Our featured joint publication is: Dietary Fat-Induced Development of Colon Neoplasia in ApcMin Mice Exposed to Benzo(a)pyrene. Harris, DL, Washington MK, Hood DB, Roberts LJ, Ramesh A. Toxicol Pathol, Oct 19, 2009. [Epub ahead of print] dol:10.1177/0192623309351722** .
Background. Benzo(a)pyrene [B(a)P] is a polycyclic aromatic hydrocarbon and environmental toxin which can be generated as a by-product of industrial emissions, automobile exhaust fumes, cigarette smoke, wood combustion, or even as a dietary contaminant created by red meat cooked at high temperatures. The Hood lab started working with B(a)P and similar environmental toxins because of studies showing that children, often low-income, living in defined industrial areas in the South had neurological deficits. While this laboratory continues to focus on early CNS development in offspring of pregnant rats or mice exposed to B(a)P aerosols, other investigators like Dr. Ramesh have turned to risks associated with damage to other tissues.
- Aramandla Ramesh, PhD
Treatment. In this study the authors used the ApcMin mouse. This mouse, with a point mutation in the Apc gene, is used to study intestinal polyposis and colorectal cancer. The mouse (untreated) develops a number of small intestinal polyps which only on occasion progress to an adenocarcinoma. Genetic and environmental modifiers, however, can promote adenoma and adenocarcinoma formation in these mice, and it is presumed, by analogy, that such factors may also play a role in the development of some sporadic colorectal cancers in humans. For this study, ApcMin male mice, given free access to rodent chow, were gavaged daily x 60 days with one of two doses of B(a)P given in diluent, diluent alone (tricaprylin), or B(a)P dissolved in unsaturated fat (peanut oil) or saturated fat (coconut oil). The oils alone were also given as additional controls. Post sacrifice, the jejunums and colons were examined by pathologists who were unaware of the treatment group.
Treatment neither statistically affected total body weight nor the amount of food eaten during this period. In a dose-dependent manner, B(a)P alone and B(a)P in unsaturated fat increased the number of polyps to a similar degree, and in general polyps seen post B(a)P were larger. However when given in saturated fat, there was a significantly higher number of polyps compared to B(a)P alone or B(a)P in unsaturated fat. Further B(a)P polyps (adenomas) were more likely to be localized in the distal colon. A few invasive adenocarcinomas were also found in the higher dose B(a)P group when given with saturated fat.
The authors are currently studying why saturated fat enhances the tumorigenic activity of B(a)P, and if B(a)P-DNA adduct formation contributes to the enhanced proportion of distal tumors in the toxin-treated mice. Most importantly, these results may provide a clue as to how consumption of well-done red meats and unsaturated fat diets may result in an increased risk of colorectal cancer.
**The senior author, Dr. Aramandla Ramesh, and the first author, graduate student Deacqunita Harris, are from the Department of Biochemistry and Cancer Biology at Meharry. Drs. Roberts and Washington are from the Departments of Medicine/Pharmacology and Pathology at Vanderbilt. Dr. Darryl Hood, PI of the joint ARCH S11 grant from NIEHS, is from the Department of Neuroscience and Pharmacology at Meharry, and is indeed the ‘parent’ of a plethora of studies on environmental toxins emanating from Meharry over the last 10 years. Out of a total of > 25 Meharry publications over the past 10 years, several are cited below and highlight the widespread tissue effects of this compound and its metabolites.
Archibong AE, Ramesh A, Niaz MS, Brooks CM, Roberson Si, Lunstra D. Effect of benzo(a)pyrene on intra-testicular function in F-344 rats. Int J Environ Res Public Health 5:32-40, 2008.
Brown LA, Khousbouei H, Goodwin JS, Irvin-Wilson CV, Ramesh A, Sheng L, McCallister MM, Jiang GC, Aschner M, Hood DB. Down-regulation of early ionotrophic glutamate receptor subunit developmental expression as a mechanism for observed plasticity deficits following gestational exposure to benzo(a)pyene. Neurotoxicology 28:965-78, 2007.
McCallister MM, Maguire M, Ramesh A, Aimin Q, Liu S, Khoshbouei H, Aschner M, Ebner FF, Hood DB. Prenatal exposure to benzo(a)pyrene impairs later-life cortical neuronal function. Neurotoxicology 29:846-54, 2008.
Walker SA, Addai AB, Mathis M, Ramesh A. Effect of dietary fat on metabolism and DNA adduct formation after acute oral exposure of F-344 rats to fluoranthene. J Nutr Biochem., 18: 236-249, 2007.
Ramesh A, Inyang F, Lunstra DD, Niaz MR, Kopsombut P, Jones KM, Hood DB, Hills ER, Archibong AE. Alteration of fertility endpoints in adult male F-344 rats by subchronic exposure to inhaled benzo(a)pyrene. Exp Toxic Pathol 60:269-80, 2008.
Saunders CR, Das SK, Ramesh A, Shockley DC, Mukherjee S. Benzo(a)pyrene-induce acute neurotoxicity in the F-344 rat: role of oxidative stress. J Appl Toxicol 26:427-38, 2006.
Wang Z, Yang H, Ramesh A, Roberts LJ, Zhou LC, Lin X, Zhao Y, Guo ZM. Overexpression of Cu/Zn-superoxide dismutase and/or catalase accelerates benzo(a)pyrene detoxification by upregulation of the aryl hydrocarbon receptor in mouse endothelial cells. Free Radic Biol Med 47:1221-29, 2009.
Wormley DD, Ramesh A, Hood DB. Environmental contaminant-mixture effects on CNS development, plasticity, and behavior. Toxicol Appl Pharmacol 197:46-65, 2004.
Wormley DD, Chirwa S, Nayyar T, Wu J, Johnson S, Brown LA, Harris E, Hood DB. Inhaled benzo(a)pyrene impairs long term potentiation in the F1 generation rat dentate gyrus. Cell Mol Biol (Noisy-le-grand) 50:715-21, 2004.
Yang H, Zhou LD, Want Z, Roberts LJ, Lin C, Chao Y, Guo ZM. Overexpression of antioxidant enzymes in ApoE-deficient mice suppresses benzo(a)pyrene-accelerated atherosclerosis. Atherosclerosis 207:51-8, 2009.