighting the importance of drug formulation in determining the biological effects of cannabinoids on the male reproductive system.