Chemical exposure in females of childbearing age associated with sex hormones: Evidence from an untargeted exposomic approach

Exposure to organic chemicals can cause reproductive hormones disturbance in women. However, there is very limited evidence regarding real-world chemical exposures in reproductive-aged women and their joint effects on sex hormone levels. Here, we applied non-targeted screening workflow based on High-Performance Liquid Chromatography-High-Resolution Mass Spectrometry to investigate the serum chemical exposome of 156 women of childbearing age from Jinan, China. A total of 185 exogenous chemicals from 19 categories were identified in at least 80% of serum samples with confidence levels 1-3, 84 of which have never been reported in humans, and 9 of those showed active effects on multiple biological targets in ToxCast program. A combination of grouped weighted quantile sum regression (GWQS), weighted quantile sum regression (WQS), quantile g calculation (q g-comp), and Bayesian kernel machine regression (BKMR) models indicated significant associations of chemical mixture exposure with progesterone (P4), testosterone (T), and luteinizing hormone (LH)/follicle-stimulating hormone (FSH) ratios, and 7, 4, and 8 priority contributors were identified, respectively, such as fipronil sulfone for P4, dicyclohexyl phthalate for T, and 3-hydroxybenzyl alcohol for LH/FSH. Three chemicals closely related to androgen synthesis and metabolism were proposed. Restricted cubic spline curves showed that 10 of the 28 priority compound-hormone pairs displayed significant non-monotonic exposure-response relationships. This study provides more information on the chemical exposome in Chinese women of childbearing age and has important implications for understanding the effect of chemical co-exposure on sex hormone homeostasis in women.