Exploring the mechanism link between endocrine disrupting chemicals and metabolic diseases: Observational and GWAS evidence.

Endocrine disrupting chemicals (EDCs) are widespread environmental contaminants that may contribute to the development of metabolic diseases. However, their causal roles and biological mechanisms remain unclear. This study aimed to investigate the associations between EDC exposure and metabolic disorders by integrating epidemiological and genetic approaches. A pooled analysis of 53 observational studies, comprising 109394 participants, demonstrated that EDC exposure significantly increased the risk of metabolic diseases (OR=1.38, 95 %CI=1.28-1.48, I2=82.3 %, P < 0.01). Positive associations were observed across several metabolic outcomes, including hypertension, non-alcoholic fatty liver disease (NAFLD), type 2 diabetes mellitus (T2DM), and polycystic ovary syndrome (PCOS). Subgroup analyses by age, sex, and geographic region revealed generally consistent associations across populations. In addition, an dose-related association analysis for bisphenol A (BPA) suggested an increasing exposure-risk trend. To further explore the causality, we conducted a two-sample Mendelian randomization (MR) analysis using Genome-Wide Association Study (GWAS) data from 15 EDCs and 9 metabolic outcomes. After false discovery rate correction, MR results supported robust causal relationships between specific EDCs and coronary atherosclerosis, hypertension, and testicular dysfunction. In addition, suggestive associations were observed for obesity, fasting plasma glucose, and PCOS. Pathway enrichment analysis implicated phospholipase D signaling and MAPK signaling as potential biological pathways underlying EDC-related metabolic dysfunction. Our findings provide robust epidemiological and genetic evidence linking EDC exposure to metabolic disease risk and highlight the need for regulatory policies to reduce EDC-related health burdens.