Benzo(a)pyrene [B(a)P] is a lipophilic environmental toxicant that is widely distributed in foods and air. This chemical is known to cause cancer in various organ systems. Our preliminary studies have shown that dietary exposure of mice to B(a)P via saturated fat results in an increased incidence of polyps in colon, some of which were invasive compared to mice that received B(a)P through unsaturated fat. Exposure of mice to B(a)P through saturated fat causes induction of cytochrome P450 family of enzymes resulting in an increased concentration of reactive metabolites, compared to those that received B(a)P through unsaturated fat. Similarly, exposure of mice to B(a)P via saturated fat also contributed to oxidative stress in mouse colon, shown by an increased concentration of F2-isoprostanes (markers of oxidative stress) in mouse colon. Our central hypothesis is that dietary fat enhances B(a)P-induced colon carcinogenesis through enhanced bioavailability of B(a)P, and possibly a greater accumulation of B(a)P in tissues, and greater levels of B(a)P metabolites. A linked hypothesis is that B(a)P effects are secondary to production of epoxide or quinones some of which form DNA adducts that cause genotoxicity. We will test our hypothesis by studying the effects of oral exposure of adult ApcMin mice to B(a)P in saturated versus unsaturated fat via the following specific aims: 1. Characterize the potentiating effect of saturated vs. unsaturated dietary fat on B(a)P-induced adenomas and carcinomas in the small intestine and colon of the ApcMin mouse;2. Assess the impact of the type of dietary fat on B(a)P-induced expression of biotransformation enzymes, their activities and disposition of B(a)P metabolites in the ApcMin mouse;3. Test whether B(a)P- induced colon cancer is mediated via epoxide- (genomic DNA adducts) or quinone (quinone, 8-oxo-dG and etheno adduct) pathways, or both, in the ApcMin mouse. Relevance of this project to human health Every year 56,000 deaths are attributed to colorectal cancer (CRC) in USA and in a great majority of the cases surveyed;consumption of well-done red meat and other saturated fats, rich in B(a)P were implicated as a possible causative factor. Our approach is novel in that it uses a mouse model system that replicates a human CRC scenario. Another novel aspect of our proposal is that it will evaluate the role of B(a)P metabolic pathway- specific biotransformation events in the causation of CRC. Our findings will serve as a prelude to conducting chemoprevention studies for CRC and help to synthesize drugs to prevent or delay the onset of colon cancer.

Public Health Relevance

This project looks into how environmental toxicants such as benzo(a)pyrene [B(a)P] cause colorectal cancer. This project also focuses on how consumption of foods rich in fat accelerates the development of environmentally-induced (sporadic) colorectal cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA142845-04
Application #
8403767
Study Section
Cancer Etiology Study Section (CE)
Program Officer
Johnson, Ronald L
Project Start
2010-03-10
Project End
2014-12-31
Budget Start
2013-01-01
Budget End
2014-12-31
Support Year
4
Fiscal Year
2013
Total Cost
$277,176
Indirect Cost
$87,977
Name
Meharry Medical College
Department
Biochemistry
Type
Schools of Medicine
DUNS #
041438185
City
Nashville
State
TN
Country
United States
Zip Code
37208
Mantey, Jane A; Rekhadevi, Perumalla V; Diggs, Deacqunita L et al. (2014) Metabolism of benzo(a)pyrene by subcellular fractions of gastrointestinal (GI) tract and liver in Apc(Min) mouse model of colon cancer. Tumour Biol 35:4929-35
Rekhadevi, P V; Diggs, D L; Huderson, A C et al. (2014) Metabolism of the environmental toxicant benzo(a)pyrene by subcellular fractions of human ovary. Hum Exp Toxicol 33:196-202
Harris, Kelly L; Myers, Jeremy N; Ramesh, Aramandla (2013) Benzo(a)pyrene modulates fluoranthene-induced cellular responses in HT-29 colon cells in a dual exposure system. Environ Toxicol Pharmacol 36:358-67
Harris, Kelly L; Banks, Leah D; Mantey, Jane A et al. (2013) Bioaccessibility of polycyclic aromatic hydrocarbons: relevance to toxicity and carcinogenesis. Expert Opin Drug Metab Toxicol 9:1465-80
Diggs, Deacqunita L; Myers, Jeremy N; Banks, Leah D et al. (2013) Influence of dietary fat type on benzo(a)pyrene [B(a)P] biotransformation in a B(a)P-induced mouse model of colon cancer. J Nutr Biochem 24:2051-63
Huderson, Ashley C; Myers, Jeremy N; Niaz, Mohammad S et al. (2013) Chemoprevention of benzo(a)pyrene-induced colon polyps in ApcMin mice by resveratrol. J Nutr Biochem 24:713-24
Jules, G E; Pratap, S; Ramesh, A et al. (2012) In utero exposure to benzo(a)pyrene predisposes offspring to cardiovascular dysfunction in later-life. Toxicology 295:56-67
Prins, Petra A; Perati, Prudhvidhar R; Kon, Valentina et al. (2012) Benzo[a]pyrene potentiates the pathogenesis of abdominal aortic aneurysms in apolipoprotein E knockout mice. Cell Physiol Biochem 29:121-30
Myers, Jeremy N; Rekhadevi, Perumalla V; Ramesh, Aramandla (2011) Comparative evaluation of different cell lysis and extraction methods for studying benzo(a)pyrene metabolism in HT-29 colon cancer cell cultures. Cell Physiol Biochem 28:209-18
Diggs, Deacqunita L; Huderson, Ashley C; Harris, Kelly L et al. (2011) Polycyclic aromatic hydrocarbons and digestive tract cancers: a perspective. J Environ Sci Health C Environ Carcinog Ecotoxicol Rev 29:324-57

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