Adolescence is a sensitive period for acrylamide-induced sex hormone disruption: Evidence from NHANES populations and experimental mice

Acrylamide (AA) is widely contaminated in environment and diet. However, the association of AA and sex hormones has rarely been investigated, especially in adolescents, a period of particular susceptibility to sex hormone disruption. In this study, survey-weighted multivariate linear regression models were conducted to determine the association between AA Hb biomarkers [HbAA and glycidamide (HbGA)] and sex hormones [total testosterone (TT) and estradiol (E2)] in a total of 3268 subjects from National Health and Nutrition Examination Survey (NHANES) 2013-2016 waves. Additionally, adult and pubertal mice were treated with AA to assess the effect of AA on sex hormones and to explore the potential mechanisms. Among all the subjects, significant negative patterns for HbGA and sex hormones were identified only in youths (6-19 years old), with the lowest β being - 0.53 (95% CI: -0.80 to -0.26) for TT in males and - 0.58 (95% CI: -0.93 to -0.23) for E2 in females. Stratified analysis further revealed significant negative associations between HbGA and sex hormones in adolescents, with the lowest β being - 0.58 (95% CI: -1.02 to -0.14) for TT in males and - 0.54 (95% CI: -1.03 to -0.04) for E2 in females, while there were no significant differences between children or late adolescents. In mice, the levels of TT and E2 were dramatically reduced in AA-treated pubertal mice but not in adult mice. AA disturbed the expression of genes in the hypothalamic-pituitary-gonadal (HPG) axis, induced apoptosis of hypothalamus-produced gonadotropin-releasing hormone (GnRH) neurons in the hypothalamus and reduced serum and hypothalamic GnRH levels in pubertal mice. Our study indicates AA could reduce TT and E2 levels by injuring GnRH neurons and disrupting the HPG axis in puberty, which manifested as severe endocrine disruption on adolescents. Our findings reinforce the idea that adolescence is a vulnerable stage in AA-induced sex hormone disruption.