Bisphenol M Impairs Ovarian Function through Disrupting Estrogen Synthesis in Female Mice: A Comparative Study with...

Bisphenol M (BPM) has been increasingly used as a substitute for bisphenol A (BPA), yet its reproductive toxicity remains poorly characterized. Unlike BPA, which is well characterized as a weak estrogen receptor (ER) agonist, BPM has been identified as an ER antagonist. In this study, we systematically compared the effects of BPM and BPA on the reproductive neuroendocrine system of female mice during puberty. Five-week-old female ICR mice were exposed to BPM and BPA at doses of 1 μg/kg bw/day, 50 μg/kg bw/day, and 1 mg/kg bw/day for 14 days. Both chemicals induced comparable adverse reproductive outcomes at 50 μg/kg bw/day and 1 mg/kg bw/day, including reduced uterine weight, disrupted estrous cyclicity, depletion of primordial follicles, and increased follicle atresia. However, BPM and BPA had divergent effects on molecular and hormonal end points. BPM exposure significantly elevated ovarian Cyp19a1 expression, as well as serum estradiol (E2), follicle-stimulating hormone (FSH), and luteinizing hormone (LH) levels, whereas BPA did not significantly alter any of these parameters. Mechanistically, BPM acts as an ER antagonist, reducing functional E2-ER complexes and creating a perceived "E2 signaling deficiency". This triggers compensatory upregulation of ovarian ERs and steroidogenic genes (Star, Cyp19a1, and Hsd17b1), leading to enhanced E2 synthesis. The resulting hyperestrogenism exerts positive feedback on hypothalamic GnRH neurons, driving sustained gonadotropin secretion and creating a self-sustaining high-E2 loop that disrupts estrous cyclicity and follicle dynamics. In contrast, BPA, as a weak ER agonist, partially substitutes for endogenous E2 at ERs, preventing the perception of E2 deficiency. Consequently, no compensatory steroidogenic activation occurs, and hormone levels remain unchanged. Despite these distinct mechanisms, both compounds impair female reproductive function. Importantly, BPM exerted more pronounced endocrine disturbances than BPA, raising concerns regarding its use as a safer alternative. These findings highlight the necessity of comprehensive toxicological evaluation of BPA analogues and emphasize that ER antagonism does not necessarily imply reduced reproductive risk.