Date of Award

2000

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Veterinary Physiology, Pharmacology, and Toxicology (Veterinary Medical Sciences)

First Advisor

Jay C. Means

Abstract

Release of energy-related contaminants occurs ubiquitously in the environment. Cancer induction by polycyclic aromatic hydrocarbons (PAHs) and aromatic amines have been well recognized in the workplace and are also suspected among the general population. Environmental PAHs exposure and effects have been investigated using biomarkers in aquatic and, to a lesser extent, terrestrial animals. Attempts to monitor the presence and effects of PAHs through the detection of point mutations in genes involved in carcinogenesis (p53 and K-ras) would yield interesting clues regarding possible etiologic agents and their potential effect. The identification of a mutation type, known to be G→T transversion predominantly with PAHs and aromatic amines, would be indicative of these families of chemicals, while their presence in a tumor suppressor gene and an oncogene represents additional molecular hits with potential biological significance. Achievement of this goal requires the development of Polymerase Chain Reaction/Restriction Enzyme/Ligase Chain Reaction assays which are able to detect and identify rare mutations in non-neoplastic tissues with sensitivities greater than 10--6 for various genomic sites in humans. Cotton rats (Sigmodon hispidus) appeared to be a good candidate bioindicator. Inbred Cotton rats were used to assess the sensitivity of this species to the toxic effects of PAHs using benz[a]anthracene (BaA) and 2-aminoanthracene (2AA). Although Cotton rats appeared to have the metabolic capabilities to yield reactive diol epoxide and aromatic nitrenium. intermediates, their response to the toxic effects of BaA was not obvious after two weeks per os exposure as compared to F344 rats based on their food intake. 2AA toxicity and carcinogenicity were also reduced in Cotton rats compared to F344 rats following per os and intraperitoneal exposure as assessed by the absence of decrease in food intake and in weight gain, and the non-occurrence of preneoplastic and neoplastic lesions. However, the adaptation of the mutation detection assay to the selected species did not yield the desired sensitivity secondary to primer misalignment and polymerase fidelity error. These results highlight the risk inherent in extrapolation from one species to another and suggest that Cotton rats may not be a sensitive bioindicator of PAHs exposure.

ISBN

9780599906044

Pages

158

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