TCDD (2,3, 7, 8-tetrachlorodibenzo-p-dioxin) is a representative from the class of environmental polyhalogenated aromatic hydrocarbons (PHAHs) that increase cancer risk, as well as causing disorders in reproduction, development, and immunological disorder. PHAHs are poorly metabolized and extremely hydrophobic, and remain in mammalian tissues for extended periods of time. Their effects are mediated by a cytosoloic ligand-activated transcription factor, the aromatic hydrocarbon receptor (AHR). Although generally considered to be nongenotoxic, based on negative results in prokaryotic short-term assays, many PHAHs produce an oxidative stress response leading to mutations and cellular transformation in mammalian cells. In Hepa-1 cells TCDD increases intracellular calcium and generates reactive oxygen, while in mice TCDD produces oxidation of DNA bases and hepatic thiols, mitochondrial production of reactive oxygen, and partial mitochondrial uncoupling. Based on these observations, the applicant proposed the hypothesis that acute exposure to TCDD triggers a chronic oxidative stress response mediated by mitochondria. The applicant will examine this hypothesis with three specific aims: 1. To determine the mechanism for the TCDD-mediate oxidative stress response in cultured cells. 2. To determine the mechanism for the TCDD-mediated oxidative stress response in mice, using Ahr, Cyp1a1 and cyp1a2 knockout mice. 3. To determine the involvement of the Ahr, cyp1a1 and cyp1a2 in TCDD-mediated mutagenesis in vivo, using Big Blue lacI transgenic/Ahr, Cyp1a1, and cyp1a2 knockout mice. These studies will improve our understanding of how PHAHs such as TCDD generate oxidative stress and mutagenesis, leading to better models for risk assessment and novel strategies for intervention in PHAH-mediated toxicity.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES010133-03
Application #
6525221
Study Section
Chemical Pathology Study Section (CPA)
Program Officer
Packenham, Joan P
Project Start
2000-09-30
Project End
2004-08-31
Budget Start
2002-09-30
Budget End
2003-08-31
Support Year
3
Fiscal Year
2002
Total Cost
$225,361
Indirect Cost
Name
University of Cincinnati
Department
Public Health & Prev Medicine
Type
Schools of Medicine
DUNS #
City
Cincinnati
State
OH
Country
United States
Zip Code
45221
Chen, Ying; Yang, Yi; Miller, Marian L et al. (2007) Hepatocyte-specific Gclc deletion leads to rapid onset of steatosis with mitochondrial injury and liver failure. Hepatology 45:1118-28
Shertzer, Howard G; Genter, Mary B; Talaska, Glenn et al. (2007) 7H-dibenzo[c,g]carbazole metabolism by the mouse and human CYP1 family of enzymes. Carcinogenesis 28:1371-8
Dragin, Nadine; Dalton, Timothy P; Miller, Marian L et al. (2006) For dioxin-induced birth defects, mouse or human CYP1A2 in maternal liver protects whereas mouse CYP1A1 and CYP1B1 are inconsequential. J Biol Chem 281:18591-600
Shertzer, Howard G; Genter, Mary Beth; Shen, Dongxiao et al. (2006) TCDD decreases ATP levels and increases reactive oxygen production through changes in mitochondrial F(0)F(1)-ATP synthase and ubiquinone. Toxicol Appl Pharmacol 217:363-74
Genter, Mary Beth; Clay, Corey D; Dalton, Timothy P et al. (2006) Comparison of mouse hepatic mitochondrial versus microsomal cytochromes P450 following TCDD treatment. Biochem Biophys Res Commun 342:1375-81
Uno, Shigeyuki; Dalton, Timothy P; Dragin, Nadine et al. (2006) Oral benzo[a]pyrene in Cyp1 knockout mouse lines: CYP1A1 important in detoxication, CYP1B1 metabolism required for immune damage independent of total-body burden and clearance rate. Mol Pharmacol 69:1103-14
Shen, Dongxiao; Dalton, Timothy P; Nebert, Daniel W et al. (2005) Glutathione redox state regulates mitochondrial reactive oxygen production. J Biol Chem 280:25305-12
Chen, Ying; Shertzer, Howard G; Schneider, Scott N et al. (2005) Glutamate cysteine ligase catalysis: dependence on ATP and modifier subunit for regulation of tissue glutathione levels. J Biol Chem 280:33766-74
Shertzer, Howard G; Clay, Corey D; Genter, Mary Beth et al. (2004) Uncoupling-mediated generation of reactive oxygen by halogenated aromatic hydrocarbons in mouse liver microsomes. Free Radic Biol Med 36:618-31
Shertzer, Howard G; Clay, Corey D; Genter, Mary Beth et al. (2004) Cyp1a2 protects against reactive oxygen production in mouse liver microsomes. Free Radic Biol Med 36:605-17

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