Systematic analyses uncover endocrine-disrupting chemical-responsive genes linked to endometriosis

Endometriosis is a chronic, estrogen-dependent disorder influenced by both genetic and environmental factors, including endocrine-disrupting chemicals (EDCs). This study aimed to identify EDC-responsive genes contributing to endometriosis risk by integrating Mendelian randomization (MR), Bayesian colocalization, and single-cell RNA sequencing (scRNA-seq). We first compiled a list of EDC-responsive genes using curated chemical-gene interaction databases. MR and Bayesian colocalization analyses were applied to integrate gene expression quantitative trait loci (eQTL) data with genome-wide association study (GWAS) data for endometriosis. We identified eight genes (PRLR, SULT1B1, DIP2B, FBXO5, CDCA2, AGPAT1, PDE5A, and VPS13B) with strong evidence for causal association and shared genetic regulation. The scRNA-seq revealed that these genes are differentially expressed across key cell types, including mesenchymal, epithelial, and smooth muscle cells. PRLR was enriched in mesenchymal cells, while PDE5A showed high expression in smooth muscle cells. The chemical-gene interaction network further highlighted specific EDCs linked to these genes, such as perfluorooctanoic acid, triphenyl phosphate, and bisphenol A. This study uncovers molecular pathways by which EDCs may influence endometriosis risk and identifies potential biomarkers and therapeutic targets. The findings also establish a scalable approach for studying gene-environment interactions in other hormone-sensitive conditions.