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. 2025 Jul 17;15(1):25996.
doi: 10.1038/s41598-025-09909-9.

Prenatal exposure to bisphenol A disrupts RNA splicing in the prefrontal cortex and promotes behaviors related to autism in offspring

Pawinee Panjabud  1 , Songphon Kanlayaprasit  2 , Surangrat Thongkorn  3 , Kwanjira Songsritaya  4 , Pattanachat Lertpeerapan  1 , Kasidit Kasitipradit  1 , Thanawin Jantheang  1 , Suthathip Sarobol  5 , Thanit Saeliw  2 , Valerie W Hu  6 , Takeshi Imai  7 , Tewarit Sarachana  8
Affiliations

Prenatal exposure to bisphenol A disrupts RNA splicing in the prefrontal cortex and promotes behaviors related to autism in offspring

Pawinee Panjabud et al. Sci Rep. .

Abstract

Prenatal exposure to bisphenol A (BPA), a common endocrine disruptor, has been increasingly implicated in neurodevelopmental disorders, including autism spectrum disorder. This study explores the molecular mechanisms by which prenatal BPA exposure affects alternative RNA splicing in the prefrontal cortex and investigates the potential link between alternative RNA splicing and autism-related behaviors in rat offspring. Using RNA sequencing and high-resolution melting real-time PCR, we identified differentially alternative splicing events associated with autism candidate genes. Gene ontology and pathway analyses revealed significant enrichment of differentially alternative splicing genes and neurological pathways relevant to autism. BPA appears to act through autism-related transcription factors, affecting RNA-binding proteins. Altered expressions of these RNA-binding proteins influenced alternative RNA splicing events within key autism-related genes, implicating them in disrupted synaptogenesis. Behavioral analyses of offspring exposed to BPA revealed autism-associated traits, including hyperactivity, anxiety, and aggression, which correlated with the observed sex-specific alternative RNA splicing patterns. These findings suggest that BPA-induced alterations of transcription factors and RNA-binding proteins affect alternative RNA splicing and synaptic development, potentially contributing to autism pathophysiology. This research underscores the role of environmental factors in autism etiology and highlights the importance of awareness and preventive measures against prenatal BPA exposure.

Keywords: Alternative splicing; Autism spectrum disorder; Autism-related behavior; Bisphenol A; Prefrontal cortex; Prenatal exposure.

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Conflict of interest statement

Declarations. Competing interests: The authors declare no competing interests. Ethics approval and consent to participate: All animal experiment procedures were approved by the Chulalongkorn University Animal Care and Use Committee (animal use protocol numbers: 1673007, 1773011, and 2073011), Chulalongkorn University. Consent for publication: Not applicable.

Figures

Fig. 1
Fig. 1
Schematic overview of the experimental workflow. Figure created with BioRender.com.
Fig. 2
Fig. 2
Alternative splicing patterns of ASD-related genes differentially changed in response to prenatal BPA exposure. The column graphs show the percentage of IC and SC events of selected DAS genes in the prefrontal cortex. The AS patterns of (a) Hs3st5, (b) Dhcr7, and (c) Chd2 were determined in both sexes (n = 6 pups/treatment group), males (n = 3 pups/treatment group), and females (n = 3 pups/treatment group). *p-value < 0.05 was considered statistically significant. Figure created with BioRender.com.
Fig. 3
Fig. 3
Predicted pathways associated with DAS genes from rat offspring’s prefrontal cortex prenatally exposed to BPA: (a) both sexes, (b) males, and (c) females.
Fig. 4
Fig. 4
Box plots showing expression levels of RBP genes in the prefrontal cortex. Expression levels of Elavl4, Enox1, Fxr2, Hnrnpc, Hnrnph2, Prr3, Ptbp1, Rbm24, Rbms2, and Sfpq were determined in (a) both sexes (n = 6 pups/group), (b) males (n = 3 pups/treatment group), and (c) females (n = 3 pups/treatment group). *p-value < 0.05 was considered statistically significant.
Fig. 5
Fig. 5
Correlation heatmap showing the relationships between the alternative splicing patterns of Hs3st5, Dhcr7, and Chd2 and the expression levels of RBP genes (Elavl4, Enox1, Fxr2, Hnrnpc, Hnrnph2, Prr3, Ptbp1, Rbm24, Rbms2, Sfpq). The color scale denotes R-values from red (negative correlation) to blue (positive correlation).
Fig. 6
Fig. 6
Prenatal BPA exposure disrupts synaptogenesis in the prefrontal cortex. (a) Representative images of synapses from males control, males BPA, females control, and females BPA groups. (b) Zoomed-in images from areas indicated by red boxes in (a). Pink: SYN1; Green: PSD-95; Blue: DAPI. (c) Quantification of synaptogenesis, showing the average colocalization of SYN1 and PSD-95 puncta per 10 μm spine length in both sexes (n = 30 neurons/treatment group) and separately in males and females (n = 15 neurons/treatment each). *p-value < 0.05 was considered statistically significant.
Fig. 7
Fig. 7
Prenatal BPA exposure exhibited sex-dependent effects in the open field test. The open field test measured (a) average speed, (b) average acceleration, (c) total distance traveled, (d) area explored, and (e) mobility rate in both sexes (n = 14 pups/treatment group), males (n = 7 pups/treatment group), and females (n = 7 pups/treatment group). (f) Representative trajectory images showed differences between control and BPA-exposed groups. *p-value < 0.05 was considered statistically significant.
Fig. 8
Fig. 8
Prenatal BPA exposure exhibited sex-dependent effects in the elevated plus maze and dominant tube tests. (a) Time spent in open arms and (b) number of entries into open arms in the elevated plus maze were assessed in both sexes (n = 14 pups/treatment group) and separately in males and females (n = 7 pups/treatment group). (c) Winning scores in the dominant tube test were measured in both sexes (n = 10 pups/treatment group) and separately in males and females (n = 5 pups/treatment group). *p-value < 0.05 was considered statistically significant.
Fig. 9
Fig. 9
Correlation heatmap showing relationships between alternative splicing patterns of Hs3st5, Dhcr7, and Chd2 and neurobehavioral outcomes and synaptogenesis. The color scale denotes R-values from red (negative correlation) to blue (positive correlation).
Fig. 10
Fig. 10
Schematic summary of the main findings of this study. Figure created with BioRender.com.
See this image and copyright information in PMC

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