Age-Dependent Effects of Heavy Metals on the Hypothalamic–Pituitary–Testicular Axis-Related Hormones in Men

The effect of heavy metals on male hormonal regulation-particularly the hypothalamic-pituitary-testicular (HPT) axis-remains poorly characterized. We aim to investigate associations between heavy metal exposure and HPT axis-related hormones. We analyzed data, including male participants aged 3-80 years, from a nationally representative survey. Five metals and twelve sex hormones were measured. We used multivariate linear regression and restricted cubic splines to assess associations and dose-response relationships. Mixture effects were quantified using quantile-based g computation. The modifying effects of vitamin D and folate were examined. The underlying mechanisms were explored through a narrative review and integrative bioinformatics analysis. A total of 6547 males were included. Metal exposure was predominantly associated with hormonal perturbations in adolescents and older adults. Specifically, metal mixture was associated with hormones in adolescent males [effect range: -5.10% (95% CI: -9.24, -0.76) to 18.12% (95% CI: 9.80, 27.07)] and older males [effect range: 3.17% (95% CI: 0.07, 6.37) to 10.94% (95% CI: 4.82, 17.43)]. Effect modifications were observed for vitamin D in children and adolescents, and for folate across all age groups. The <i>PI3K-Akt</i> signaling pathway was identified as a potential mechanism. Our findings provide novel insights into the association and potential pathway between heavy metals and male hormonal disturbance.