Polychlorinated biphenyl Endocrine Disruptor Alters Estrogen Receptor beta-Mediated Epigenetic Regulation, Promoting Endometriosis.

BACKGROUND

Endometriosis is a pathological condition characterized by the ectopic proliferation of endometrial cells, resulting in chronic pelvic pain and infertility. Exposure to endocrine-disrupting chemicals (EDCs) has been implicated in the development and progression of endometriosis; however, the underlying mechanisms remain largely unclear. Among these EDCs, elevated levels of polychlorinated biphenyl-126 (PCB-126) have been strongly associated with endometriosis. Yet, how PCB-126 exposure contributes to disease progression remains an unresolved and fundamental question.

METHOD: Surgically induced endometriosis mice were randomly assigned to treatment with PCB-126 or vehicle control. To assess the effects of PCB-126 on human endometrial cells, immortalized human endometrial epithelial and stromal cell lines were utilized. To investigate the role of AXL receptor tyrosine kinase (AXL) in PCB-126-mediated endometriosis progression, surgically induced endometriosis mice were randomly treated with an AXL inhibitor. To evaluate the contribution of DNA methyltransferase 3A (DNMT3A) to endometriosis progression, ectopic lesions were generated using endometrium-specific Dnmt3a knockout mice (Dnmt3af/f:Progesterone ReceptorCre/+). RNA sequencing was then performed on Dnmt3a knockout ectopic lesions and compared to control lesions to define the role of DNMT3A in endometriosis progression.

RESULTS

In a mouse model of endometriosis, PCB-126 exposure significantly promoted the growth of ectopic lesions by activating the Steroid Receptor Coactivator-1 (SRC-1) isoform/Matrix Metalloproteinase-9 (MMP9)/Estrogen Receptor-β (ERβ) axis, a critical pathway driving disease progression. Additionally, PCB-126 enhanced ERβ activity through upregulation of the AXL/Growth Arrest-Specific 6 (GAS6) signaling pathway within endometriotic lesions. Notably, treatment with BMS-777607, an AXL inhibitor, effectively suppressed ectopic lesion growth in mice. Furthermore, the PCB-126/ERβ axis upregulated Dnmt3a expression, contributing to inflammation and immune dysregulation within ectopic lesions and thereby exacerbating endometriosis progression.

CONCLUSION

PCB-126 promotes endometriosis progression through coordinated activation of the AXL/ERβ/DNMT3A axis, disrupting estrogen-mediated epigenetic regulation and inducing endometriosis-associated immunoinflammatory responses.