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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES019583-02
Application #
8197313
Study Section
Neurotoxicology and Alcohol Study Section (NAL)
Program Officer
Tyson, Frederick L
Project Start
2010-12-01
Project End
2015-11-30
Budget Start
2011-12-01
Budget End
2012-11-30
Support Year
2
Fiscal Year
2012
Total Cost
$335,421
Indirect Cost
$110,421
Name
University of New Mexico Health Sciences Center
Department
Neurosciences
Type
Schools of Medicine
DUNS #
829868723
City
Albuquerque
State
NM
Country
United States
Zip Code
87131
Tyler, Christina R; Allan, Andrea M (2014) The Effects of Arsenic Exposure on Neurological and Cognitive Dysfunction in Human and Rodent Studies: A Review. Curr Environ Health Rep 1:132-147
Tyler, Christina R; Solomon, Benjamin R; Ulibarri, Adam L et al. (2014) Fluoxetine treatment ameliorates depression induced by perinatal arsenic exposure via a neurogenic mechanism. Neurotoxicology 44:98-109
Tyler, Christina R; Allan, Andrea M (2013) Adult hippocampal neurogenesis and mRNA expression are altered by perinatal arsenic exposure in mice and restored by brief exposure to enrichment. PLoS One 8:e73720
Martinez-Finley, Ebany J; Goggin, Samantha L; Labrecque, Matthew T et al. (2011) Reduced expression of MAPK/ERK genes in perinatal arsenic-exposed offspring induced by glucocorticoid receptor deficits. Neurotoxicol Teratol 33:530-7