Prenatal DEHP plastic chemical exposure increases the likelihood of child autism and ADHD symptoms through epigenetic programming

Increasing evidence implicates prenatal exposure to di-(2-ethylhexyl) phthalate (DEHP), a common endocrine-disrupting plastic chemical, in autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD). However, the underlying mechanisms are poorly understood. Here we examined whether cord blood DNA methylation, a key epigenetic marker, mediates the association between prenatal DEHP exposure and ASD/ADHD symptoms in 847 children enrolled in the Barwon Infant Study. ASD and ADHD are complex phenotypes characterised by differences at the gene regulatory network and neuronal circuit level, where heterogeneous genetic and environmental risk factors converge. Accordingly, we employed a data-driven computational strategy that helped elucidate broader functional epigenetic signatures of ASD and ADHD elicited by DEHP exposure. This included (1) a methylation profile score for DEHP exposure (MPSDEHP), and (2) an analysis of co-methylated gene networks. Causal mediation analysis demonstrated that both MPSDEHP and a DEHP-associated network of co-methylated genes mediated the effect of DEHP exposure on increased ASD and ADHD symptoms at ages 2 and 4 years (proportion of effect mediated ranged from 0.21 to 0.80). The co-methylation network was enriched for neural cell-type markers, ASD risk genes (including FOXP1, SHANK2, and PLXNB1), and targets of endocrine receptors previously linked to DEHP (including targets of the estrogen receptor ER and the glucocorticoid receptor GR), providing biological plausibility. We validated key results in independent blood (n=66) and postmortem brain (n=40) DNA methylation datasets. These findings provide mechanistic evidence linking DEHP to ASD and ADHD symptoms and reinforce growing concerns regarding the risks of prenatal exposure.\n\nSignificanceExposure to endocrine-disrupting plastic chemicals has been linked to adverse neurodevelopment, but the underlying biological mechanisms remain unclear. We demonstrate that prenatal exposure to di-(2-ethylhexyl) phthalate (DEHP), a common plasticizer, increases autism and ADHD symptoms through alterations in DNA methylation, a key epigenetic regulator of gene activity. Using birth cohort data, we identify epigenetic signatures of prenatal DEHP exposure, including alterations in an endocrine-related co-methylation network enriched for neural cell-type markers and known autism-associated genes. These signatures mediate the effects of DEHP on autism and ADHD symptoms and are also associated with autism in external blood and postmortem-brain datasets, providing independent validation. This causal evidence further underscores concerns regarding the consequences of prenatal plastic-chemical exposure on the developing brain.