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Graduation date: 2002

Thesis (Ph. D.)--West Virginia University, 2006. / Title from document title page. Document formatted into pages; contains xiv, 139 p. : ill. (some col.). Includes abstract. Includes bibliographical references (p. 129-138).

Wild populations of fish are faced with a multitude of stressors, which may include human interaction, toxins, and disease. Benzo(a)pyrene (BaP), a known carcinogen and immunotoxin, has been reported in the stomach contents of juvenile chinook salmon, Oncorhynchus tshawytscha, in urban waterways. We investigated the impact of chronic dietary exposure of environmentally relevant levels of BaP on the immune system and cytochrome P4501A1 (CYP1A1) expression in juvenile chinook salmon. Two experiments were carried out in which juvenile fish were fed food treated with ethanol (control diet), low or high concentrations of BaP, or cortisol. In the first experiment we measured mitogen-stimulated proliferation of splenic leukocytes using flow cytometry and a colorimetric assay using Alamar Blue[superscript TM] Susceptibility to a microsporidian parasite, Loma salmonae, was evaluated in the second experiment by quantification of xenomas in the gills. Hepatic CYP1A1 and plasma cortisol were measured in both experiments. No significant trends were found in leukocyte mitogen activation or plasma cortisol between treatments or days. However, western blot analysis of CYP1A1 concentration in liver revealed interesting patterns of induction: in cortisol fed groups CYP1A1 was <20% of control on all days, groups fed low levels of BaP were 250% of control values on days 8 and 21 then dropped below control values on day 29, and groups fed high levels of BaP had less CYP1A1 than controls on all days. Similar patterns of CYP1A1 levels were found in the second experiment, and diseased control groups showed about a 55% decrease in CYP1A1 concentration when compared with non-diseased control groups. Susceptibility to L. salmonae was significantly higher in groups receiving cortisol. Whereas there was no effect of the high BaP dose, the low BaP dose appeared to increase disease susceptibility. This study supports concerns of stress and toxin induced immune dysfunction in wild populations of fish. / Graduation date: 2004

Chlorophyllin (CHL), a water-soluble derivative of the green plant pigment, chlorophyll, is an effective antimutagen and anticarcinogen in various model systems when used as a modulator against a class of carcinogens that, in general, have a structure consisting of at least three fused rings. Dibenzo[a,l]pyrene (DBP), an extremely potent environmental carcinogen, has been isolated from urban air samples, tobacco smoke, and coal smoke condensate. A study was conducted to evaluate the complex interrelationships among dietary DBP doses with co-exposure to a range of CHL doses. In order to achieve adequate statistical power in the generation of multiple dose-response curves, this dose-dose matrix experiment utilized over 12,000 rainbow trout. The resulting DNA adducts were assessed and evaluated as biomarkers of exposure to discern their relationship with the final tumor outcome. CHL was highly effective in reducing DBP-initiated DNA adduct formation in the liver and stomach and strongly inhibited tumor formation in the liver (56-79% inhibition), stomach (30-68%), and swim bladder (over 80% at the highest DBP dose). Molecular dosimetry revealed adduct formation to be predictive of final tumor response in both organs regardless of CHL dose. Other parameters evaluated were consistent with CHL-mediated protection. A clinical CHL preparation, evaluated in a human population subsequent to the seminal demonstration of CHL chemopreventive properties against AFB��� in trout (1), revealed CHL to be just as effective in reducing biomarkers of alfatoxin exposure to humans (2). Dietary administration of this clinical preparation along with DBP in the rainbow trout demonstrated CHL protective capacity against DBP-initiated multi-organ DNA adduct formation and final tumor incidence. Sucrose was evaluated, deemed unlikely to be sequestered in a complex with CHL, and was used as a control in a pharmacokinetic study evaluating the biodistribution of DBP with and without CHL. The results provide evidence against a non-specific masking mechanism for CHL-mediated blocking of DBP (or aflatoxin)-initiated tumorigenesis. CHL at multiple doses provided significant protection against multi-dose DBP-initiated DNA adduction and tumor formation in multiple organs. CHL-mediated protection, primarily by reduced carcinogen biouptake and consistent with a complexation mechanism, is supported by these results. / Graduation date: 2003

Diss. (sammanfattning) Uppsala : Sveriges lantbruksuniv., 2003. / Härtill 5 uppsatser.

Cigarette smoke condensates from all cigarettes tested were found to be potent inducers of AHH enzyme in cultured human lymphocytes and, with the exception of Kent Lights and Carlton CSC's, all were found to be toxic under the experiment conditions. Most of the AHH inducing activity was found in basic and neutral fractions of the lAl standard cigarettes. A radiometric assay of BP metabolites in cultured human lymphocytes was developed in which we were able to separate the primary metabolites and the secondary metabolites from the parent compound (BP) by neutral alumnia HPLC. The primary metabolites were further separated by a selective enzyme hydrolysis and/or reverse phase HPLC.

The role of meat consumption in the development of cancer, including colorectal cancer (CRC), has been subject of much investigation in recent years. The observation of geographical variation in CRC incidence and increased CRC risks in populations consuming high levels of meat prompted researchers to hypothesise a link between meat and CRC. An area of particular interest in CRC pathogenesis is the meat-derived compounds such are heterocyclic amines (HCAs), polycyclic aromatic hydrocarbons (PAHs), and meatderived mutagenic activity. Australia is among the countries with high incidence of CRC and also high levels of per capita meat consumption. Hence, clarifying the possible link between meat consumption and the risk of CRC in order that this can be translated into preventive dietary recommendations for the public is important. The objective of this thesis was to examine whether meat consumption is related to risk of CRC in an Australian population. The term meat consumption in this thesis means meaures of consumption of red and white meat that incorporate frequency and cooking method. The following hypotheses were investigated: 1. Increasing intake of meat prepared by methods that involve higher cooking temperature and time is positively associated with the risk of CRC; 2. Increasing exposure to meat-derived heterocyclic amines (HCAs) is positively associated with the risk of CRC; 3. Higher levels of exposure to polycyclic aromatic hydrocarbons (PAHs) from meat consumption is a risk factor for CRC; 4. Exposure to meat-derived mutagens increases the risk of CRC.