Bisphenol A, the once-ubiquitous plastic hardener that still lingers in food-can linings, thermal receipts, and countless household products, has long been suspected of interfering with the developing brain. Now a team of researchers based largely at Chulalongkorn University in Bangkok has added a striking new layer to that suspicion. In a study published in the journal Biology of Sex Differences, they report that pregnant rats given BPA throughout gestation produced offspring whose cerebella — the hindbrain region that fine-tunes movement and has been repeatedly implicated in autism — showed patterns of gene-expression disruption that differed sharply between males and females. The work, led by first author Kwanjira Songsritaya and corresponding author Tewarit Sarachana, connects a common endocrine-disrupting chemical to sex-specific molecular signatures and measurable changes in motor behavior, two hallmarks of autism spectrum disorder biology.
The experimental design was deliberately straightforward. Eight-week-old female Wistar Furth rats were mated, and from the first day of pregnancy until parturition, the dams received a daily oral dose of either corn oil vehicle or BPA at 5,000 micrograms per kilogram of maternal body weight. This dosing regimen, delivered by gavage, was intended to model prenatal exposure during the entire window of cerebellar development. Once the offspring were born and matured, the researchers dissected out the cerebellum and performed RNA sequencing, a technique that captures a snapshot of every transcript the tissue is actively producing. They then validated key findings with quantitative RT-PCR, a more targeted method that measures the abundance of specific messenger RNAs with high precision.
The transcriptomic results were unambiguous in one respect: BPA left a molecular fingerprint on the developing cerebellum, and that fingerprint was not the same in both sexes. In male offspring, the most notable expression differences involved genes such as Lrfn5, which encodes a synaptic scaffolding protein involved in excitatory synapse formation, and Ntrk3, the receptor for neurotrophin-3, a growth factor critical for neuronal survival and differentiation. In females, the standout genes were Dixdc1, a signaling scaffold linked in human genetics studies to autism risk, and Pax6, a master transcription factor that orchestrates cerebellar development from the earliest stages of patterning. A fifth gene, Dmd, which encodes the muscle-associated protein dystrophin and has known roles in both brain and neuromuscular function, also showed altered expression. The fact that different gene programs were perturbed in each sex provides a molecular correlate for one of the most persistent puzzles in autism research: why the disorder is diagnosed roughly four times more often in boys than in girls.
That connection to autism is not merely rhetorical. When the team compared their BPA-responsive gene lists against the SFARI database, a curated catalog of candidate autism risk genes maintained by the Simons Foundation, the overlap was statistically significant. In other words, the genes whose expression shifted after prenatal BPA exposure were far more likely than chance to be genes already flagged by autism researchers. The picture became more cautious, however, when the authors turned to two reanalyzed human datasets of postmortem cerebellar tissue from people with autism. There, descriptive overlaps with previously reported genes could be seen, but the gene-level enrichment did not reach statistical significance. The authors are careful on this point: the rat findings are consistent with autism-relevant biology, but they do not claim to have reproduced the human cerebellar signature of the disorder.
Behavioral testing added a functional dimension to the molecular data. The researchers ran a battery of motor assessments covering coordination, sensorimotor function, locomotor activity, and neuromuscular strength — domains that are clinically relevant because motor abnormalities are among the earliest observable signs in children later diagnosed with autism. The outcome was strikingly sex-dependent. Male and female offspring did not simply show the same motor deficits in different degrees; the affected domains themselves differed between the sexes. This mirrors the molecular story, where different gene sets were perturbed in males and females, and it suggests that the consequences of prenatal BPA exposure are not a uniform insult to the developing cerebellum but a sex-stratified reorganization of its developmental program.
Crucially, the molecular and behavioral threads converge. The genes that showed expression differences — Dmd, Lrfn5, Ntrk3, Dixdc1, and Pax6 — did so alongside the observed alterations in motor-test outcomes, hinting that the transcriptomic changes are not incidental noise but plausibly linked to the functional deficits. Dmd, for example, is essential not only for muscle membrane stability but also for synaptic organization in the central nervous system, making its disruption a candidate bridge between cerebellar transcription and motor performance. Ntrk3 signaling supports the maturation of proprioceptive and cerebellar circuits, while Pax6 sits near the top of the regulatory hierarchy governing cerebellar cell fate. When a chemical exposure perturbs a developmental master regulator, the downstream consequences can cascade across entire cellular programs.
To probe how BPA might produce these effects mechanistically, the team turned to annotation and computational modeling. They found that the differentially expressed transcripts in the offspring cerebellum were annotated as targets of a set of transcription factors with established ties to autism biology: the androgen receptor (AR), estrogen receptor alpha (ESR1), RORA, SMAD4, TCF4, YY1, PAX6, and STAT1. This list is itself telling. AR and ESR1 are the canonical hormone receptors through which endocrine disruptors exert their effects, and their presence suggests a plausible route by which BPA could rewire gene regulation in a sex-specific manner — males and females differ in their hormonal milieu, so the same chemical acting through the same receptors can produce different transcriptional outcomes. RORA, meanwhile, has been proposed in prior work as a protective factor against autism that is itself hormonally regulated, and PAX6 is indispensable for cerebellar morphogenesis.
The researchers then used molecular docking, a computational technique that predicts how small molecules fit into the three-dimensional structures of proteins, to evaluate whether BPA could physically bind these transcription factors. The docking analyses generated predicted binding poses for BPA with AR, ESR1, RORA, SMAD4, TCF4, YY1, PAX6, and STAT1. Docking is a hypothesis-generating tool rather than proof of binding — the predicted poses must be confirmed experimentally with binding assays and functional studies — but the results nominate a concrete set of molecular targets for future investigation. If BPA does indeed engage these regulators directly or indirectly, it would provide a mechanistic account of how an environmental exposure could produce sex-specific, autism-relevant changes in a developing brain region.
The study’s limitations deserve honest framing, and the authors provide it. This is a rat model using a single, relatively high dose of BPA delivered throughout gestation; human exposures are typically lower, chronic, and mixed with hundreds of other chemicals. The behavioral changes were described as alterations in selected motor-test outcomes rather than a uniform syndrome, and the overlap with human autism cerebellum datasets, while descriptively interesting, was not statistically significant at the gene level. The findings are associative in the sense that they link exposure to molecular and behavioral outcomes within a controlled model, and the docking results are computational predictions. None of this diminishes the value of the work; it defines the roadmap. The next steps — experimental confirmation of BPA binding to the nominated transcription factors, dose-response studies, and tests of whether the same sex-specific signatures appear at environmentally relevant exposures — follow directly from the data.
What makes the study resonate beyond toxicology is its contribution to the sex-differences question in neurodevelopmental disorders. Autism’s male bias has been attributed to genetic factors, hormonal influences, and ascertainment bias, but mechanistic animal evidence tying an environmental exposure to divergent molecular outcomes in male and female brains is rare. Here, a single prenatal exposure produced different transcriptomic perturbations, different behavioral consequences, and a plausible receptor-mediated mechanism that could explain the divergence. As regulatory agencies worldwide continue to reassess BPA’s safety — the chemical has already been banned in baby bottles in many jurisdictions and is under ongoing review as an endocrine disruptor — studies like this one supply the granular, mechanistic evidence that such decisions require. The cerebellum, long dismissed as a mere movement coordinator, emerges once again as a sensitive window into the biology of neurodevelopmental risk, and one that appears to keep score of whether the developing brain is male or female.
Subject of Research: Sex-specific effects of prenatal bisphenol A exposure on cerebellar gene expression and motor behavior in rat offspring
Article Title: Prenatal bisphenol A exposure is associated with sex-specific cerebellar transcriptomic alterations and altered motor performance in rat offspring
Article References: Songsritaya, K., Panjabud, P., Kanlayaprasit, S., Thongkorn, S., Lertpeerapan, P., Kasitipradit, K., Jantheang, T., Sarobol, S., Borisutsawat, N., Hu, V. W., Saeliw, T., & Sarachana, T. (2026). Prenatal bisphenol A exposure is associated with sex-specific cerebellar transcriptomic alterations and altered motor performance in rat offspring. Biology of Sex Differences. https://doi.org/10.1186/s13293-026-00978-7
Image Credits: AI Generated
DOI: 10.1186/s13293-026-00978-7
Keywords: bisphenol A, prenatal exposure, cerebellum, autism spectrum disorder, sex differences, endocrine-disrupting chemicals, transcriptomics, motor performance, transcription factors, rat model, neurodevelopment, RNA sequencing
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Tags: animal models of autismautism spectrum disorderautism spectrum disorder neurobiologybisphenol Acerebellar gene expressioncerebellumcerebellum and motor behaviordevelopmental neurotoxicityEndocrine disrupting chemicalsenvironmental chemical impact on offspringlong-term neurobehavioral consequences of prenatal chemical exposurematernal BPA exposure in ratsmolecular signatures of BPA exposuremotor performanceneurodevelopmentprenatal BPA exposureprenatal exposurerat modelRNA sequencingsex differencessex differences in brain developmentsex-specific effects of endocrine disruptorstranscription factorsTranscriptomics
