Autism-Related Transcription Factors Underlying the Sex-Specific Effects of Prenatal Bisphenol A Exposure on Transcriptome-Interactome Profiles in the Offspring Prefrontal Cortex

Int J Mol Sci. 2021 Dec 8;22(24):13201. doi: 10.3390/ijms222413201.


Bisphenol A (BPA) is an environmental risk factor for autism spectrum disorder (ASD). BPA exposure dysregulates ASD-related genes in the hippocampus and neurological functions of offspring. However, whether prenatal BPA exposure has an impact on genes in the prefrontal cortex, another brain region highly implicated in ASD, and through what mechanisms have not been investigated. Here, we demonstrated that prenatal BPA exposure disrupts the transcriptome-interactome profiles of the prefrontal cortex of neonatal rats. Interestingly, the list of BPA-responsive genes was significantly enriched with known ASD candidate genes, as well as genes that were dysregulated in the postmortem brain tissues of ASD cases from multiple independent studies. Moreover, several differentially expressed genes in the offspring's prefrontal cortex were the targets of ASD-related transcription factors, including AR, ESR1, and RORA. The hypergeometric distribution analysis revealed that BPA may regulate the expression of such genes through these transcription factors in a sex-dependent manner. The molecular docking analysis of BPA and ASD-related transcription factors revealed novel potential targets of BPA, including RORA, SOX5, TCF4, and YY1. Our findings indicated that prenatal BPA exposure disrupts ASD-related genes in the offspring's prefrontal cortex and may increase the risk of ASD through sex-dependent molecular mechanisms, which should be investigated further.

Keywords: autism spectrum disorder; bisphenol A; endocrine-disrupting chemical; interactome; molecular docking; prefrontal cortex; prenatal exposure; sex differences; transcription factor; transcriptome.

MeSH terms

  • Animals
  • Autism Spectrum Disorder / chemically induced
  • Autism Spectrum Disorder / genetics*
  • Benzhydryl Compounds / adverse effects*
  • Disease Models, Animal
  • Estrogen Receptor alpha / genetics
  • Female
  • Gene Expression Profiling / methods*
  • Gene Expression Regulation
  • Molecular Docking Simulation
  • Nuclear Receptor Subfamily 1, Group F, Member 1 / genetics
  • Phenols / adverse effects*
  • Prefrontal Cortex / chemistry*
  • Pregnancy
  • Prenatal Exposure Delayed Effects / chemically induced
  • Prenatal Exposure Delayed Effects / genetics*
  • Rats
  • Receptors, Androgen / genetics
  • Sequence Analysis, RNA
  • Sex Characteristics
  • Transcription Factors / genetics*


  • Benzhydryl Compounds
  • Estrogen Receptor alpha
  • Nuclear Receptor Subfamily 1, Group F, Member 1
  • Phenols
  • Receptors, Androgen
  • Transcription Factors
  • bisphenol A