(provided by candidate): Bisphenol A (BPA) is highly prevalent in food and beverage containers, and human exposure is ubiquitous. Current BPA research has assessed the genotoxicity of BPA alone but does not examine its potential to damage DNA in human tissues constantly subjected to a variety of environmental DNA damaging agents, e.g., the food additive potassium bromate, or UV-radiation. To address this critical gap, the proposed study will examine co-exposure of BPA with dietary and environmental DNA damaging agents. Preliminary results indicate that co-exposure of BPA with exogenous oxidants enhances cell survival and suppresses removal of oxidative DNA lesions. The studies proposed will investigate the hypothesis that co-exposure of BPA and environmental DNA damaging agents alters DNA repair capacity and induces BPA genotoxic effects. During the mentored K99 phase, I will characterize the effect of BPA on the removal of oxidative DNA damage by base excision repair. Under the mentorship of Dr. Samuel H. Wilson, a leader in the DNA repair field, I will investigate the mechanism that BPA utilizes to suppress DNA damage recognition and/or excision by the OGG1 DNA glycosylase, responsible for removing the oxidative damage lesion, 8-oxoG. Studies will utilize in vivo and in vitro assays to quantify DNA strand breaks, determine the persistence of 8-oxoG lesions, and identify mechanisms of down-regulation of OGG1 activity. This will establish the working hypothesis that BPA alters DNA repair, and provide the essential training for me to continue as an independent investigator. In the R00 phase, I will extend the studies of the K99 period by examining the specificity of BPA for suppressing base excision repair. Co-exposure of BPA with other DNA damaging agents, like UV-radiation, will be characterized to determine if BPA specifically suppresses removal of 8-oxoG vs. other lesions. During this phase, I will also investigate whether BPA-induced suppression of BER results in genomic instability. I will determine if lesion persistence results in increased mutagenesis and chromosomal rearrangements will be examined to determine if lesion removal is accomplished by stimulation of homologous recombination. The K99 proposal will provide the mentoring and critical research techniques necessary to characterize the effects of BPA alone and BPA in combination with damaging agents on BER. This phase of the project will provide me with the foundation of skills necessary to transition into an independent environmental health investigator at a research university. As an independent investigator, I will continue to investigate the abilit of BPA, other genotoxic agents, and deficiencies in DNA repair to modulate DNA repair capacity, and I will characterize the consequences of these effects on human disease and disease progression. These short- and long-term studies will fulfill the strategic goals of the NIEHS by: 1) understanding of integrated effects of BPA, 2) connecting genotoxicity of BPA with human health implications, and 3) determining the molecular mechanism of the exposure response, and 4) training the next generation of environmental scientists.
The human genome is constantly subjected to DNA damaging agents from our own metabolic products to the environmental agents around us. This exposure is now coupled with continual exposure to BPA, a prevalent chemical in consumer goods. Among a variety of molecular responses, BPA exposure has been linked to DNA damage and a number of human diseases. To better understand the role of BPA in DNA damage and repair, this proposal examines 'real world' type situations where BPA exposure happens in concert with exposure to other DNA damaging agents or conditions such as oxidative stress from inflammation or high calorie dietary intake. Examining this relevant exposure condition will provide better insight into BPA and its human health implications.
|Gassman, Natalie R; Coskun, Erdem; Jaruga, Pawel et al. (2016) Combined Effects of High-Dose Bisphenol A and Oxidizing Agent (KBrO3) on Cellular Microenvironment, Gene Expression, and Chromatin Structure of Ku70-deficient Mouse Embryonic Fibroblasts. Environ Health Perspect 124:1241-52|
|Kirby, Thomas W; Gassman, Natalie R; Smith, Cassandra E et al. (2016) DNA polymerase Î² contains a functional nuclear localization signal at its N-terminus. Nucleic Acids Res :|
|Kirby, Thomas W; Gassman, Natalie R; Smith, Cassandra E et al. (2015) Nuclear Localization of the DNA Repair Scaffold XRCC1: Uncovering the Functional Role of a Bipartite NLS. Sci Rep 5:13405|
|Gassman, Natalie R; Wilson, Samuel H (2015) Micro-irradiation tools to visualize base excision repair and single-strand break repair. DNA Repair (Amst) 31:52-63|