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

Surangrat Thongkorn,Valerie W Hu,Songphon Kanlayaprasit,Tewarit Sarachana,Depicha Jindatip,Tewin Tencomnao

doi:10.1038/s41598-019-39386-w

Surangrat Thongkorn, Valerie W Hu + Show 4 more

Open Access

https://doi.org/10.1038/s41598-019-39386-w

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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.

Highlights

EDCs are a group of chemicals that can be found in various products widely used in daily life
To examine whether prenatal bisphenol A (BPA) exposure could lead to dysregulation of Autism spectrum disorder (ASD) candidate genes in the developing brain in vivo, we conducted an RNA-seq analysis of hippocampal tissues isolated from male and female neonatal rats exposed to 5,000 μg/kg·maternal BW of BPA in utero or vehicle control
The hub gene in the interactome generated using differentially expressed genes (DEGs) from the male hippocampus is MeCP2, which is the key gene responsible for Rett syndrome. These findings suggest that prenatal BPA exposure alters the expression of genes in the brain, which may in turn disrupt gene regulatory networks/pathways and neurological functions underlying the pathobiology of ASD

Summary

Introduction

EDCs are a group of chemicals that can be found in various products widely used in daily life. Stein et al (2015) determined the concentrations of free and total BPA in urine obtained from 46 children with ASD and 52 typically developing children using liquid chromatography-mass spectrometry (LC-MS/MS) analysis. Similar to Kardas et al (2016), Kondolot et al (2016) measured the plasma concentrations of BPA and phthalates in 51 ASD children and 50 age-/sex-matched typically developing children using HPLC analysis[38]. They found that the average plasma BPA level of children with a specific disorder in the autism spectrum called PDD-NOS (pervasive developmental disorder not otherwise specified) was significantly higher than that of the control, and the average level of BPA detected in the plasma was as high as 6.91 ng/ml[38]. The list of significant genes was overlapped with lists of ASD candidate genes obtained from two different ASD databases to predict whether BPA-responsive genes were significantly associated with ASD candidate genes

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