Prenatal BPA exposure perturbs RNA-binding protein-mediated splicing regulation and synaptogenesis in the developing cerebellum in a sex-dependent manner.

Overview

1. The Ph.D. Program in Clinical Biochemistry and Molecular Medicine, Department of Clinical Chemistry, Faculty of Allied Health Sciences, Chulalongkorn University,Bangkok, 10330 Thailand
2. Chulalongkorn Autism Research and Innovation Center of Excellence (ChulaACE), Department of Clinical Chemistry, Faculty of Allied Health Sciences, Chulalongkorn University,Bangkok, 10330 Thailand
3. Excellence Center for Genomics and Precision Medicine, King Chulalongkorn Memorial Hospital, The Thai Red Cross Society,Bangkok, 10330 Thailand
4. The M.Sc. Program in Clinical Biochemistry and Molecular Medicine, Department of Clinical Chemistry, Faculty of Allied Health Sciences, Chulalongkorn University,Bangkok, 10330 Thailand
5. Research Unit of Immunomodulation of Natural Products, Department of Transfusion Medicine and Clinical Microbiology, Faculty of Allied Health Sciences, Chulalongkorn University,Bangkok, 10330 Thailand
6. Department of Biotechnology and Biomedicine (DTU Bioengineering), Technical University of Denmark,2800 Kongens Lyngby, Denmark
7. Department of Anatomy, Faculty of Medicine, Chulalongkorn University,Bangkok, 10330 Thailand
8. Department of Biochemistry and Molecular Medicine, School of Medicine and Health Sciences, The George Washington University,Washington, DC 20037 USA

Abstract

Background: Autism spectrum disorder (ASD) is a pervasive neurodevelopmental condition characterized by social communication deficits, exhibiting a male bias in prevalence. Emerging evidence suggests that prenatal exposure to bisphenol A (BPA) may perturb neurodevelopmental trajectories relevant to ASD. While the cerebellum is increasingly recognized as a brain region implicated in ASD pathophysiology, the impact of gestational BPA exposure on its post-transcriptional alternative splicing machinery remains fundamentally undefined.

Methods: Here, we investigated sex-dependent effects of prenatal BPA exposure on the alternative splicing landscape of the neonatal rat cerebellum. We utilized RNA-seq to profile differential alternative splicing (DAS) events. Ingenuity Pathway Analysis (IPA) was used to predict biological functions and canonical pathways, and to construct the interactome network of DAS genes. To explore candidate upstream regulatory mechanisms, we performed in silico molecular docking and used high-resolution melting (HRM) qRT-PCR to validate selected splicing events. Furthermore, we assessed in vitro cellular phenotypes in primary cerebellar neurons by measuring MTS-based viability and Syn1/Psd95 puncta colocalization.

Results: Prenatal BPA exposure was associated with widespread DAS in genes enriched for ASD-relevant pathways in the neonatal rat cerebellum. To our knowledge, this study is the first to report molecular docking analyses predicting favorable interactions between BPA and several candidate RNA-binding proteins (RBPs), including CPEB1, RALYL, HNRNPDL, and ACO1. Our findings support a model in which BPA may perturb RBP-associated splicing regulation, including altered splicing of chromatin regulators such as Ccar1 in males. These molecular and cellular findings were accompanied by sex-stratified differences in neuronal viability and synaptic puncta measurements. BPA exposure was associated with an increased MTS viability signal in male primary cerebellar neurons, together with significant reductions in Psd95 and Syn1 puncta density, whereas female neurons showed significantly increased synaptic puncta colocalization together with reduced viability.

Conclusions: In this study, we propose that prenatal BPA may be relevant to ASD-related neurodevelopmental pathways through sex-dependent changes in RBP-associated alternative splicing, including altered splicing of Ccar1 in males, together with distinct cellular outcomes. Together, these findings identify the developing cerebellum as a sensitive target of prenatal BPA exposure and highlight alternative splicing as a candidate pathway relevant to ASD biology.

Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1186/s13293-026-00941-6.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Data

Datasets cited

• figshare:33421463, at figshare; found in DataCite
• figshare:33421469, at figshare; found in DataCite
• figshare:33421472, at figshare; found in DataCite
• figshare:33421475, at figshare; found in DataCite
• figshare:33421478, at figshare; found in DataCite
• figshare:33421481, at figshare; found in DataCite
• figshare:33421484, at figshare; found in DataCite
• figshare:33421487, at figshare; found in DataCite
• figshare:33421490, at figshare; found in DataCite
• figshare:33421493, at figshare; found in DataCite

Data availability

The RNA-seq data generated in this study have been submitted to the NCBI Gene Expression Omnibus (GEO). The accession number will be provided upon acceptance or once assigned. During peer review, private reviewer access can be made available upon request.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Version 1, 27 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 11 authors, 7 keywords, 16 MeSH terms, 8 funders, 90 references.

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This paper

Jantheang, T., Kanlayaprasit, S., Songsritaya, K., Panjabud, P., Lertpeerapan, P., Kasitipradit, K., Thongkorn, S., Jindatip, D., Hu, V. W., Saeliw, T., & Sarachana, T. (2026). Prenatal BPA exposure perturbs RNA-binding protein-mediated splicing regulation and synaptogenesis in the developing cerebellum in a sex-dependent manner. Biology of sex differences, 17(1), 149. https://doi.org/10.1186/s13293-026-00941-6

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