Investigation of autism-related transcription factors underlying sex differences in the effects of bisphenol A on transcriptome profiles and synaptogenesis in the offspring hippocampus

Abstract

Highlights Prenatal BPA exposure altered the transcriptome profiles of genes associated with ASD in the offspring hippocampus through several ASD-related transcription factors, including AR and ESR1, in a sex-dependent manner. In addition to the known BPA targets (i.e., AR and ESR1), other ASD-related transcription factors, including KDM5B, SMAD4, and TCF7L2, are also involved in the BPA effects in the offspring hippocampus, possibly by direct interactions with BPA. Prenatal BPA exposure also caused a significant reduction in the expression of ASD-related TFs in the hippocampus of female offspring but not in that of males. ASD candidate genes (i.e., AUTS2, SMARCC2, and KMT2C), which are known AR targets, were differentially expressed in response to BPA in the human neuronal cell line with AR overexpression compared to the cell line with low AR protein levels, indicating that AR is involved in BPA-mediated effects on these ASD candidate genes. BPA-responsive genes that are transcriptional targets of AR and other ASD-related transcription factors are associated with synaptogenesis. Prenatal BPA exposure caused an increase in synaptic protein levels in primary hippocampal neurons and in hippocampal tissues of male offspring but not in females.

Keywords

• Sex difference
• Endocrine-disrupting chemical
• Bisphenol A
• Transcription factor
• Molecular docking
• Androgen receptor