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

IF 13.3 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Med Pub Date : 2026-10-09 Epub Date: 2026-09-11 DOI:10.1016/j.medj.2026.101291

Samuel Tanner, Alex Eisner, Boris Novakovic, Lada Holland, Toby Mansell, Gillian England-Mason, Sarah Merrill, Deborah Dewey, Martin O'Hely, Christos Symeonides, Richard Saffery, Mimi L K Tang, Peter D Sly, Peter Vuillermin, Chol-Hee Jung, Daniel Park, Anne-Louise Ponsonby

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引用次数: 0

Abstract

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 (MPS_DEHP), and (2) a targeted analysis of DEHP-associated co-methylated gene networks.

Findings: Causal mediation analysis showed that both MPS_DEHP 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).

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产前暴露于增塑剂DEHP会通过表观遗传程序增加早期自闭症和ADHD症状的可能性。

背景：越来越多的证据表明，产前暴露于二-（2-乙基己基）邻苯二甲酸二酯（DEHP），一种常见的内分泌干扰增塑剂，与自闭症和注意缺陷/多动障碍（ADHD）的发展有关。然而，潜在的机制尚不清楚。方法：在这里，我们检查了脐带血DNA甲基化，一个关键的表观遗传标记，是否介导产前DEHP暴露与自闭症和ADHD症状之间的关联，这些儿童来自Barwon婴儿研究。自闭症和多动症是由高级基因网络和神经元回路的改变驱动的复杂表型，其中多种遗传和环境风险因素汇聚在一起。因此，我们采用数据驱动的策略来阐明DEHP暴露引发的自闭症和ADHD的更广泛的功能表观遗传特征，而不是逐个基因的方法。这包括(1)DEHP暴露的甲基化谱评分（MPSDEHP），以及(2)DEHP相关共甲基化基因网络的针对性分析。结果：因果中介分析显示，MPSDEHP和531个共甲基化基因网络都介导了DEHP对2岁和4岁时自闭症和ADHD症状增加的影响（比例中介：0.21-0.80）。共甲基化网络丰富了神经细胞类型标记物、自闭症和ADHD风险基因（包括FOXP1、SHANK2和PLXNB1）以及先前与DEHP相关的内分泌受体靶标（包括雌激素和糖皮质激素受体），提供了生物学上的可行性。我们验证了独立血液（n = 66）和死后脑（n = 40） DNA甲基化数据集的关键结果。结论：这些发现提供了将DEHP与不良神经发育联系起来的机制证据，并加强了对产前暴露风险的日益关注。资金：资金来自NHMRC、Minderoo基金会和其他来源（详见致谢）。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Med MEDICINE, RESEARCH & EXPERIMENTAL-

CiteScore

17.70

自引率

0.60%

发文量

102

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