Perinatal exposure to potential endocrine disrupting chemicals and autism spectrum disorder: From Norwegian birth cohort to zebrafish studies

Background: The etiology of autism spectrum disorder (ASD) is multifactorial, involving genetic and environmental contributors such as endocrine-disrupting chemicals (EDCs).Objective: To evaluate the association between perinatal exposure to 27 potential EDCs and ASD among Norwegian children, and to further examine the neurodevelopmental toxicity of associated chemicals using zebrafish embryos and larvae.Method: 1,199 mothers enrolled in the prospective birth-cohort (HUMIS, 2002-2009) study. Breastmilk levels of 27 chemicals were measured: polychlorinated biphenyls, organochlorine pesticides, polybrominated diphenyl ethers, and perfluoroalkyl substances as a proxy for perinatal exposure. We employed multivariable logistic regression to determine association, utilized elastic net logistic regression as variable selection method, and conducted an in vivo study with zebrafish larvae to confirm the neurodevelopmental effect.Results: A total of 20 children had specialist confirmed diagnosis of autism among 1,199 mother-child pairs in this study. beta-Hexachlorocyclohexane (beta-HCH) was the only chemical associated with ASD, after adjusting for 26 other chemicals. Mothers with the highest levels of beta-HCH in their milk had a significant increased risk of having a child with ASD (OR = 1.82, 95 % CI: 1.20, 2.77 for an interquartile range increase in ln-transformed beta-HCH concentration). The median concentration of beta-HCH in breast milk was 4.37 ng/g lipid (interquartile range: 2.92-6.47), and the estimated daily intake (EDI) for Norwegian children through breastfeeding was 0.03 mu g/kg of body weight. The neurodevelopmental and social behavioral effects of beta-HCH were established in zebrafish embryos and larvae across various concentrations, with further analysis suggesting that perturbation of dopaminergic neuron development may underlie the neurotoxicity associated with beta-HCH.Conclusions: Prenatal exposure to beta-HCH was associated with an increased risk of specialist-confirmed diagnoses of ASD among Norwegian children, and the EDI surpasses the established threshold. Zebrafish experiments confirm beta-HCH neurotoxicity, suggesting dopaminergic neuron disruption as a potential underlying mechanism.