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Bisphenol A delays the perinatal chloride shift in cortical neurons by epigenetic effects on the Kcc2 promoter.

Publication ,  Journal Article
Yeo, M; Berglund, K; Hanna, M; Guo, JU; Kittur, J; Torres, MD; Abramowitz, J; Busciglio, J; Gao, Y; Birnbaumer, L; Liedtke, WB
Published in: Proc Natl Acad Sci U S A
March 12, 2013

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.

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Published In

Proc Natl Acad Sci U S A

DOI

EISSN

1091-6490

Publication Date

March 12, 2013

Volume

110

Issue

11

Start / End Page

4315 / 4320

Location

United States

Related Subject Headings

  • Symporters
  • Sex Characteristics
  • Response Elements
  • Rats
  • Phenols
  • Neurons
  • Nerve Tissue Proteins
  • Mice
  • Male
  • K Cl- Cotransporters
 

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Yeo, M., Berglund, K., Hanna, M., Guo, J. U., Kittur, J., Torres, M. D., … Liedtke, W. B. (2013). Bisphenol A delays the perinatal chloride shift in cortical neurons by epigenetic effects on the Kcc2 promoter. Proc Natl Acad Sci U S A, 110(11), 4315–4320. https://doi.org/10.1073/pnas.1300959110
Yeo, Michele, Ken Berglund, Michael Hanna, Junjie U. Guo, Jaya Kittur, Maria D. Torres, Joel Abramowitz, et al. “Bisphenol A delays the perinatal chloride shift in cortical neurons by epigenetic effects on the Kcc2 promoter.Proc Natl Acad Sci U S A 110, no. 11 (March 12, 2013): 4315–20. https://doi.org/10.1073/pnas.1300959110.
Yeo M, Berglund K, Hanna M, Guo JU, Kittur J, Torres MD, et al. Bisphenol A delays the perinatal chloride shift in cortical neurons by epigenetic effects on the Kcc2 promoter. Proc Natl Acad Sci U S A. 2013 Mar 12;110(11):4315–20.
Yeo, Michele, et al. “Bisphenol A delays the perinatal chloride shift in cortical neurons by epigenetic effects on the Kcc2 promoter.Proc Natl Acad Sci U S A, vol. 110, no. 11, Mar. 2013, pp. 4315–20. Pubmed, doi:10.1073/pnas.1300959110.
Yeo M, Berglund K, Hanna M, Guo JU, Kittur J, Torres MD, Abramowitz J, Busciglio J, Gao Y, Birnbaumer L, Liedtke WB. Bisphenol A delays the perinatal chloride shift in cortical neurons by epigenetic effects on the Kcc2 promoter. Proc Natl Acad Sci U S A. 2013 Mar 12;110(11):4315–4320.
Journal cover image

Published In

Proc Natl Acad Sci U S A

DOI

EISSN

1091-6490

Publication Date

March 12, 2013

Volume

110

Issue

11

Start / End Page

4315 / 4320

Location

United States

Related Subject Headings

  • Symporters
  • Sex Characteristics
  • Response Elements
  • Rats
  • Phenols
  • Neurons
  • Nerve Tissue Proteins
  • Mice
  • Male
  • K Cl- Cotransporters