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.
|Reif, David M; Truong, Lisa; Mandrell, David et al. (2016) High-throughput characterization of chemical-associated embryonic behavioral changes predicts teratogenic outcomes. Arch Toxicol 90:1459-70|
|Brooks, Samira A; Martin, Elizabeth; Smeester, Lisa et al. (2016) miRNAs as common regulators of the transforming growth factor (TGF)-Î² pathway in the preeclamptic placenta and cadmium-treated trophoblasts: Links between the environment, the epigenome and preeclampsia. Food Chem Toxicol 98:50-57|
|Wu, Tao P; Wang, Tao; Seetin, Matthew G et al. (2016) DNA methylation on N(6)-adenine in mammalian embryonic stem cells. Nature 532:329-33|
|Zabinski, Joseph W; Garcia-Vargas, Gonzalo; Rubio-Andrade, Marisela et al. (2016) Advancing Dose-Response Assessment Methods for Environmental Regulatory Impact Analysis: A Bayesian Belief Network Approach Applied to Inorganic Arsenic. Environ Sci Technol Lett 3:200-204|
|Tian, Xu; Patel, Keyur; Ridpath, John R et al. (2016) Homologous Recombination and Translesion DNA Synthesis Play Critical Roles on Tolerating DNA Damage Caused by Trace Levels of Hexavalent Chromium. PLoS One 11:e0167503|
|Smith, Martyn T; Guyton, Kathryn Z; Gibbons, Catherine F et al. (2016) Key Characteristics of Carcinogens as a Basis for Organizing Data on Mechanisms of Carcinogenesis. Environ Health Perspect 124:713-21|
|Chappell, Grace; Silva, Grace O; Uehara, Takeki et al. (2016) Characterization of copy number alterations in a mouse model of fibrosis-associated hepatocellular carcinoma reveals concordance with human disease. Cancer Med 5:574-85|
|Sharma, Vyom; Collins, Leonard B; Chen, Ting-Huei et al. (2016) Oxidative stress at low levels can induce clustered DNA lesions leading to NHEJ mediated mutations. Oncotarget 7:25377-90|
|Lai, Yongquan; Yu, Rui; Hartwell, Hadley J et al. (2016) Measurement of Endogenous versus Exogenous Formaldehyde-Induced DNA-Protein Crosslinks in Animal Tissues by Stable Isotope Labeling and Ultrasensitive Mass Spectrometry. Cancer Res 76:2652-61|
|Adrion, Alden C; Nakamura, Jun; Shea, Damian et al. (2016) Screening Nonionic Surfactants for Enhanced Biodegradation of Polycyclic Aromatic Hydrocarbons Remaining in Soil After Conventional Biological Treatment. Environ Sci Technol 50:3838-45|
Showing the most recent 10 out of 453 publications