Abstract
Bisphenol A (BPA) is an environmental risk factor for autism spectrum disorder (ASD). BPA exposure dysregulates ASD-related genes in the hippocampus and neurological functions of offspring. However, whether prenatal BPA exposure has an impact on genes in the prefrontal cortex, another brain region highly implicated in ASD, and through what mechanisms have not been investigated. Here, we demonstrated that prenatal BPA exposure disrupts the transcriptome–interactome profiles of the prefrontal cortex of neonatal rats. Interestingly, the list of BPA-responsive genes was significantly enriched with known ASD candidate genes, as well as genes that were dysregulated in the postmortem brain tissues of ASD cases from multiple independent studies. Moreover, several differentially expressed genes in the offspring’s prefrontal cortex were the targets of ASD-related transcription factors, including AR, ESR1, and RORA. The hypergeometric distribution analysis revealed that BPA may regulate the expression of such genes through these transcription factors in a sex-dependent manner. The molecular docking analysis of BPA and ASD-related transcription factors revealed novel potential targets of BPA, including RORA, SOX5, TCF4, and YY1. Our findings indicated that prenatal BPA exposure disrupts ASD-related genes in the offspring’s prefrontal cortex and may increase the risk of ASD through sex-dependent molecular mechanisms, which should be investigated further.
Highlights
Autism spectrum disorder (ASD) is a neurodevelopmental disorder that can be diagnosed in early childhood and is characterized by two behavioral domains, i.e., social communication/interaction deficits and restricted interests or repetitive patterns of behavior according to the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) [1]
To investigate whether prenatal bisphenol A (BPA) exposure alters the transcriptome profiles of the offspring’s prefrontal cortex, rat dams were treated with 5000 μg/kg maternal body weight or vehicle control daily using oral gavage from gestational day (GD) 1 until parturition
We propose that maternal exposure alters the transcriptome–ininteractome profiles in the prefrontal cortex of offspring in a sex-dependent manner through ASDteractome profiles in the prefrontal cortex of offspring in a sex-dependent manner through ASDrelated transcription factors (e.g., AR, ESR1, RORA, SOX5, TCF4, and YY1), as well as other gene regulatory mechanisms
Summary
Autism spectrum disorder (ASD) is a neurodevelopmental disorder that can be diagnosed in early childhood and is characterized by two behavioral domains, i.e., social communication/interaction deficits and restricted interests or repetitive patterns of behavior according to the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) [1]. Environmental factors that are associated with ASD include endocrine-disrupting chemicals (EDCs) [5,9,10], heavy metals [11,12], smoke from cigarettes [13], and traffic-related air pollutants [14]. BPA ((CH3 ) C(C6 H4 OH)2 ) is an organic synthetic compound frequently found in polycarbonate plastic and epoxy resin products, the linings inside beverages and food cans, thermal paper, and dental sealants. In addition to such products, BPA is found in polycarbonate micro/nanoplastics, which have become one of the major environmental problems worldwide [20,21].
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