title: Bisphenol A delays the perinatal chloride shift in cortical neurons by epigenetic effects on the Kcc2 promoter.
abstract: Bisphenol A (BPA) is a ubiquitous compound that is emerging as a possible toxicant during embryonic development. BPA has been shown to epigenetically affect the developing nervous system, but the molecular mechanisms are not clear. Here we demonstrate that BPA exposure in culture led to delay in the perinatal chloride shift caused by significant decrease in potassium chloride cotransporter 2 (Kcc2) mRNA expression in developing rat, mouse, and human cortical neurons. Neuronal chloride increased correspondingly. Treatment with epigenetic compounds decitabine and trichostatin A rescued the BPA effects as did knockdown of histone deacetylase 1 and combined knockdown histone deacetylase 1 and 2. Furthermore, BPA evoked increase in tangential interneuron migration and increased chloride in migrating neurons. Interestingly, BPA exerted its effect in a sexually dimorphic manner, with a more accentuated effect in females than males. By chromatin immunoprecipitation, we found a significant increase in binding of methyl-CpG binding protein 2 to the "cytosine-phosphate-guanine shores" of the Kcc2 promoter, and decrease in binding of acetylated histone H3K9 surrounding the transcriptional start site. Methyl-CpG binding protein 2-expressing neurons were more abundant resulting from BPA exposure. The sexually dimorphic effect of BPA on Kcc2 expression was also demonstrated in cortical neurons cultured from the offspring of BPA-fed mouse dams. In these neurons and in cortical slices, decitabine was found to rescue the effect of BPA on Kcc2 expression. Overall, our results indicate that BPA can disrupt Kcc2 gene expression through epigenetic mechanisms. Beyond increase in basic understanding, our findings have relevance for identifying unique neurodevelopmental toxicity mechanisms of BPA, which could possibly play a role in pathogenesis of human neurodevelopmental disorders.
authors: Department of Medicine/Neurology, Duke University, Durham, NC 27710, USA.
authors: Michele
authors: M
authors: Yeo
authors: Ken
authors: K
authors: Berglund
authors: Michael
authors: M
authors: Hanna
authors: Junjie U
authors: JU
authors: Guo
authors: Jaya
authors: J
authors: Kittur
authors: Maria D
authors: MD
authors: Torres
authors: Joel
authors: J
authors: Abramowitz
authors: Jorge
authors: J
authors: Busciglio
authors: Yuan
authors: Y
authors: Gao
authors: Lutz
authors: L
authors: Birnbaumer
authors: Wolfgang B
authors: WB
authors: Liedtke
mesh_terms: D000395:Air Pollutants, Occupational / Q000009:adverse effects* / Q000494:pharmacology; D000818:Animals; D001559:Benzhydryl Compounds / Q000009:adverse effects* / Q000494:pharmacology; D002478:Cells, Cultured; D002493:Central Nervous System Diseases / Q000139:chemically induced / Q000378:metabolism; D002540:Cerebral Cortex / Q000378:metabolism* / Q000473:pathology; D002712:Chlorides / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism; D044127:Epigenesis, Genetic / Q000187:drug effects*; D005260:Female; D056284:Histone Deacetylase 1 / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D010636:Phenols / Q000009:adverse effects* / Q000494:pharmacology; D051381:Rats; D020218:Response Elements; D012727:Sex Characteristics; D027981:Symporters / Q000096:biosynthesis*; D000096922:K Cl- Cotransporters; D000098826:Bisphenol A Compounds
chemical_list: D000395:Air Pollutants, Occupational; D001559:Benzhydryl Compounds; D002712:Chlorides; D004268:DNA-Binding Proteins; D056284:Histone Deacetylase 1; D009419:Nerve Tissue Proteins; D010636:Phenols; D027981:Symporters; D000096922:K Cl- Cotransporters; C489325:MBD2 protein, human; C489326:Mbd2 protein, mouse; C110550:HDAC1 protein, human; C484389:Hdac1 protein, mouse; C515890:Hdac1 protein, rat; C006780:bisphenol A; D000098826:Bisphenol A Compounds