Polychlorinated Biphenyls Alter Estrogen Receptor beta–Mediated Epigenetic Regulation, Promoting Endometriosis

Endometriosis is a pathological condition characterized by the ectopic growth of endometrial cells, leading to chronic pelvic pain and infertility. Epidemiological studies have associated exposure to dioxin-like polychlorinated biphenyls (PCBs), particularly PCB126, with an increased risk of endometriosis. However, the underlying mechanisms of this association remain poorly understood. We utilized a surgically induced endometriosis mouse model and human endometrial cell lines to assess the impact of PCB126 on endometriosis progression. Mice were exposed to environmentally relevant doses of PCB126. Endometriotic lesion growth, estrogen receptor signaling, receptor tyrosine kinase activity, and gene expression changes induced by PCB126-mediated elevation of DNA methyltransferase 3A (DNMT3A) were evaluated using histology, bioluminescent imaging, immunoblotting, and RNA sequencing. Functional validation was conducted using a pharmacologic AXL inhibitor and tissue-specific Dnmt3a knockout mice. PCB-126 significantly promoted the growth of ectopic lesions and humanized models of endometriosis. Mechanistically, PCB-126 enhanced estrogen receptor beta (ESR2) activity by upregulating AXL and its ligand, Growth Arrest–Specific 6 (GAS6), and elevating DNMT3A expression. The inhibition of AXL signaling suppressed the growth of endometriotic lesions. ESR2 directly regulated Dnmt3a expression, and loss of Dnmt3a reduced lesion growth and inflammatory cytokine production, thereby reversing immune dysregulation. These findings establish a mechanistic link between PCB-126 exposure and epigenetic and immune reprogramming in endometriotic lesions. Our findings establish a mechanistic connection between environmental PCB-126 exposure and endometriosis progression via the AXL/ESR2/DNMT3A axis. This study provides new insight into how endocrine-disrupting chemicals promote hormone-sensitive diseases through epigenetic and immunological pathways, offering potential targets for therapeutic intervention.