Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous pollutants that are a human health concern because they are implicated in human cancers and endocrine disruption. The fish Fundulus heteroclitus will be used as a model organism to investigate the central hypothesis that CYP1B and/or CYP19 are involved in the molecular mechanisms of benzo(a)pyrene-mediated toxicity.
The Specific Aims are to: 1) Assess the respective roles of CYP1B and CYP19s in BaP and estrogen metabolism and estrogen synthesis with in vitro recombinant systems, 2) Determine the extent, to which BaP-induced CYP1 B-mediated metabolism is important in genotoxicity.
Aim 2. 1: In adult fish following BaP exposure, the relationship between tissue specific CYP1B expression, toxic metabolite formation, DNA adducts and oxidative stress will be quantitated.
Aim 2. 2: Determine how egg or larval BaP-exposure affects CYP1B expression and associated toxicological endpoints.
Aim 2. 3: Determine how CYP1B and CYP19 are up-regulated in tumor tissues in exposed fish. 3) Measure the association between BaP-induced changes in aromatase and Fundulus reproductive or developmental success.
Aim 3. 1: Determine if maternal BaP-exposure decreases reproductive success.
Aim 3. 2: Determine if and how egg and larval BaP exposures alter aromatase expression and if this is correlated with developmental deficiencies. Successful completion of these Aims will provide a greater molecular understanding of these important P450 genes and their role in the mechanisms of action of PAHs. This research will further define the utility of Fundulus as a model organism for studying PAH-associated toxicities and in the development of human CYP19 or CYP1 B-related therapeutics.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES012710-05
Application #
7409633
Study Section
Xenobiotic and Nutrient Disposition and Action Study Section (XNDA)
Program Officer
Chadwick, Lisa
Project Start
2004-07-01
Project End
2010-08-31
Budget Start
2008-05-01
Budget End
2010-08-31
Support Year
5
Fiscal Year
2008
Total Cost
$220,178
Indirect Cost
Name
University of Mississippi
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
067713560
City
University
State
MS
Country
United States
Zip Code
38677
Fang, Xiefan; Corrales, Jone; Thornton, Cammi et al. (2013) Global and gene specific DNA methylation changes during zebrafish development. Comp Biochem Physiol B Biochem Mol Biol 166:99-108
Fang, Xiefan; Thornton, Cammi; Scheffler, Brian E et al. (2013) Benzo[a]pyrene decreases global and gene specific DNA methylation during zebrafish development. Environ Toxicol Pharmacol 36:40-50
Fang, Xiefan; Dong, Wu; Thornton, Cammi et al. (2010) Benzo[a]pyrene effects on glycine N-methyltransferase mRNA expression and enzyme activity in Fundulus heteroclitus embryos. Aquat Toxicol 98:130-8
Scornaienchi, Marcus L; Thornton, Cammi; Willett, Kristine L et al. (2010) Cytochrome P450-mediated 17beta-estradiol metabolism in zebrafish (Danio rerio). J Endocrinol 206:317-25
Scornaienchi, Marcus L; Thornton, Cammi; Willett, Kristine L et al. (2010) Functional differences in the cytochrome P450 1 family enzymes from zebrafish (Danio rerio) using heterologously expressed proteins. Arch Biochem Biophys 502:17-22
Fang, Xiefan; Dong, Wu; Thornton, Cammi et al. (2010) Benzo(a)pyrene induced glycine N-methyltransferase messenger RNA expression in Fundulus heteroclitus embryos. Mar Environ Res 69 Suppl:S74-6
Wang, Lu; Camus, Alvin C; Dong, Wu et al. (2010) Expression of CYP1C1 and CYP1A in Fundulus heteroclitus during PAH-induced carcinogenesis. Aquat Toxicol 99:439-47
Wills, Lauren P; Jung, Dawoon; Koehrn, Kara et al. (2010) Comparative chronic liver toxicity of benzo[a]pyrene in two populations of the atlantic killifish (Fundulus heteroclitus) with different exposure histories. Environ Health Perspect 118:1376-81
Wills, Lauren P; Zhu, Shiqian; Willett, Kristine L et al. (2009) Effect of CYP1A inhibition on the biotransformation of benzo[a]pyrene in two populations of Fundulus heteroclitus with different exposure histories. Aquat Toxicol 92:195-201
Zhu, Shiqian; Li, Lie; Thornton, Cammi et al. (2008) Simultaneous determination of benzo[a]pyrene and eight of its metabolites in Fundulus heteroclitus bile using ultra-performance liquid chromatography with mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci 863:141-9

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