Date of Award

12-2013

Level of Access

Campus-Only Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Biomedical Sciences

Advisor

Rebecca J. Van Beneden

Second Committee Member

Rodney J. Bushway

Third Committee Member

Derek J. Hoelz

Abstract

Arsenic exposure has been linked to numerous disorders including cancers, cardiovascular disease, diabetes and metabolic disease, although the mechanisms of arsenic toxicity are still poorly understood. Arsenic has been shown to induce oxidative stress and alter gene expression and protein activity in vitro. In vivo studies have revealed sex-specific responses to arsenic exposure. I hypothesized that low-dose sodium arsenite exposure would impact gene expression in cell cycle regulatory and lipid metabolism pathways in the liver of both mouse (Mus musculus) and zebrafish (Danio rerio). Gene expression studies were carried out in adult zebrafish exposed to 10, 50 or 500 ppb sodium arsenite for 7 or 21 days. In the mouse, F0 dams were exposed to 10, 50 or 500 ppb sodium arsenite in their drinking water from one week prior to mating through 21-days post birth of the F1 pups. Transgenerational analyses were performed on both F1 and F2 generations using targeted mRNA expression arrays. Results from zebrafish protein expression studies suggested that lipid metabolic pathways may be altered after a 7-day exposure. 21-day treated adult zebrafish, F1 mice exposed in utero, and their F2 offspring showed mRNA expression changes in lipid metabolism and cell cycle regulatory pathways. Both the zebrafish and mouse exhibited sex-specific changes in gene expression. Direct comparison between mouse and zebrafish of the effect of arsenic exposure on expression was made for three cell cycle regulatory genes (Brca2, Ccne1 and Wee1) and three lipid metabolism genes (Crot, Fabp3 and Hmgcsl). I found that female mice in particular were the most sensitive to arsenic-induced changes in cell cycle regulatory gene expression. Analysis of lipid metabolism gene expression yielded nearly opposite results in the two models. My findings suggest that low-dose exposures to arsenic can induce changes in gene expression in both cell cycle regulatory and lipid metabolic pathways, in a sex- and species-specific manner. My results support findings from other laboratories of arsenic-induced perturbations of genes within the same metabolic pathways. Both mouse and zebrafish models may be beneficial in further elucidating the different mechanisms of toxicity attributed to arsenic exposure in humans.

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