Year of Publication

2005

Document Type

Dissertation

College

Graduate School

Department

Toxicology

First Advisor

Howard Glauert

Second Advisor

Larry W. Robertson

Abstract

This study investigated the interaction between polychlorinated biphenyls (PCBs) and selenium to explain the mechanism involved that could affect selenium metabolism and its anti-cancer property. PCBs congeners and mixtures were previously found to reduce hepatic Se and Se-dependent glutathione peroxidase activity. I hypothesized that certain PCB congeners affect selenium metabolism in the rat liver resulting in diminished antioxidant capacity of selenoproteins, which could alter the ability of Se to protect against PCBs induced tumor promotion. In the first study, the influence of 3,3,4,4-tetrachlorobiphenyl (PCB 77) on hepatic Se and glutathione peroxidase (GPx1) activity as well as cytochrome P450 1A1 induction was examined by employing a time-course study, which showed that PCB 77 significantly reduced the hepatic selenium level and GPx1 activity and that this effect was influenced by gender. The next study explored how PCB 77 could deplete hepatic selenium by determining selenium concentrations in different tissues, feces and urine. This study demonstrated that PCB-77 decreased hepatic Se by increased excretion of Se in urine but not in feces. Unlike glutathione peroxidase, thioredoxin reductase activity was not affected by PCB 77. The third study investigated the effect of selenium supplementation on the tumor promoting activity of PCB 77 and 2,2,4,4,5,5-hexaclorobiphenyl (PCB 153) using a 2-stage carcinogenesis model. Se supplementation did not diminish the induction of altered hepatic foci by coplanar PCB 77 or ortho-substituted PCB 153. Instead of protection, the number of foci per cubic centimeter and per liver among the PCB-77 treated rats was increased as the selenium dietary level increased. PCB 153 did not show the same selenium dose-response effect; nevertheless, selenium supplementation did not confer protection against foci development. On the other hand, supranutritional selenium reduced the mean focal volume. Supranutritional selenium or PCBs did not affect cell proliferation or thioredoxin reductase activity. Lastly, the use of the Zeeman graphite furnace atomic absorption spectrometry (GFAAS) method and closed microwave digestion technique for selenium determination of biological samples was compared with the neutron activation analysis and fluorometry methods. I found that GFAAS was not as reliable as the other methods.

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