Effect of background strain on the hematologic toxicity ofinhaled benzene in FVB/N-Tg.AC and C57BL/6- Trp 53 +/- knockout mice.

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Title: Effect of background strain on the hematologic toxicity ofinhaled benzene in FVB/N-Tg.AC and C57BL/6- Trp 53 +/- knockout mice.
Author: Healy, Laura N
Advisors: John Cullen, Chair
Robert R. Maronpot, Member
Philip Sannes, Member
Gregg Dean, Member
Leslie Recio, Member
Abstract: Benzene is an industrial solvent and a ubiquitous environmental pollutant that induces hematopoietic damage; although, the mechanism by which this damage occurs is uncertain. The hematologic effects of benzene vary widely among different mouse strains, and intermittent exposure of mice to benzene is more highly toxic and carcinogenic than low, constant exposure. The goal of the research described in this dissertation was to investigate the sensitivity of two genetically engineered mouse models of carcinogenesis, Tg.AC and p53 +/- mice, and parental strains FVB/N and C57BL/6 respectively, to hematologic toxicicity resulting from inhaled benzene. Tg.AC mice contain an activated v-Ha-ras oncogene, and the p53 +/- mouse is haplosufficient for the p53 gene. Hypotheses of this work included that benzene ishematotoxic, and that greater genotoxic damage caused by benzene would be evident in the p53 +/- mouse. Another hypothesis was that benzene would induce Tg.AC transgene expression in the spleen. The research was divided into three specific aims. First, genotoxicity resulting from exposure to benzene was determined by micronucleus formation in blood. These studies showed a time-dependent, but not a concentration-dependent increase in micronuclei following benzene exposure. The p53 +/- mice were not more sensitive to benzene-induced micronuclei than the parental strain (p53 +/+). For the second specific aim, benzene hematotoxicity was assessed and spleen analyses were conducted. Benzene induced a significant cytopenia and reduced spleen weight in all of the strains examined. The C57BL/6 mice were less sensitive to benzene hematotoxicity than the FVB/N strain for all of the hematologic parameters examined. For the third specific aim, expression of theTg.AC transgene mRNA was assessed by reverse transcriptase-polymerase chain reaction of splenic tissue. Evidence of the Tg.AC transgene expression was absent in these tissues. Overall, the findings showed a marked strain-related difference between FVB/N and C57BL/6 mice in the hematotoxicity of benzene. In most parameters investigated, the Tg.AC or p53+/- genetic alterations were not useful adjuncts for investigating the hematotoxic mechanisms of benzene. Investigation of the genetic differences between these two mouse strains may lead to further understanding of the biological determinants of benzene hematotoxicity.
Date: 2000-01-10
Degree: PhD
Discipline: Comparative Biomedical Sciences
URI: http://www.lib.ncsu.edu/resolver/1840.16/4645


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