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

Surangrat Thongkorn, Department of Clinical Chemistry, Faculty of Allied Health Sciences, Chulalongkorn University, Bangkok, Thailand.
Songphon Kanlayaprasit, SYstems Neuroscience of Autism and PSychiatric Disorders (SYNAPS) Research Unit, Department of Clinical Chemistry, Faculty of Allied Health Sciences, Chulalongkorn University, 154 Soi Chula 12, Rama 1 Road, Wangmai, Pathumwan, Bangkok, 10330, Thailand.
Kasidit Kasitipradit, Department of Clinical Chemistry, Faculty of Allied Health Sciences, Chulalongkorn University, Bangkok, Thailand.
Pattanachat Lertpeerapan, Department of Clinical Chemistry, Faculty of Allied Health Sciences, Chulalongkorn University, Bangkok, Thailand.
Pawinee Panjabud, Department of Clinical Chemistry, Faculty of Allied Health Sciences, Chulalongkorn University, Bangkok, Thailand.
Valerie W. Hu, Department of Biochemistry and Molecular Medicine, The George Washington University School of Medicine and Health Sciences, The George Washington University, Washington, DC, USA.
Depicha Jindatip, SYstems Neuroscience of Autism and PSychiatric Disorders (SYNAPS) Research Unit, Department of Clinical Chemistry, Faculty of Allied Health Sciences, Chulalongkorn University, 154 Soi Chula 12, Rama 1 Road, Wangmai, Pathumwan, Bangkok, 10330, Thailand.
Tewarit Sarachana, SYstems Neuroscience of Autism and PSychiatric Disorders (SYNAPS) Research Unit, Department of Clinical Chemistry, Faculty of Allied Health Sciences, Chulalongkorn University, 154 Soi Chula 12, Rama 1 Road, Wangmai, Pathumwan, Bangkok, 10330, Thailand. tewarit.sa@chula.ac.th.

Document Type

Journal Article

Publication Date

2-20-2023

Journal

Biology of sex differences

Volume

14

Issue

1

DOI

10.1186/s13293-023-00496-w

Keywords

Androgen receptor; Autism spectrum disorder; Bisphenol A; Endocrine-disrupting chemical; Microplastics; Molecular docking; Sex difference; Synaptogenesis; Transcription factor

Abstract

BACKGROUND: Bisphenol A (BPA) has been linked to susceptibility to autism spectrum disorder (ASD). Our recent studies have shown that prenatal BPA exposure disrupted ASD-related gene expression in the hippocampus, neurological functions, and behaviors associated with ASD in a sex-specific pattern. However, the molecular mechanisms underlying the effects of BPA are still unclear. METHODS: Transcriptome data mining and molecular docking analyses were performed to identify ASD-related transcription factors (TFs) and their target genes underlying the sex-specific effects of prenatal BPA exposure. Gene ontology analysis was conducted to predict biological functions associated with these genes. The expression levels of ASD-related TFs and targets in the hippocampus of rat pups prenatally exposed to BPA were measured using qRT-PCR analysis. The role of the androgen receptor (AR) in BPA-mediated regulation of ASD candidate genes was investigated using a human neuronal cell line stably transfected with AR-expression or control plasmid. Synaptogenesis, which is a function associated with genes transcriptionally regulated by ASD-related TFs, was assessed using primary hippocampal neurons isolated from male and female rat pups prenatally exposed to BPA. RESULTS: We found that there was a sex difference in ASD-related TFs underlying the effects of prenatal BPA exposure on the transcriptome profiles of the offspring hippocampus. In addition to the known BPA targets AR and ESR1, BPA could directly interact with novel targets (i.e., KDM5B, SMAD4, and TCF7L2). The targets of these TFs were also associated with ASD. Prenatal BPA exposure disrupted the expression of ASD-related TFs and targets in the offspring hippocampus in a sex-dependent manner. Moreover, AR was involved in the BPA-mediated dysregulation of AUTS2, KMT2C, and SMARCC2. Prenatal BPA exposure altered synaptogenesis by increasing synaptic protein levels in males but not in females, but the number of excitatory synapses was increased in female primary neurons only. CONCLUSIONS: Our findings suggest that AR and other ASD-related TFs are involved in sex differences in the effects of prenatal BPA exposure on transcriptome profiles and synaptogenesis in the offspring hippocampus. These TFs may play an essential role in an increased ASD susceptibility associated with endocrine-disrupting chemicals, particularly BPA, and the male bias of ASD.

Department

Biochemistry and Molecular Medicine

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