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

This study looked at how a chemical called BPA (found in plastics) might increase autism risk differently in boys and girls. Researchers found that when pregnant rats were exposed to BPA, it changed how certain genes worked in their babies' brains. The changes were different between male and female babies, which might help explain why autism is more common in boys. BPA affected brain cell connections differently - increasing certain proteins in males but affecting actual connections differently in females.

This 2023 study investigated how prenatal bisphenol A (BPA) exposure affects autism-related genes and brain development differently in male and female offspring. Using transcriptome analysis, molecular docking, and cell culture experiments, researchers identified specific transcription factors (AR, ESR1, KDM5B, SMAD4, TCF7L2) that BPA targets, leading to sex-dependent changes in gene expression patterns associated with autism spectrum disorder. The study found that BPA exposure altered synaptogenesis (synapse formation) differently by sex - increasing synaptic proteins in males but increasing excitatory synapses only in females. The androgen receptor (AR) was identified as a key mediator in BPA's effects on autism-related genes.

These findings provide molecular mechanisms explaining sex differences in autism susceptibility linked to environmental chemical exposure.

Findings suggest prenatal BPA exposure may contribute to sex-biased autism risk through specific molecular pathways. Results support importance of reducing BPA exposure during pregnancy and highlight need for sex-specific approaches in autism research and intervention development.

Study conducted in rat models with unclear sample sizes. Molecular docking and in vitro experiments need validation in human subjects. Long-term behavioral outcomes not assessed. Specific BPA exposure levels and timing windows not clearly specified in abstract.

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. 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.

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. 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.