Document Type

Thesis

Date of Award

5-16-2006

School/College

Barbara Jordan-Mickey Leland School of Public Affairs (SOPA)

Degree Name

Doctor of Education

First Advisor

Desiree Jackson

Abstract

Several types of cancer have been linked to arsenic in water. Recently, the EPA set the arsenic standard for drinking water at 10 parts per billion to protect consumers served by public water systems from the effects of long-term, chronic exposure to arsenic. Arsenic concentrations in ground water are generally higher in the Western United States, and appear to be lower in the Southeastern United States. Higher doses of arsenic are known to induce apoptosis whereas the chronic exposure of lower doses may lead to various adverse effects. Thus it is crucial to understand the genotoxicity and alteration in gene expression due to lower doses of arsenic. It has been reported that arsenic levels in drinking water are increased for populations living near arsenic-producing sites. It has also been reported that arsenic crosses the placenta and is also found in breast milk. Fetuses are therefore exposed in utero and postnatally. To date, there are no reports of the genotoxic effects of arsenic from these types of exposures. In the literature, animal studies have indicated an increased incidence of chromosomal abnormalities when rats were given oral doses of sodium arsenate (4mg As/kg/day) for 2-3 weeks, suggesting ingested arsenic may cause chromosomal effects. In human fibroblast cells, 1 2 arsenite is known to induce oxidative damage, chromosomal aberrations, cell cycle arrest, and aneuploidy. The manifestation of these cellular responses is dependent on changes in gene expression, which can be analyzed. The hypothesis behind this study is that prenatal exposure to arseruc alters gene expression during development to cause various tumor types. The purpose of this research is to explore the changes in gene expression after chronic exposure to the lower doses of the toxin arsenic, which may lead to possible adverse health outcomes. In this study, we have examined the effect of arsenic at low levels on rat fetuses to determine the effects on fetal gene expression. Timed pregnant female rats were exposed to 200ppm sodium arsenate ad libitum via drinking water during the embryonic period gestational day 7 through 21. The pups were retrieved immediately after birth for dissection. Fetal kidney tissue was harvested and pooled from treated and control animals. Maternal kidney samples were also collected. RNA isolation was performed from the tissue samples and analysis for Bcl2, Bax, Cyclin D 1, MnSOD and PCNA genes was done using real time PCR. The results of this study revealed significant increases in the expression of PCNA, MnSOD, and Bax of the mother kidney. There were no significant changes observed in the expression of these genes in arsenic-exposed fetal kidney as compared to the age-matched untreated fetal kidney. The finding of this study indicates that lower dose arsenic exposure enhances cell proliferation, increases antioxidant,...defense as well as accelerates cell apoptosis by increasing the expression of Bax, a pro-apoptotic gene in the maternal kidney. The arsenic induced increased cell proliferation, increased antioxidant defense, and acceleration of cell apoptosis may ultimately lead to cell transformation and tumor development. In summary, this study provides an insight into the mechanism of arsenic-induced carcinogenesis.

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