Integrative genomics reveals pathogenic mediator of valproate-induced neurodevelopmental disability.
Integrative genomics reveals pathogenic mediator of valproate-induced neurodevelopmental disability.
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DOI：
10.1093/brain/awac296
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发表时间：
2022-11-21
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影响因子：
--
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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. Feleke et al. investigate the molecular mechanisms by which chronic gestational exposure to sodium valproate can disrupt neurodevelopment. Transcriptomics analysis reveals changes in the expression of genes associated with synaptic function and with the heritability of intelligence, schizophrenia and bipolar disorder. See Meador and Li (https://doi.org/10.1093/brain/awac374) for a scientific commentary on this article.
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影响因子：
30.8
作者：
Finucane HK;Bulik-Sullivan B;Gusev A;Trynka G;Reshef Y;Loh PR;Anttila V;Xu H;Zang C;Farh K;Ripke S;Day FR;ReproGen Consortium;Schizophrenia Working Group of the Psychiatric Genomics Consortium;RACI Consortium;Purcell S;Stahl E;Lindstrom S;Perry JR;Okada Y;Raychaudhuri S;Daly MJ;Patterson N;Neale BM;Price AL
通讯作者：
Price AL
影响因子：
26.1
作者：
Boukhris, Takoua;Sheehy, Odile;Berard, Anick
通讯作者：
Berard, Anick
影响因子：
3.7
作者：
Casillas-Espinosa, Pablo M.;Powell, Kim L.;Petrovski, Slave
通讯作者：
Petrovski, Slave
DOI：
10.1111/j.1749-6632.2003.tb07517.x
发表时间：
2003-01-01
期刊：
NEUROPROTECTIVE AGENTS
影响因子：
--
作者：
Bittigau, P;Sifringer, M;Ikonomidou, C
通讯作者：
Ikonomidou, C
影响因子：
3.6
作者：
Avery, Lindsay B.;Bumpus, Namandje N.
通讯作者：
Bumpus, Namandje N.