Mapping Steroidogenic Perturbations Under Endocrine Disruptor Mixtures Across Demographic Subgroups: Structural and Metabolomic Insights

Endocrine-disrupting chemicals (EDCs) are pervasive environmental chemicals affecting hormone homeostasis, yet mapping mixture exposures to mechanisms at the population scale remains challenging. Here, analyses of 4255 U.S. participants are integrated with computational and experimental validation, linking population signals to molecular targets. Profiling 37 EDCs reveals consistent associations between phthalate metabolites and lower testosterone, strongest in adult males. Mono-(3-carboxypropyl) phthalate (MCPP) is identified as a key disruptor and is shown to inhibit CYP17A1, consistent with engagement of the enzyme's iron-protoporphyrin IX (heme) center. Docking/molecular dynamics prioritizes this interaction, which is supported by surface plasmon resonance, multi-matrix metabolomics in vivo and in vitro, and functional assays in primary Leydig cells. An interactive web resource (https://chembio.njmu.edu.cn/edc-hormone-explorer.html) provides open access to the association landscape and supports risk prioritization.