Bisphenol A alters JUN promoter methylation, impairing steroid metabolism in placental cells and linking to sub-representative phenotypes.

Abstract

Bisphenol A (BPA) is a widely used industrial compound commonly found in various everyday plastic products. Known for its endocrine-disrupting properties, BPA can enter the human body through multiple pathways. Prenatal exposure to BPA not only disrupts placental structure and function but also interferes with normal steroid metabolism. This study investigates the epigenetic regulatory mechanisms by which BPA influences steroid metabolism in the placenta. Using BPA-treated JEG3 cells, we analyzed hormone levels, gene promoter DNA methylation, and gene expression, further validating our findings in placental samples. Additionally, we explored the role of epigenetic modifications in regulating steroid metabolism at the cellular level and assessed related phenotypes in cohort samples. The results demonstrated that BPA significantly reduced the levels of progesterone, estradiol, and testosterone, and notably affected the promoter methylation and expression levels of 63 genes. Enrichment analysis highlighted PLA2G4F, JUN, MRAS, ERBB4, DUSP1, and GADD45G as being primarily enriched in the MAPK signaling pathway. Further studies revealed that the methylation level of the JUN promoter regulates its expression, impacting hormone levels by modulating downstream signaling pathways. In placental samples, male offspring in the hypermethylated JUN promoter group had shorter anogenital distance (AGD) compared to those in the hypomethylated group. These findings suggest that BPA reduces the expression of steroid metabolism genes via the epigenetic regulation of the JUN gene, thereby decreasing progesterone, estradiol, and testosterone levels and leading to shortened AGD in offspring.