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A Novel Role of Xenoestrogens in DNA Repair and Tumorigenesis: Implications for Aquatic Organisms

EPA Grant Number: F07D10668
Title: A Novel Role of Xenoestrogens in DNA Repair and Tumorigenesis: Implications for Aquatic Organisms
Investigators: Notch, Emily
Institution: University of Maine
EPA Project Officer: Manty, Dale
Project Period: September 1, 2007 through September 1, 2010
RFA: STAR Graduate Fellowships (2007)
Research Category: Aquatic Ecology and Ecosystems , Fellowship - Biochemistry and Molecular Biology , Academic Fellowships

Description:

Objective:

Estrogens and estrogen mimics represent a wide range of contaminants in the aquatic environment. While reproductive effects of environmental estrogens have been well delineated, other non-reproductive endpoints have yet to be examined. Despite known carcinogenic effects of estrogens, including attenuation of nucleotide excision repair (NER) in human cells, no previous research has examined effects of estrogens on DNA repair in aquatic organisms. The impact of environmental estrogens on nucleotide excision repair in aquatic organisms is currently unknown; however estrogens promote hepatic tumors in many species. Nucleotide excision repair is the DNA repair pathway that removes a variety of bulky DNA adducts such as those caused by ubiquitous environmental carcinogens. Bulky DNA adducts have the potential to become fixed mutations if not repaired before cell division. Decreased DNA repair and increased mutations have significant implications for overall fitness of aquatic organisms. This study will investigate a novel, non-reproductive role of xenoestrogens as co-carcinogens that promote tumorigenesis by suppressing DNA repair.

Approach:

Zebrafish will be used as a model organism to examine the effects of xenoestrogens on DNA repair. Hepatic NER gene expression after estrogen exposure will be examined using quantitative RT-PCR. Bulky adduct repair capacity after estrogen exposure in zebrafish liver cells will be quantified with host cell reactivation and unscheduled DNA synthesis assays. Finally, adult zebrafish will be co-exposed to estrogen and bulky adduct forming mutagens to examine whether estrogen exposure increased mutagen-induced tumorigenesis.

Expected Results:

Estrogen exposure decreases hepatic mRNA abundance of key NER genes in adult zebrafish. It is predicted that this decreased expression will result in altered NER function, resulting in higher incidence of hepatic tumors as a result of uncorrected DNA lesions. This research is relevant not only for aquatic organisms, but also for human health by uncovering a new mechanism of estrogen induced carcinogenesis.

Supplemental Keywords:

estrogen, xenoestrogens, DNA repair, nucleotide excision repair, zebrafish, Danio rerio, bulky DNA adducts, environmental carcinogenesis, , Scientific Discipline

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The perspectives, information and conclusions conveyed in research project abstracts, progress reports, final reports, journal abstracts and journal publications convey the viewpoints of the principal investigator and may not represent the views and policies of ORD and EPA. Conclusions drawn by the principal investigators have not been reviewed by the Agency.

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