The effects of bisphenol compounds on endocrine disruption and reproductive function from epidemiological analysis to animal exposure: A mixture analysis

Bisphenol F (BPF) and Bisphenol S (BPS) are widely used substitutes for Bisphenol A (BPA). However, growing evidence indicated that BPF and BPS may induce physiological effects similar to those of BPA. Furthermore, chemical management and control is primarily focus on the risk assessment of individual compounds, often overlooking the implications of chemical mixtures. We hypothesize that exposure to a mixture of BPA and its substitutes will enhance their endocrine-disruptive effects, disrupt steroid hormone homeostasis, and further impair reproductive system functionality. In the animal study, both female and male mice were exposed to 333 μg/kg of BPA, BPF, BPS, their mixture (333 μg/kg (MIXL), and 1 mg/kg (MIXH)) via gavage daily for four weeks. The study demonstrated that bisphenols (BPs) affected the expression of genes related to steroid hormone synthesis. The MIXL group of female mice exhibited an increasing trend in estradiol (E2) levels and a decreasing trend in progesterone (Pg) and testosterone (TT) levels. Additionally, follicular development was impacted, resulting in an increased number of atretic follicles. In contrast, a significant increase in E2 concentration and disruption of testicular morphology were observed in the MIXH group of male mice, accompanied by a decline in sperm quality. Importantly, these results were corroborated by a population-based investigation. Collectively, the animal experiments indicate that mixed exposure to BPs disrupts hormone levels and adversely affects reproductive function, while epidemiological evidence further establishes correlative links between bisphenols and hormone levels. These findings underscore the necessity of considering chemical mixtures during testing and risk assessment.