Noble Alexandra J, Adams Alex T, Satsangi Jack, Boden Joseph M, Osborne Amy J
Translational Gastroenterology Unit, Nuffield Department of Experimental Medicine, University of Oxford, Oxford, UK.
Biomedical Research Centre, University of Oxford, Oxford, UK.
Mol Psychiatry. 2025 Apr;30(4):1418-1429. doi: 10.1038/s41380-024-02752-w. Epub 2024 Sep 14.
Prenatal cannabis exposure (PCE) is of increasing concern globally, due to the potential impact on offspring neurodevelopment, and its association with childhood and adolescent brain development and cognitive function. However, there is currently a lack of research addressing the molecular impact of PCE, that may help to clarify the association between PCE and neurodevelopment. To address this knowledge gap, here we present epigenome-wide association study data across multiple time points, examining the effect of PCE and co-exposure with tobacco using two longitudinal studies, the Avon Longitudinal Study of Parents and Children (ALSPAC) and the Christchurch Health and Development Study (CHDS) at birth (0 y), 7 y and 15-17 y (ALSPAC), and ~27 y (CHDS). Our findings reveal genome-wide significant DNA methylation differences in offspring at 0 y, 7 y, 15-17 y, and 27 y associated with PCE alone, and co-exposure with tobacco. Importantly, we identified significantly differentially methylated CpG sites within the genes LZTS2, NPSR1, NT5E, CRIP2, DOCK8, COQ5, and LRP5 that are shared between different time points throughout development in offspring. Notably, functional pathway analysis showed enrichment for differential DNA methylation in neurodevelopment, neurotransmission, and neuronal structure pathways, and this was consistent across all timepoints in both cohorts. Given the increasing volume of epidemiological evidence that suggests a link between PCE and adverse neurodevelopmental outcomes in exposed offspring, this work highlights the need for further investigation into PCE, particularly in larger cohorts.
由于产前接触大麻（PCE）可能对后代神经发育产生潜在影响，且与儿童和青少年的大脑发育及认知功能相关，因此在全球范围内日益受到关注。然而，目前缺乏关于PCE分子影响的研究，而这可能有助于阐明PCE与神经发育之间的关联。为填补这一知识空白，我们在此展示了跨多个时间点的全表观基因组关联研究数据，利用两项纵向研究——阿冯父母与儿童纵向研究（ALSPAC）以及克赖斯特彻奇健康与发展研究（CHDS），分别在出生时（0岁）、7岁以及15 - 17岁（ALSPAC）和大约27岁（CHDS）时，研究PCE以及与烟草共同接触的影响。我们的研究结果显示，仅与PCE以及与烟草共同接触相关的后代在0岁、7岁、15 - 17岁和27岁时，全基因组存在显著的DNA甲基化差异。重要的是，我们在基因LZTS2、NPSR1、NT5E、CRIP2、DOCK8、COQ5和LRP5中鉴定出了显著差异甲基化的CpG位点，这些位点在后代整个发育过程的不同时间点之间是共享的。值得注意的是，功能通路分析表明，在神经发育、神经传递和神经元结构通路中，差异DNA甲基化存在富集现象，并且在两个队列的所有时间点都是一致的。鉴于越来越多的流行病学证据表明PCE与受暴露后代的不良神经发育结果之间存在联系，这项工作凸显了对PCE进行进一步研究的必要性，特别是在更大的队列中。
