Department of Brain Sciences, Imperial College London, London, UK.
The Departments of Medicine and Neurology, The Royal Melbourne Hospital, The University of Melbourne, Parkville, Victoria, Australia.
Brain. 2022 Nov 21;145(11):3832-3842. doi: 10.1093/brain/awac296.
Prenatal exposure to the anti-seizure medication sodium valproate (VPA) is associated with an increased risk of adverse postnatal neurodevelopmental outcomes, including lowered intellectual ability, autism spectrum disorder and attention-deficit hyperactivity disorder. In this study, we aimed to clarify the molecular mechanisms underpinning the neurodevelopmental consequences of gestational VPA exposure using integrative genomics. We assessed the effect of gestational VPA on foetal brain gene expression using a validated rat model of valproate teratogenicity that mimics the human scenario of chronic oral valproate treatment during pregnancy at doses that are therapeutically relevant to the treatment of epilepsy. Two different rat strains were studied-inbred Genetic Absence Epilepsy Rats from Strasbourg, a model of genetic generalized epilepsy, and inbred non-epileptic control rats. Female rats were fed standard chow or VPA mixed in standard chow for 2 weeks prior to conception and then mated with same-strain males. In the VPA-exposed rats maternal oral treatment was continued throughout pregnancy. Foetuses were extracted via C-section on gestational Day 21 (1 day prior to birth) and foetal brains were snap-frozen and genome-wide gene expression data generated. We found that gestational VPA exposure via chronic maternal oral dosing was associated with substantial drug-induced differential gene expression in the pup brains, including dysregulated splicing, and observed that this occurred in the absence of evidence for significant neuronal gain or loss. The functional consequences of VPA-induced gene expression were explored using pathway analysis and integration with genetic risk data for psychiatric disease and behavioural traits. The set of genes downregulated by VPA in the pup brains were significantly enriched for pathways related to neurodevelopment and synaptic function and significantly enriched for heritability to human intelligence, schizophrenia and bipolar disorder. Our results provide a mechanistic link between chronic foetal VPA exposure and neurodevelopmental disability mediated by VPA-induced transcriptional dysregulation.
产前暴露于抗癫痫药物丙戊酸钠（VPA）与出生后神经发育不良结局的风险增加有关，包括智力下降、自闭症谱系障碍和注意缺陷多动障碍。在这项研究中，我们旨在使用整合基因组学阐明妊娠期 VPA 暴露导致神经发育后果的分子机制。我们使用经过验证的丙戊酸钠致畸大鼠模型评估了妊娠期 VPA 对胎儿大脑基因表达的影响，该模型模拟了人类在怀孕期间慢性口服 VPA 治疗的情况，剂量与治疗癫痫的相关。研究了两种不同的大鼠品系——来自斯特拉斯堡的遗传性癫痫大鼠，一种遗传性全身性癫痫模型，以及非癫痫性对照大鼠。雌性大鼠在受孕前 2 周喂食标准饲料或 VPA 混合标准饲料，然后与同品系雄性大鼠交配。在 VPA 暴露的大鼠中，母体口服治疗在整个怀孕期间持续进行。在妊娠第 21 天（出生前 1 天）通过剖宫产提取胎儿，并对胎儿大脑进行快速冷冻，生成全基因组基因表达数据。我们发现，通过慢性母体口服给药的妊娠期 VPA 暴露与幼鼠大脑中大量药物诱导的差异基因表达相关，包括剪接失调，并且观察到这种情况发生在没有明显神经元增加或减少的证据的情况下。使用途径分析和与精神疾病和行为特征的遗传风险数据的整合来探索 VPA 诱导的基因表达的功能后果。VPA 在幼鼠大脑中下调的基因集显著富集了与神经发育和突触功能相关的途径，并且显著富集了与人类智力、精神分裂症和双相情感障碍的遗传力相关的途径。我们的结果为慢性胎儿 VPA 暴露与 VPA 诱导的转录失调介导的神经发育障碍之间提供了机制联系。
