Exposure to mixed chemicals elevated triiodothyronine (T3) and follicle-stimulating hormone (FSH) levels: epidemiology and in silico toxicogenomic involvement.

There is a dearth of evidence on the effects of a mixture of numerous different types of chemicals on hormone functions. We hypothesized that exposure to mixed chemicals may alter hormone levels. Thus, this study was to identify an association between the mixed chemicals (25 chemicals) and hormone levels (thyroxine (T4) and triiodothyronine (T3), thyroid-stimulating hormone (TSH), and follicle-stimulating hormone (FSH)) among 5687 Korean adults using four different statistical approaches. Furthermore, we elucidate the effects of the key chemicals on thyroid disease and infertility based on the findings from epidemiology data. The positive associations between mixed chemicals and T3 and between mixed chemicals and FSH were observed across different methods after adjusting for all possible confounders. In the weighted quantile sum regression models, there were positive associations between mixed chemicals and T3 (β = 4.43, 95%CI: 2.81-5.88) and ln-transformed FSH (lnFSH) (β = 0.15, 95%CI: 0.10-0.20). In the quantile g-computation models, positive associations were found between mixed chemicals and T3 (β=2.15, 95%CI: 0.17-4.14) and lnFSH (β=0.15, 95%CI: 0.07-0.22). In the Bayesian kernel machine regression models, culminative effects of mixed chemicals showed positive associations with T3 and lnFSH; mercury (group posterior inclusion probabilities (PIPs) = 0.557 and conditional PPI = 0.556) and lead (group PIP group = 0.815 and conditional PPI = 0.951) were the most important chemicals for T3 and FSH, respectively. The results obtained were partially robust when subjected to in silico toxicogenomic data. We identified several molecular mechanisms that were implicated in Hg-induced thyroid disease, including the selenium micronutrient network, oxidative stress response, IL-17 signaling pathway, poorly differentiated thyroid carcinoma, and primary hyperthyroidism. The molecular processes implicated in Pb-induced infertility were "response to nutrient levels," "gonad development," "male infertility," "female infertility," and "intrinsic pathway for apoptosis," with a particular focus on FSH. The present study investigated the threshold levels of the studied chemicals and their potential impact on the disruption of T3 and FSH hormones. Future research is warranted to determine the effects of mixed chemicals on various hormones because there have been few studies on the disruption of hormones caused by such mixed chemicals.