# Polychlorinated Biphenyl-126 Activates AXL/ERb/DNMT3A Axis to Drive Endometriosis Progression

## TL;DR

This study shows how a chemical called PCB-126 worsens endometriosis by activating specific molecular pathways, leading to inflammation and disease progression.

## Contribution

The study identifies a novel AXL/ERβ/DNMT3A signaling axis activated by PCB-126 that drives endometriosis progression.

## Key findings

- PCB-126 promotes endometriotic lesion growth via the SRC-1/MMP9/ERβ axis in a mouse model.
- AXL/GAS6 signaling enhances ERβ activity in endometriotic lesions, and AXL inhibition suppresses lesion growth.
- PCB-126/ERβ signaling increases DNMT3A expression, contributing to inflammation and immune dysregulation.

## Abstract

Endometriosis is a pathological condition in which endometrial cells proliferate outside the uterine cavity, resulting in pelvic pain and infertility. Exposure to endocrine-disrupting chemicals (EDCs) has been implicated in the progression of endometriosis, though the precise mechanisms remain largely undefined. Among EDCs, elevated levels of polychlorinated biphenyl (PCB)-126 have been strongly associated with endometriosis, particularly in patients with deep infiltrating disease. 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 key driver of disease progression. PCB-126 also enhanced ERβ activity via upregulation of the AXL Receptor Tyrosine Kinase (AXL)/Growth Arrest-Specific 6 (GAS6) signaling pathway in endometriotic lesions. Notably, BMS-777607, an AXL inhibitor, effectively suppressed lesion growth in this model. Moreover, the PCB-126/ERβ axis directly increased expression of DNA Methyltransferase 3A (DNMT3A), contributing to inflammation and immune dysregulation in endometriotic tissue. Collectively, these findings suggest that PCB-126 promotes endometriosis progression through coordinated activation of the AXL/ERβ/DNMT3A axis, driving estrogen-mediated epigenetic and immunoinflammatory responses.