Many hydrophobic and lipophilic environmental toxicants when consumed through diet are absorbed by passive diffusion across the gastrointestinal tract. The extent of absorption of these chemicals during gut passage and the factors governing their absorption are critical in determining the absorption efficiency of chemicals ingested through diet. In this research we will test the hypothesis that lipid load in the diet modulates fluoranthene (FLA; a toxic, and mutagenic polycyclic aromatic hydrocarbon compound) absorption resulting in conversion of FLA to its reactive metabolites in the body and in the extent of DNA-adduct formation. We propose the following three specific aims to test the hypothesis i) to study the bioavailability, metabolism and toxicokinetics of orally administered FLA and the fate of reactive metabolites in different concentrations of dietary fat and at different doses, ii) to estimate the disposition of FLA using a physiologically based pharmacokinetic model, and iii) to investigate the influence of dietary fat on formation and persistence of FLA-DNA adducts in target tissues. Our expectation is that findings from this research will provide us with a comprehensive picture of the fate and consequences of carcinogenic chemicals ingested through lipid rich diet. Results from these studies are significant in that they contribute to a greater understanding of the role played by dietary modulation on disposition of FLA in the body and the mechanisms by which bioavailable dose contributes to carcinogenicity.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Academic Research Enhancement Awards (AREA) (R15)
Project #
1R15ES012168-01
Application #
6595058
Study Section
Alcohol and Toxicology Subcommittee 4 (ALTX)
Program Officer
Thompson, Claudia L
Project Start
2003-05-06
Project End
2006-04-30
Budget Start
2003-05-06
Budget End
2006-04-30
Support Year
1
Fiscal Year
2003
Total Cost
$145,500
Indirect Cost
Name
Meharry Medical College
Department
Neurosciences
Type
Schools of Medicine
DUNS #
041438185
City
Nashville
State
TN
Country
United States
Zip Code
37208
Archibong, Anthony E; Ramesh, Aramandla; Inyang, Frank et al. (2012) Endocrine disruptive actions of inhaled benzo(a)pyrene on ovarian function and fetal survival in fisher F-344 adult rats. Reprod Toxicol 34:635-43
Harris, Deacqunita L; Hood, Darry B; Ramesh, Aramandla (2008) Vehicle-dependent disposition kinetics of fluoranthene in Fisher-344 rats. Int J Environ Res Public Health 5:41-8
Ramesh, Aramandla; Inyang, Frank; Lunstra, Donald D et al. (2008) Alteration of fertility endpoints in adult male F-344 rats by subchronic exposure to inhaled benzo(a)pyrene. Exp Toxicol Pathol 60:269-80
Smith, Tene L; Merry, Shayla T; Harris, Deacqunita L et al. (2007) Species-specific testicular and hepatic microsomal metabolism of benzo(a)pyrene, an ubiquitous toxicant and endocrine disruptor. Toxicol In Vitro 21:753-8
Walker, Stormy A; Addai, Amma B; Mathis, Malcolm et al. (2007) Effect of dietary fat on metabolism and DNA adduct formation after acute oral exposure of F-344 rats to fluoranthene. J Nutr Biochem 18:236-49
Saunders, Crystal R; Das, Salil K; Ramesh, Aramandla et al. (2006) Benzo(a)pyrene-induced acute neurotoxicity in the F-344 rat: role of oxidative stress. J Appl Toxicol 26:427-38
Walker, Stormy A; Whitten, Linwood B; Seals, George B et al. (2006) Inter-species comparison of liver and small intestinal microsomal metabolism of fluoranthene. Food Chem Toxicol 44:380-7
Ramesh, Aramandla; Knuckles, Maurice E (2006) Dose-dependent benzo(a)pyrene [B(a)P]-DNA adduct levels and persistence in F-344 rats following subchronic dietary exposure to B(a)P. Cancer Lett 240:268-78
Ramesh, Aramandla; Walker, Stormy A; Hood, Darryl B et al. (2004) Bioavailability and risk assessment of orally ingested polycyclic aromatic hydrocarbons. Int J Toxicol 23:301-33
Knuckles, Maurice E; Inyang, Frank; Ramesh, Aramandla (2004) Acute and subchronic oral toxicity of fluoranthene in F-344 rats. Ecotoxicol Environ Saf 59:102-8

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