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.

Optogenetic Sensors for Monitoring Intracellular Chloride

“…Yeo et al (2013) studied the effect of bisphenol A (BPA), an additive commonly used during plastics manufacturing, on perinatal KCC2 regulation and found that BPA inhibits KCC2 upregulation and raises [Cl − ] i in neurons through an epigenetic mechanism. In addition to this GABA switch, KCC2 upregulation and subsequent [Cl − ] i downregulation signal interneuron precursors to halt migration during development (Bortone and Polleux 2009).…”

Loss of Hippocampal Oligodendrocytes Contributes to the Deficit of Contextual Fear Learning in Adult Rats Experiencing Early Bisphenol A Exposure

“…By acting as a low-affinity ER agonists, BPA regulates the expression of synthetic enzymes of estrogen in neurons and thus the production of endogenous estrogen [16], affects the nuclear translocation of ER [17], and alters the genetic and epigenetic programming [18,19]. Consequently, EBE causes a wide range of effects on the mature neurons and their precursor cells: it alters the expression of development-related genes [18], shifts the ionic balance between the internal and external environment [20], and causes the hypotrophy of dendritic spines [21].…”

The Neuroendocrine and Neurodevelopmental Effects of Endocrine Disrupting Chemicals

“…Yeo ve ark.nın yaptığı bir çalışmada, BPA'nın gelişmekte olan kortikal nöronlarda Kcc2 mRNA ekspresyonunu önemli ölçüde azalttığı gö-rülmüştür. 64 Nöroendokrin PC12 hücre hattı, hücre kültü-ründe sinir büyüme faktörü ile muamele edildiğinde; nöronal yapı kazanıp, dopamin başta olmak üzere nörotransmitterler salgılamaktadır ve dopaminerjik aktivite tayini için oldukça kullanışlıdır. Chen ve ark., MEHP [mono(zetilhekzil)ftalat] maruziyetinin PC12 hücrelerinin çoğalması ve gelişimi üzerindeki etkilerini incelemişlerdir.…”