Sex Differences in the Effects of Prenatal Bisphenol A Exposure on Genes Associated with Autism Spectrum Disorder in the Hippocampus

Abstract

Autism spectrum disorder (ASD) is a neurodevelopmental disorder inexplicably biased towards males. Although prenatal exposure to bisphenol A (BPA) has recently been associated with the ASD risk, whether BPA dysregulates ASD-related genes in the developing brain remains unclear. In this study, transcriptome profiling by RNA-seq analysis of hippocampi isolated from neonatal pups prenatally exposed to BPA was conducted and revealed a list of differentially expressed genes (DEGs) associated with ASD. Among the DEGs, several ASD candidate genes, including Auts2 and Foxp2 , were dysregulated and showed sex differences in response to BPA exposure. The interactome and pathway analyses of DEGs using Ingenuity Pathway Analysis software revealed significant associations between the DEGs in males and neurological functions/disorders associated with ASD. Moreover, the reanalysis of transcriptome profiling data from previously published BPA studies consistently showed that BPA-responsive genes were significantly associated with ASD-related genes. The findings from this study indicate that prenatal BPA exposure alters the expression of ASD-linked genes in the hippocampus and suggest that maternal BPA exposure may increase ASD susceptibility by dysregulating genes associated with neurological functions known to be negatively impacted in ASD, which deserves further investigations.

Prenatal exposure to bisphenol A alters the transcriptome-interactome profiles of genes associated with Alzheimer’s disease in the offspring hippocampus

“…To examine the effects of prenatal BPA exposure on the expression of genes associated with AD, we obtained transcriptome profiling data from RNA-seq analysis of hippocampal tissues isolated from six independent litters prenatally exposed to BPA (male n = 3; female n = 3) or a vehicle control (male n = 3; female n = 3) from the NCBI Gene Expression Omnibus (GEO) DataSets database (Accession: GSE140298; https://www.ncbi.nlm.nih.gov/gds/). As reported by Thongkorn et al (2019), when all male and female rat pups under the same treatment conditions were combined into one group, as many as 5,624 transcripts corresponding to 4,525 genes were significantly differentially expressed in the hippocampal tissues of BPA-treated rats ( Supplementary Table S1). When each sex was analyzed separately, a total of 2,496 transcripts (corresponding to 1,633 genes) and 4,021 transcripts (corresponding to 2,780 genes) in the hippocampal tissues of BPA-treated male and female pups, respectively, were significantly differentially expressed compared to those in the hippocampal tissues of controls (P-value < 0.05 and FDR < 0.05, (Supplementary Tables S2,S3).…”

“…In vivo studies have shown that maternal BPA exposure can disrupt brain functions and induce aggression 29 , anxiety 30 , cognitive deficits 30 , and learning-memory impairment in offspring mice 31 . Recently, our transcriptome profiling analysis of rat hippocampus revealed that maternal BPA exposure dysregulated genes associated with autism in the offspring hippocampus 32 . In addition to genes linked to autism, several genes were also found to be associated with AD.…”

Bisphenol A (BPA)-Induced Changes in the Number of Serotonin-Positive Cells in the Mucosal Layer of Porcine Small Intestine—the Preliminary Studies

“…In light of previous studies, it is also known that BPA may impair the functioning of internal organs and systems, including (among others) the nervous, gastrointestinal, cardiovascular, reproductive, and excretory systems [1,2]. Moreover, some investigations have shown a correlation between the degree of exposure to BPA and the risk of diabetes, heart attack, neoplasms, and even autism [1][2][3][4].…”

Bisphenols as a Legacy Pollutant, and Their Effects on Organ Vulnerability

“…Prenatal BPA exposure of Wistar rats causes changes in the hippocampal expressions of genes associated with ASD in a sex-specific manner. BPA disrupts the expression of ASD candidate genes (Auts2, Foxp2, and Smarcc2) more significantly in the male hippocampus than in females [130]. Subcutaneous injection of 20 µg BPA/kg BW/day in pregnant mice resulted in impaired neurotransmission.…”