Biomedical Sciences ETDs

Publication Date

12-1-2014

Abstract

Arsenic is a pervasive environmental contaminant derived from both natural and anthropogenic sources. Epidemiological evidence supports a correlation between arsenic exposure in drinking water and increased rates of psychiatric disorders, including depression, in exposed populations. Previous studies have established that perinatal exposure to arsenic (through all three trimesters of fetal/neonatal development, DAE) has long-lasting consequences into adulthood including deficits in learning and memory, molecular aberrations in the hypothalamic-adrenal-pituitary (HPA) axis, and depressive-like symptoms in mice. The studies described in this dissertation were designed to assess the impact of DAE on adult hippocampal neurogenesis (AHN) as a possible mechanism of action for arsenic-induced susceptibility to depression. Three sets of experiments were developed to test the hypothesis that DAE induces aberrant epigenetic regulation of neuronal genes involved in AHN leading to depressive-like symptoms. First, arsenic-induced morphological and functional damage to the hippocampus was assessed: DAE reduced differentiation and survival of neural progenitor cells in the dentate gyrus (DG) of the hippocampus and induced depressive-like behaviors after exposure to a predator odor (2,4,5-trimethylthiazoline, TMT) in adult male offspring. DAE also blunted the HPA axis stress response, as measured by plasma corticosterone levels, after TMT exposure. Second, two treatment paradigms, environmental enrichment (EE) or chronic treatment with fluoxetine, were performed to determine the reversibility of damage and the causality of aberrant AHN as a mechanism of action. Both treatments ameliorated deficits in AHN, while fluoxetine prevented depressive-like behaviors and reversed arsenic-blunted stress responses in exposed animals. Third, morphological deficits in AHN were associated with abnormal gene expression in the DG of several factors in pathways associated with neurogenesis. Global histone modifications and next-generation sequencing following chromatin immunoprecipitation (ChIP-Seq) were performed to assess the regulation of gene expression in the DG. DAE increased levels of activating histone marks, including H3K4 trimethylation and H3K9 acetylation, specifically in the DG of adult males, with altered expression of their respective chromatin modifiers, Mll1 and GCN5/PCAF. ChIP-Seq analysis is currently underway to demonstrate the specific genes associated H3K4 trimethylation (indicative of increased gene expression) after DAE in the DG. The research presented in this dissertation demonstrates that aberrant AHN is a likely candidate for DAE-induced hippocampal damage leading to greater susceptibility to stress-induced depression in adulthood via aberrant epigenetic regulation of gene expression. These studies provide a basis for investigating the effect of DAE on epigenetic programming during embryonic development leading to neurogenic deficits observed in adulthood.

Keywords

neurobiology, arsenic, depression, epigenetics, neurogenesis

Sponsors

National Institutes of Mental Health (NIMH) and National Institutes of Environmental Health Sciences (NIEHS)

Document Type

Dissertation

Language

English

Degree Name

Biomedical Sciences

Level of Degree

Doctoral

Department Name

Biomedical Sciences Graduate Program

First Advisor

Allan, Andrea

First Committee Member (Chair)

Peronne-Bizzozero, Nora

Second Committee Member

Osley, Mary Ann

Third Committee Member

Roitbak, Tamara

Fourth Committee Member

Escalona, Rodrigo

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