The long-term goal of this project is to understand the role that SYP1A1 (cytochrome P1-450) plays in toxicity caused by environmental pollutants. Cyp1a1 is a member of the dioxin-inducible [ah] battery, the genes of which are up-regulated by the ah receptor (AHR). The CYP1A1 enzyme oxgenates halogenated and polycyclic aromatic hydrocarbons, e.g. polychlorniated biphenyls (PCBs) and benzo[a]pyrene(BaP). AHR ligands include dioxin (which is metabolised extremely slowly) and PCBs and BaP (which are metabolised more rapidly). The [Ah] battery plays a major role in toxicity of the skin, bone marrow, liver, eye, ovary, and immune system--as well as carcinogenesis. In the mouse the dosage and route of BaP administration are important determinants in target organ toxicity. Genetic differences in BaP toxicity depends upon the high-affinity C57BL/6-type (Ahr(b) allele) or the low-affinity DBA/2-type(Ahr(d) allele) of Ah receptor. Expression of mouse CYP1A1 mRNA is constitutively low absent, but is highly inducible in virtually every tissue and cell type in the body--following exposure to polycyclic aromatic chemicals. Toxicity can occur by either metabolism-dependent or receptor-dependent (metabolism- independent) mechanism. This laboratory has recently collaborated in making the Ahr(-/-) knockout mouse line. To investigate the mechanisms of CYP1A1 metabolism-mediated, vs. AHR-mediated toxicity caused by environmental chemicals, we therefore propose to: [1] develop a conventional, as well as an inducible, Cypla(-/-) knockout transgenic mouse line; [2] develop a (global, rather than tissue-specific) Cyp1a1(u/u) (ultra-expression) transgenic mouse line, and then generate, by breeding, the combined mouse lines Cyp1a1(-/-)Ahr(-/-), Cyp1a1 (-/-)Ahrd/d), Cyp1a1(-/-)Ahr(b/b), Cyp1a1(u/u)Ahr(-/-), Cyp1a1(u/u)Ahr(d/d), and Cyp1a1(u/u)Ahr(b/b). [3] study bone marrow toxicity and skin inflammation, following treatment of these mouse lines with oral BaP and with topical 7,12-dimethylbenzo[a]anthracene(DMBA), respectively, to determine which forms of environmental toxicity are dependent on CYP1A1 metabolism, and which forms of toxicity are dependent on the Ah receptor. These studies will greatly enhance our understanding of CYP1A1 metabolism-dependent, compared with AHR-dependent, toxicity caused by environmental pollutants. Because of conservation between human and mouse, and human polymorphisms in the CYP1A1 and AHR genes are known to exist, studies in these intact mice should help elucidate the mechanisms surrounding genetic differences in susceptibility to toxicity caused by substrates of CYP1A1, as well as ligands of the AHR.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES008147-03
Application #
2749694
Study Section
Special Emphasis Panel (ZRG4-ALTX-1)
Project Start
1996-08-01
Project End
2000-07-31
Budget Start
1998-08-01
Budget End
1999-07-31
Support Year
3
Fiscal Year
1998
Total Cost
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
Nebert, Daniel W (2017) Aryl hydrocarbon receptor (AHR): ""pioneer member"" of the basic-helix/loop/helix per-Arnt-sim (bHLH/PAS) family of ""sensors"" of foreign and endogenous signals. Prog Lipid Res 67:38-57
Lingappan, Krithika; Jiang, Weiwu; Wang, Lihua et al. (2014) Mice deficient in the gene for cytochrome P450 (CYP)1A1 are more susceptible than wild-type to hyperoxic lung injury: evidence for protective role of CYP1A1 against oxidative stress. Toxicol Sci 141:68-77
Uno, Shigeyuki; Sakurai, Kenichi; Nebert, Daniel W et al. (2014) Protective role of cytochrome P450 1A1 (CYP1A1) against benzo[a]pyrene-induced toxicity in mouse aorta. Toxicology 316:34-42
Nebert, Daniel W; Shi, Zhanquan; Gálvez-Peralta, Marina et al. (2013) Oral benzo[a]pyrene: understanding pharmacokinetics, detoxication, and consequences--Cyp1 knockout mouse lines as a paradigm. Mol Pharmacol 84:304-13
Gálvez-Peralta, Marina; Shi, Zhanquan; Chen, Jing et al. (2013) Oral benzo[a]pyrene in Cyp1a1/1b1(-/-) double-knockout mice: Microarray analysis during squamous cell carcinoma formation in preputial gland duct. Int J Cancer 132:2065-75
Iqbal, Jameel; Sun, Li; Cao, Jay et al. (2013) Smoke carcinogens cause bone loss through the aryl hydrocarbon receptor and induction of Cyp1 enzymes. Proc Natl Acad Sci U S A 110:11115-20
Dong, Hongbin; Shertzer, Howard G; Genter, Mary Beth et al. (2013) Mitochondrial targeting of mouse NQO1 and CYP1B1 proteins. Biochem Biophys Res Commun 435:727-32
Divanovic, Senad; Dalli, Jesmond; Jorge-Nebert, Lucia F et al. (2013) Contributions of the three CYP1 monooxygenases to pro-inflammatory and inflammation-resolution lipid mediator pathways. J Immunol 191:3347-57
Chen, Ying; Curran, Christine P; Nebert, Daniel W et al. (2012) Effect of chronic glutathione deficiency on the behavioral phenotype of Gclm-/- knockout mice. Neurotoxicol Teratol 34:450-7
Chen, Y; Curran, C P; Nebert, D W et al. (2012) Effect of vitamin C deficiency during postnatal development on adult behavior: functional phenotype of Gulo-/- knockout mice. Genes Brain Behav 11:269-77

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