Abstract
Endocrine disrupting chemicals (EDCs) have been associated with disorders affecting female reproductive health, although the precise causal connections and underlying pathways between these substances and such disorders remain incompletely elucidated. Our research implemented multidimensional Mendelian randomization techniques to assess potential causal associations between EDCs and female reproductive diseases (FRDs), while simultaneously evaluating the intermediary functions of metabolites in plasma. Harnessing summary data, we implemented inverse variance weighting method (IVW) as our principal analytical framework to explore causal relationships between 15 EDCs and 11 prevalent FRDs. Additionally, we deployed 4 supplementary methodologies, encompassing MR-Egger regression, weighted median, simple model, and weighted model, to conduct extended investigations. To ensure robustness, we used Cochran's Q test, MR-Egger regression, Mendelian randomization pleiotropy residual sum and outlier, and the leave-one-out method to conduct sensitivity analyses. Moreover, comparable analytical strategies were employed to explore the intermediary contributions of plasma metabolites. Four EDCs showed causal associations with FRDs. Specifically, mono-(2-ethyl-5-carboxypentyl) phthalate was found to increase gestational hypertension susceptibility (OR = 1.541, 95% confidence interval [CI]: 1.063-2.232, P = .022), whereas mono-methyl phthalate demonstrated heightened associations with endometriosis occurrence (OR = 1.058, 95% CI: 1.013-1.104, P = .011) and pregnancy-induced hypertensive conditions (OR = 1.113, 95% CI: 1.001-1.238, P = .047). Furthermore, mediation analysis identified 13 plasma metabolites that mediated EDCs-FRDs associations, including sulfated steroids (e.g., 5α-androstan-3α,17β-diol disulfate) and lipid derivatives. The other 4 auxiliary methods yielded consistent directional estimates. EDCs indicate evidence consistent with causal effects on FRDs risk. Plasma metabolites may represent essential intermediary regulators in the causal pathway between EDCs and FRDs. These findings advocated reducing EDCs exposure and targeting metabolic pathways for FRDs prevention.