Epigenetic Changes in the Glucocorticoid Receptor Gene Due to Arsenic Exposure
Principal Investigator: Andrea M Allan
Abstract: DESCRIPTION (provided by applicant): Arsenic is one of the most common naturally occurring environment contaminants, and while most studies have focused on its carcinogenic potential, a few studies have shown that arsenic adversely affects cognitive development. Arsenic has been shown to perturb the hypothalamic-pituitary-adrenal (HPA) axis. One parameter of this axis, the glucocorticoid receptor (GR), has been shown to be directly altered by arsenic. The GRs are particularly concentrated in areas of central importance for cognition (hippocampus, amygdala and frontal cortex). The mechanism through which arsenic decreases glucocorticoid receptor function has not yet been elucidated, but several studies suggest that arsenic may alter epigenetic modifications to the GR gene. Epigenetic mechanisms, including DNA methylation, histone modification, and noncoding RNA-mediated processes, are known to play significant roles in development and cellular functions. Because epigenetic changes can be inherited mitotically in somatic cells as well as through germ-line, they can be a means to imprint environmental insults onto the mammalian genome, which leads to long-lasting effects on gene expression in the developing brain. Using our prenatal mouse model, we have found that moderate arsenic-exposure (50 ppb) reduced performance on a variety of learning and memory, anxiety and depression associated tasks and significantly altered the hypothalamic-pituitary-adrenal axis (HPA) function. Further studies showed that there was a decrease in glucocorticoid receptor level and a decrease in several proteins whose promoters contain glucocorticoid response elements (GREs) and are activated by GR binding. Methylation specific DNA sequencing of the GR promoter showed greater methylation at one of the transcription binding sites in the prenatal arsenic offspring. Our strategy is to develop an innovative, integrated approach that capitalizes on the molecular genetic (Dr. Zhao), neuropharmacological and behavioral (Allan) expertise of our laboratories. The specific aims developed for this project are focused on demonstrating that: (1) prenatal arsenic increases GR promoter methylation;(2) this leads to a decreased GR expression;(3) these prenatal epigenetic changes persist into postnatal development;and (4) these changes are responsible for the decrease in cognition. Understanding the molecular basis of PAE-induced cognitive deficits will be critical in developing treatments for environmental insults. PUBLIC HEALTH RELEVANCE: Arsenic is one of the most common naturally occurring contaminants found in the environment, and studies have shown that it can increase cancer as well as adversely affect human cognitive development. Arsenic has been shown to perturb the hypothalamic-pituitary-adrenal (HPA) axis and lower the expression of the glucocorticoid receptor, but the mechanism through which it produces this damage is yet to be elucidated. Our investigation will use a prenatal arsenic-exposed mouse model to explore the epigenetic changes to the expression of the glucocorticoid receptor gene.
Funding Period: 2010-12-01 - 2015-11-30
more information: NIH RePORT
- Reduced expression of MAPK/ERK genes in perinatal arsenic-exposed offspring induced by glucocorticoid receptor deficitsEbany J Martinez-Finley
Department of Neurosciences, University of New Mexico School of Medicine, United States
Neurotoxicol Teratol 33:530-7. 2011..GR-mediated transcriptional deficits in the MAPK/ERK pathway could be an underlying cause of previously reported learning deficits and provide the link to arsenic-induced deficiencies in cognitive development...
- Perinatal exposure to 50 ppb sodium arsenate induces hypothalamic-pituitary-adrenal axis dysregulation in male C57BL/6 miceSamantha L Goggin
Department of Neuroscience, University of New Mexico School of Medicine, Albuquerque, NM 87131, USA
Neurotoxicology 33:1338-45. 2012..Our findings suggest that the dysregulation of this critical regulatory axis could underlie important molecular and cognitive pathology observed following exposure to arsenic...
- Adult hippocampal neurogenesis and mRNA expression are altered by perinatal arsenic exposure in mice and restored by brief exposure to enrichmentChristina R Tyler
Department of Neuroscience, University of New Mexico School of Medicine, Albuquerque, New Mexico, United States of America
PLoS ONE 8:e73720. 2013..This study is the first to determine the impact of arsenic exposure during development on adult hippocampal neurogenesis and related gene expression. ..
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