Prenatal phenol exposure and child behaviour: insights into the hypothalamic-pituitary-adrenal axis from two prospective mother-child cohorts

Abstract

Background: Synthetic phenols are widely used chemicals with potential neurodevelopmental toxicity. Human studies are often limited by small sample sizes and exposure misclassification. Identifying the biological pathways affected by these substances is crucial for understanding key drivers of toxicity. We aimed to study associations between prenatal exposure to synthetic phenols and child behaviour, exploring the potential mediating role of maternal steroid hormones. Methods: We pooled data from two European cohorts: the Barcelona Life Study Cohort (BiSC; Barcelona, Spain, 2018-21, N=1080) and Suivi de l'Exposition à la Pollution Atmosphérique durant la Grossesse et Effets sur la Santé (SEPAGES; Grenoble, France, 2014-17, N=484). Mothers older than 18 years having a singleton pregnancy of less than 19 weeks gestational age were eligible for inclusion in the cohorts; those having multiple pregnancies were excluded. Repeated urine samples (up to 24 in BiSC; up to 42 in SEPAGES) collected in the second and third trimesters were pooled and analysed for 12 synthetic phenols. Child behavioural outcomes were assessed at 18 months in BiSC and 24 months in SEPAGES using the Child Behavior Checklist for Ages 1·5-5 (CBCL). Concentrations of total cortisol, total cortisone, and 11-dehydrocorticosterone-steroid hormones involved in the hypothalamic-pituitary-adrenal axis-were measured from maternal hair samples. Associations between phenol exposure and behavioural outcomes were estimated by adjusted linear regression analysis, and mediation by steroid hormones was assessed with regression-based causal mediation analysis within the counterfactual framework. Findings: 1024 mother-child pairs were included in the study: 607 from BiSC and 417 from SEPAGES. Maternal exposure to methylparaben in the third trimester of pregnancy was associated with higher internalising scores (change in score of 0·44 [95% CI 0·10-0·79] points) and externalising scores (0·67 [0·12-1·24]) in the CBCL. In boys, maternal exposure to bisphenol S in the third trimester was linked to increased internalising scores (0·92 [0·15 to 1·75]; p=0·019) and could be linked to increased externalising scores (1·14 [-0·09 to 2·44]; p=0·070). In girls, second-trimester butylparaben and propylparaben exposure were associated with lower internalising (-1·03 [-1·84 to -0·09], p=0·033) and externalising (-0·68 [-1·23 to -0·12]; p=0·019) scores. No mediation by steroid hormones was observed. Interpretation: Prenatal exposure to phenols might influence early behavioural development, with sex-specific patterns. There was no strong evidence of mediation by maternal steroid hormones, suggesting the involvement of alternative pathways in the biological effects of phenols. Together with previous findings, these results highlight the need for stricter regulation of these compounds to reduce prenatal exposure.