Lipid clues: Decoding the effects of endocrine-disrupting chemicals on female reproductive health

Multiple epidemiological studies across countries have linked exposure to endocrine-disrupting chemicals (EDCs) with adverse reproductive outcomes; however, the underlying mechanisms remain incompletely characterized. In this study, we profiled EDCs, lipids, and fatty acid metabolites in follicular fluid (FF) to elucidate metabolic pathways through which EDCs may affect reproductive outcomes. We further integrated network toxicology with an adverse outcome pathway (AOP) framework to delineate mechanistic routes by which EDCs may impair female reproductive health via metabolic disruption. We measured EDCs and metabolites in FF, and assessed assisted reproductive outcomes in 173 women from the SEARCH cohort. Overall, associations between EDCs and lipid or fatty acid profiles varied by chemical and class, consistent with previous studies. We further observed evidence of oocyte lipid metabolism dysregulation in relation to EDC exposure. Specifically, the diacylglyceride (DG) and phosphatidylethanolamine (PE) → phosphatidylcholine (PC) and lysophosphatidylcholine (LPC) pathway was upregulated. Poorer oocyte developmental outcomes were characterized by significantly lower PE and LPE levels (log2FC: −0.30 and −0.07, respectively), and PE and LPE levels were associated with oocyte development (β: 0.141 and 0.090, respectively). Notably, phthalate exposure was associated with lower LPE (β [95% CI]: −0.001 [-0.002, 0.000]). Network and adverse outcome pathway (AOP) analysis identified mitochondrial dysfunction as a central mechanism mediating the association between EDC exposure and impaired fertility. In conclusion, these findings provide novel molecular insights into environmental determinants of female reproductive success. • The first study to investigate the association between EDCs and lipid/fatty acid metabolism in FF. • Different EDCs in FF exerted distinct effects on lipid/fatty acid metabolites. • PE and LPE in FF are significantly associated with early ART outcomes. • Disruption of the lipid cycle leads to poor oocyte development. • Network analysis and AOP analysis identified key mediators of EDCs in causing infertility.