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

Area of Science:

• Reproductive biology
• Environmental toxicology
• Molecular endocrinology

Background:

• Endometriosis is a condition causing pelvic pain and infertility.
• Endocrine-disrupting chemicals (EDCs), like PCB-126, are linked to endometriosis progression.
• Mechanisms linking EDCs to endometriosis are not fully understood.

Purpose of the Study:

• To investigate the role of PCB-126 in endometriosis progression.
• To elucidate the molecular pathways involved in PCB-126-induced endometriosis.
• To evaluate the therapeutic potential of targeting the AXL pathway.

Main Methods:

• Utilized a mouse model of endometriosis.
• Assessed the impact of PCB-126 exposure on ectopic lesion growth.
• Investigated the activation of SRC-1/MMP9/ERβ and AXL/GAS6 signaling pathways.
• Evaluated the efficacy of the AXL inhibitor BMS-777607.
• Examined the expression of DNMT3A and its role in inflammation and immune dysregulation.

Main Results:

• PCB-126 exposure significantly promoted ectopic lesion growth in mice.
• PCB-126 activated the SRC-1/MMP9/ERβ axis and enhanced ERβ activity via the AXL/GAS6 pathway.
• The AXL inhibitor BMS-777607 suppressed PCB-126-induced lesion growth.
• PCB-126/ERβ axis upregulated DNMT3A, leading to inflammation and immune dysregulation.

Conclusions:

• PCB-126 promotes endometriosis progression by activating the AXL/ERβ/DNMT3A axis.
• This pathway drives estrogen-mediated epigenetic changes and immunoinflammatory responses.
• Targeting the AXL pathway offers a potential therapeutic strategy for endometriosis.