Prenatal exposure to the plasticizer DEHP increases the likelihood of early-life autism and ADHD symptoms through epigenetic programming.

BACKGROUND

Growing evidence implicates prenatal exposure to di-(2-ethylhexyl) phthalate (DEHP), a common endocrine-disrupting plasticizer, in the development of autism and attention-deficit/hyperactivity disorder (ADHD). Yet underlying mechanisms remain unclear.

METHODS

Here, we examined whether cord blood DNA methylation, a key epigenetic marker, mediates the association between prenatal DEHP exposure and autism and ADHD symptoms in 847 children from the Barwon Infant Study. Autism and ADHD are complex phenotypes driven by alterations in higher-level gene networks and neuronal circuits, where diverse genetic and environmental risk factors converge. Accordingly, rather than a gene-by-gene approach, we employed a data-driven strategy to elucidate broader functional epigenetic signatures of autism and ADHD elicited by DEHP exposure. This included (1) a methylation profile score for DEHP exposure (MPSDEHP), and (2) a targeted analysis of DEHP-associated co-methylated gene networks.

FINDINGS: Causal mediation analysis showed that both MPSDEHP and a network of 531 co-methylated genes mediated the effect of DEHP on increased autism and ADHD symptoms at ages 2 and 4 years (proportion mediated: 0.21-0.80). The co-methylation network was enriched for neural cell-type markers, autism and ADHD risk genes (including FOXP1, SHANK2, and PLXNB1), and targets of endocrine receptors previously linked to DEHP (including estrogen and glucocorticoid receptors), providing biological plausibility. We validated key results in independent blood (n = 66) and postmortem brain (n = 40) DNA methylation datasets.

CONCLUSION

These findings provide mechanistic evidence linking DEHP to adverse neurodevelopment and reinforce mounting concerns regarding the risks of prenatal exposure.

FUNDING: Funding was obtained from the NHMRC, the Minderoo Foundation, and additional sources (detailed in acknowledgments).