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Transcription factor binding and individual genetic risk for valproate teratogenicity

ABSTRACT: Valproate (VPA) use during pregnancy is associated with a wide range of birth defects and adverse neurodevelopmental outcomes, but not all exposed children are affected and there is evidence for a genetic predisposition. We hypothesised that genomic variants that impact on the binding affinity of transcription factors (TFs) are integral to VPA-associated teratogenicity and a plausible explanation for variance in interindividual risk. We interrogated maternal exomes from women recruited through international epilepsy genomics consortia. The variant burden within genes associated with 32 different birth defect types was higher for those exposed to VPA as compared to other antiseizure medications (OR 1·73 [95% CI 1·40 to 2·14], p = 2·25E-07). Variants in women exposed to VPA were predicted to impact the binding affinity of 359 TFs and network analysis of encoded proteins indicated that a master regulator, EP300, interacts with 42% (151/359) of all variant sensitive TFs. We then profiled coexpression between EP300 and other TFs in differentiating neurons derived from human embryonic stem cells (hESCs) exposed to VPA at 300µM and 700 µM, or unexposed, and a reference map generated using public data. Almost all coexpressed pairs observed in the cell assay data were also observed in the reference map. In contrast, only 30% (119/400) of the coexpressed pairs observed in unexposed cells were present in cells exposed to VPA; suggesting that VPA activates alternative biologically valid, but context inappropriate, signaling cascades. Our findings suggest that VPA-induced disruption of EP300-related regulation is common across birth defect types and that genetic variation can modify subsequent transcriptional dysregulation, explaining why only some pregnancies are affected. The results have implications for the development of genetic risk biomarkers and safer drugs.

ORGANISM(S): Homo sapiens

PROVIDER: GSE290300 | GEO | 2026/03/01

REPOSITORIES: GEO

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Project description:Prenatal exposure to the anti-seizure drug 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. First, we assessed the effect of gestational VPA on fetal 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 which are therapeutically relevant to the treatment of epilepsy. Two different rat strains were studied - inbred Genetic Absence Epilepsy Rats from Strasbourg (GAERS), a model of genetic generalized epilepsy, and inbred Non-Epileptic Control (NEC) 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. Fetuses were extracted via C-section on gestational day 21 (one day prior to birth) and fetal 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 set of genes down-regulated 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 fetal VPA exposure and adverse neurodevelopmental outcomes mediated by VPA-induced transcriptional dysregulation.

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Transcription factor binding and individual genetic risk for valproate teratogenicity

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