Neonatal exposure to bisphenol A and bisphenol S induces reproductive toxicity without altering sexual differentiation of the anteroventral periventricular nucleus in female rats.

Bisphenol A (BPA) is a prevalent endocrine disruptor, and bisphenol S (BPS), increasingly used as an alternative, is suspected of sharing similar biological activity. We investigated whether acute neonatal exposure to BPA and BPS affects sexual differentiation of the anteroventral periventricular nucleus (AVPV) and whether chronic developmental exposure impairs female reproductive physiology in Sprague-Dawley rats. For acute exposure, pups received four subcutaneous injections on postnatal days 1 and 2 (PND1-2) at 12-hour intervals. Experimental groups were vehicle (castor oil, 50 µL), estradiol (E2, 50 µg), BPA (250 µg), and BPS (250 µg). On PND19, the hypothalamus was isolated and analyzed for AVPV tyrosine hydroxylase (TH)-positive neurons and estrogen receptor alpha (ERα) expression. To assess chronic effects, female pups received daily subcutaneous injections from PND1 to 75 with vehicle, BPA (2 and 200 µg/kg), and BPS (2 and 200 µg/kg). Acute estradiol exposure significantly reduced TH-positive neurons, validating the model's sensitivity, whereas BPA and BPS did not significantly alter TH-neuronal density and estrogen receptor-α expression. However, chronic BPA and BPS exposure induced marked reproductive toxicity, including increased body weight, decreased ovarian and uterine weights, and a dose-dependent reduction in the gonadosomatic index. Folliculogenesis was disrupted, with fewer antral follicles and corpora lutea and greater follicular atresia, accompanied by reduced progesterone, elevated testosterone, and reduced myometrial thickness at higher doses. These findings indicate that despite the absence of measurable AVPV masculinization after acute neonatal exposure, chronic BPA and BPS exposure induced endocrine and reproductive toxicity. The comparable effects of BPS and BPA therefore call into question BPS as a safer substitute.