Heavy metals exposure and HPG-axis related hormones in women across the lifespan: An integrative epidemiological and bioinformatic perspective

Background: Hormonal disruption evidence of metal exposure is lacking and contradictory. Objectives: To elucidate the association of multiple metals exposure with a comprehensive panel of sex hormones in women across the lifespan. Methods: 5492 women aged 3–80 from a national survey were included. Multivariable linear regression, restricted cubic splines, and receiver operating characteristic curves were employed to assess individual metal exposure with sex hormones. Quantile-based g computation was used to explore mixture exposure association. Vitamin D and folate were examined as the modifiers. Integrative bioinformatics analysis was conducted leveraging a network of databases to reveal underlying mechanisms. Results: Exposure to cadmium, lead (Pb), mercury (Hg), selenium, and manganese was associated with sex hormones. For example, in young adult (20–49 years), Pb was associated with androstenedione [3.89 %, 95 % CI: 0.81, 7.06], estrone sulfate [8.14 %, 95 % CI: 1.54, 15.18], and luteinizing hormone [12.29 %, 95 % CI: 5.01, 20.07]; Hg was associated with estrone sulfate [4.84 %, 95 % CI: 0.62, 9.22]. Metals mixture was mainly associated with young adults’ increased sex hormones with effect ranging from 5.37 % (95 % CI: 1.77, 9.10) to 17.83 % (95 % CI: 9.04, 27.34). Folate modified such associations with hazardous effect appeared in high folate level in young adults, while in low folate level in other age groups. Inflammatory signaling pathways such as TNF and IL-17 may mediate metal-induced sex hormones disturbance. Conclusions: Our findings highlight the significant associations, folate modifications, and potential pathways of metal exposure on female sex hormones, which provides insights for prevention avenues and mechanisms.