Sex-specific impacts of prenatal bisphenol A exposure on genes associated with cortical development, social behaviors, and autism in the offspring's prefrontal cortex

Authors

Songphon Kanlayaprasit, Chulalongkorn Autism Research and Innovation Center of Excellence (Chula ACE), Department of Clinical Chemistry, Faculty of Allied Health Sciences, Chulalongkorn University, 154 Soi Chula 12, Rama 1 Road, Bangkok, Wangmai, Pathumwan, 10330, Thailand.
Thanit Saeliw, Chulalongkorn Autism Research and Innovation Center of Excellence (Chula ACE), Department of Clinical Chemistry, Faculty of Allied Health Sciences, Chulalongkorn University, 154 Soi Chula 12, Rama 1 Road, Bangkok, Wangmai, Pathumwan, 10330, Thailand.
Surangrat Thongkorn, Chulalongkorn Autism Research and Innovation Center of Excellence (Chula ACE), Department of Clinical Chemistry, Faculty of Allied Health Sciences, Chulalongkorn University, 154 Soi Chula 12, Rama 1 Road, Bangkok, Wangmai, Pathumwan, 10330, Thailand.
Pawinee Panjabud, The Ph.D. Program in Clinical Biochemistry and Molecular Medicine, Department of Clinical Chemistry, Faculty of Allied Health Sciences, Chulalongkorn University, Bangkok, Thailand.
Kasidit Kasitipradit, The Ph.D. Program in Clinical Biochemistry and Molecular Medicine, Department of Clinical Chemistry, Faculty of Allied Health Sciences, Chulalongkorn University, Bangkok, Thailand.
Pattanachat Lertpeerapan, The Ph.D. Program in Clinical Biochemistry and Molecular Medicine, Department of Clinical Chemistry, Faculty of Allied Health Sciences, Chulalongkorn University, Bangkok, Thailand.
Kwanjira Songsritaya, The M.Sc. Program in Clinical Biochemistry and Molecular Medicine, Department of Clinical Chemistry, Faculty of Allied Health Sciences, Chulalongkorn University, Bangkok, Thailand.
Wasana Yuwattana, The Ph.D. Program in Clinical Biochemistry and Molecular Medicine, Department of Clinical Chemistry, Faculty of Allied Health Sciences, Chulalongkorn University, Bangkok, Thailand.
Thanawin Jantheang, The Ph.D. Program in Clinical Biochemistry and Molecular Medicine, Department of Clinical Chemistry, Faculty of Allied Health Sciences, Chulalongkorn University, Bangkok, Thailand.
Depicha Jindatip, Chulalongkorn Autism Research and Innovation Center of Excellence (Chula ACE), Department of Clinical Chemistry, Faculty of Allied Health Sciences, Chulalongkorn University, 154 Soi Chula 12, Rama 1 Road, Bangkok, Wangmai, Pathumwan, 10330, Thailand.
Valerie W. Hu, Department of Biochemistry and Molecular Medicine, School of Medicine and Health Sciences, The George Washington University, Washington, DC, USA.
Takako Kikkawa, Department of Developmental Neuroscience, Centers for Advanced Research and Translational Medicine (ART), Graduate School of Medicine, Tohoku University, Sendai, Miyagi, Japan.
Noriko Osumi, Department of Developmental Neuroscience, Centers for Advanced Research and Translational Medicine (ART), Graduate School of Medicine, Tohoku University, Sendai, Miyagi, Japan.
Tewarit Sarachana, Chulalongkorn Autism Research and Innovation Center of Excellence (Chula ACE), Department of Clinical Chemistry, Faculty of Allied Health Sciences, Chulalongkorn University, 154 Soi Chula 12, Rama 1 Road, Bangkok, Wangmai, Pathumwan, 10330, Thailand. tewarit.sa@chula.ac.th.

Document Type

Journal Article

Publication Date

5-15-2024

Journal

Biology of sex differences

Volume

15

Issue

1

DOI

10.1186/s13293-024-00614-2

Keywords

Autism spectrum disorder; Bisphenol A; Cortical development; Endocrine-disrupting chemical; Micro/nanoplastics; Neuritogenesis; Neuronal migration; Prefrontal cortex; Sex difference; Social behaviors

Abstract

BACKGROUND: Recent studies have shown that prenatal BPA exposure altered the transcriptome profiles of autism-related genes in the offspring's hippocampus, disrupting hippocampal neuritogenesis and causing male-specific deficits in learning. However, the sex differences in the effects of prenatal BPA exposure on the developing prefrontal cortex, which is another brain region highly implicated in autism spectrum disorder (ASD), have not been investigated. METHODS: We obtained transcriptome data from RNA sequencing analysis of the prefrontal cortex of male and female rat pups prenatally exposed to BPA or control and reanalyzed. BPA-responsive genes associated with cortical development and social behaviors were selected for confirmation by qRT-PCR analysis. Neuritogenesis of primary cells from the prefrontal cortex of pups prenatally exposed to BPA or control was examined. The social behaviors of the pups were assessed using the two-trial and three-chamber tests. The male-specific impact of the downregulation of a selected BPA-responsive gene (i.e., Sema5a) on cortical development in vivo was interrogated using siRNA-mediated knockdown by an in utero electroporation technique. RESULTS: Genes disrupted by prenatal BPA exposure were associated with ASD and showed sex-specific dysregulation. Sema5a and Slc9a9, which were involved in neuritogenesis and social behaviors, were downregulated only in males, while Anxa2 and Junb, which were also linked to neuritogenesis and social behaviors, were suppressed only in females. Neuritogenesis was increased in males and showed a strong inverse correlation with Sema5a and Slc9a9 expression levels, whereas, in the females, neuritogenesis was decreased and correlated with Anxa2 and Junb levels. The siRNA-mediated knockdown of Sema5a in males also impaired cortical development in utero. Consistent with Anxa2 and Junb downregulations, deficits in social novelty were observed only in female offspring but not in males. CONCLUSION: This is the first study to show that prenatal BPA exposure dysregulated the expression of ASD-related genes and functions, including cortical neuritogenesis and development and social behaviors, in a sex-dependent manner. Our findings suggest that, besides the hippocampus, BPA could also exert its adverse effects through sex-specific molecular mechanisms in the offspring's prefrontal cortex, which in turn would lead to sex differences in ASD-related neuropathology and clinical manifestations, which deserves further investigation.

APA Citation

Kanlayaprasit, Songphon; Saeliw, Thanit; Thongkorn, Surangrat; Panjabud, Pawinee; Kasitipradit, Kasidit; Lertpeerapan, Pattanachat; Songsritaya, Kwanjira; Yuwattana, Wasana; Jantheang, Thanawin; Jindatip, Depicha; Hu, Valerie W.; Kikkawa, Takako; Osumi, Noriko; and Sarachana, Tewarit, "Sex-specific impacts of prenatal bisphenol A exposure on genes associated with cortical development, social behaviors, and autism in the offspring's prefrontal cortex" (2024). GW Authored Works. Paper 4930.
https://hsrc.himmelfarb.gwu.edu/gwhpubs/4930

Department

Biochemistry and Molecular Medicine