This project will utilize newly developed assays for a battery of oxidative DNA adducts to better define dose and time responses for oxidative stress induced by exposure to PCBs and TCDD using liver and lung samples from 13, 30 and 52-week tissues from Sprague-Dawley rats exposed to pentachlorodibenzofuran, PCB 118, or mixtures of TCDD, PeCDF and PCB 126 from the NTP Toxic Equivalency Factor (TEF) studies. These studies will demonstrate the relationships between endogenous DNA adducts and carcinogenesis and determine if the "oxidative stress" Mode of Action for this important set of nongenotoxic chemicals is supported. Endogenous DNA adducts can be converted to mutations if DNA replication takes place before repair. Unlike DNA adducts, mutations cannot be repaired and are heritable in the progeny of the originally mutated cell. We have shown that endogenous DNA lesions are always present in genomic DNA, attaining >40,000 adducts per cell. Since most of these lesions are potentially mutagenic, this nonzero background of endogenous DNA damage is a likely cause of the nonzero spontaneous background mutation rate. We will develop new methods for studying mutations using the PIG gene in DT-40 cells and will employ this system to evaluate the dose-response for mutations resulting from chemicals that form DNA adducts identical to endogenously formed adducts in cells and tissues. This research will provide highly informative scientific data to be used in future cancer risk assessments, rather than relying on linear default science policy decisions that may not provide additional protection to public health, but pose expensive and often non-attainable clean-up levels for Superfund sites. Finally, we will collaborate with Projects 2, 3, 4 and 5 respectively, to determine the role of oxidative stress in the toxicity of trichloroethylene;identify critical DNA response pathways for cadmium;evaluate CAFLUX and CALUX cell biological responses to samples of environmental contaminants;and examine toxicity and DNA damage response pathways of original extracts and their fractionated and purified samples of PAH mixtures that have undergone bioremediation.
This research will clarify the role of oxidative stress in the toxicity and carcinogenicity of TCDD and PCBs and demonstrate the role of endogenous DNA adducts in mutagenesis. Using these data, it will determine critical dose-response relationships necessary for science-based low dose extrapolation of cancer risk assessments.
|Laine, Jessica E; Bailey, Kathryn A; Rubio-Andrade, Marisela et al. (2015) Maternal arsenic exposure, arsenic methylation efficiency, and birth outcomes in the Biomarkers of Exposure to ARsenic (BEAR) pregnancy cohort in Mexico. Environ Health Perspect 123:186-92|
|Edwards, Sharon E; Maxson, Pamela; Miranda, Marie Lynn et al. (2015) Cadmium levels in a North Carolina cohort: Identifying risk factors for elevated levels during pregnancy. J Expo Sci Environ Epidemiol 25:427-32|
|Rojas, Daniel; Rager, Julia E; Smeester, Lisa et al. (2015) Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci 143:97-106|
|Bailey, Kathryn A; Fry, Rebecca C (2014) Arsenic-Associated Changes to the Epigenome: What Are the Functional Consequences? Curr Environ Health Rep 1:22-34|
|Hu, Jing; Adrion, Alden C; Nakamura, Jun et al. (2014) Bioavailability of (Geno)toxic Contaminants in Polycyclic Aromatic Hydrocarbon-Contaminated Soil Before and After Biological Treatment. Environ Eng Sci 31:176-182|
|Chiu, Weihsueh A; Campbell Jr, Jerry L; Clewell 3rd, Harvey J et al. (2014) Physiologically based pharmacokinetic (PBPK) modeling of interstrain variability in trichloroethylene metabolism in the mouse. Environ Health Perspect 122:456-63|
|Rusyn, Ivan; Lemon, Stanley M (2014) Mechanisms of HCV-induced liver cancer: what did we learn from in vitro and animal studies? Cancer Lett 345:210-5|
|Lu, Sixin S; Sobus, Jon R; Sallsten, Gerd et al. (2014) Are urinary PAHs biomarkers of controlled exposure to diesel exhaust? Biomarkers 19:332-9|
|Nakamura, Jun; Mutlu, Esra; Sharma, Vyom et al. (2014) The endogenous exposome. DNA Repair (Amst) 19:3-13|
|Mishamandani, Sara; Gutierrez, Tony; Aitken, Michael D (2014) DNA-based stable isotope probing coupled with cultivation methods implicates Methylophaga in hydrocarbon degradation. Front Microbiol 5:76|
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