Sex-specific dysregulation of sex hormones by heavy metal mixtures: Multi-model analysis identifies cadmium as the primary driver

Environmental heavy metal exposure poses significant endocrine-disrupting risks, yet evidence regarding the impact of metal mixtures on sex hormones in susceptible populations remains limited. We conducted a cross-sectional study involving 434 participants (167 males, 267 postmenopausal females) from the Dongdagou Xinglong cohort, a well-established cohort residing in a historically heavy metal-polluted region in Northwest China. Concentrations of eight metals (aluminum, chromium, copper, zinc, arsenic, selenium, cadmium, lead) in whole blood and a panel of six sex hormones (including androgens and estrogens) in serum were measured. Multiple linear regression analysis revealed significant positive associations between blood cadmium and dehydroepiandrosterone sulfate (β = 0.468), androstenedione (β = 0.571), testosterone (β = 0.680), and estradiol (β = 0.528) in males (all P < 0.05). Conversely, in females, blood cadmium was negatively associated with dehydroepiandrosterone sulfate (β = -0.221), androstenedione (β = -0.375), testosterone (β = -0.256), progesterone (β = -0.258), estradiol (β = -0.437), and estrone (β = -0.432) (all P < 0.05). Bayesian kernel machine regression (BKMR), weighted quantile sum (WQS), and quantile-based g-computation (Qgcomp) regression models consistently demonstrated that heavy metal mixture exposure elevated androstenedione and testosterone levels in males while reducing estradiol levels in females. Cadmium was consistently identified as the primary risk factor in both males and postmenopausal females. Furthermore, animal experiments corroborated above findings: Cadmium-exposed rats exhibited dose-dependent cadmium accumulation, disruption of blood metals homeostasis, elevated serum estradiol, and reduced testosterone levels (all P < 0.05). Collectively, our analyses of a metal-exposed cohort highlight that heavy metal mixtures are associated with sex-specific dysregulation of sex hormones, wherein cadmium appears to be a primary driver. This study offers insights for assessing reproductive health risks in similar metal-polluted contexts.