The goal of this project is to identify and evaluate factors that may influence response in laboratory studies. Below is a sampling of the laboratory studies in which we are involved. In one investigation, we studied the reproductive effects of acrylamide exposure in mice that lack CYP2E1 and are thus unable to metabolize acrylamide to glycidamide. These mice were unaffected by acrylamide, while mice that did not lack CYP2E1 had very few pregnancies at high doses, and produced excessive early fetal deaths at lower doses. This finding is important because humans may be exposed to acrylamide through foods fried at high temperatures, in addition to industrial exposures. In another study, we examined gene expression and blood cell development in genetically modified mice (Tg.AC) following exposure to benzene. Benzene is known to be a carcinogen, but its mode of action is unclear. Our study showed that benzene inhibited growth and proliferation of hematopoietic progenitor cells in mice which would eventually lead to anemia. Consistent with this inhibition, we also showed that certain genes were induced that are involved in cell distress signaling, inflammation, DNA damage, cell cycle arrest and apoptosis. In most NTP studies, a genotoxicity component includes examination of micronuclei in the bone marrow or peripheral blood of mice and/or rats exposed to the chemical of interest. In the past, 5 animals were exposed to each dose level, the numbers of micronuclei among 2000 cells were microscopically counted, then the statistical analysis involved pooling the data to obtain the proportion of micronuclei present at each dose. These proportions were then analyzed with trend tests, adjusting for possible overdispersion. In examining control animals from approximately 100 studies, we found that micronuclei counts do not follow a Poisson distribution, as might be expected; rather, the counts are underdispersed. Therefore, the current method of statistical analysis may be misleading. We are evaluating several different statistical tests to determine if the method of analysis can be improved. In addition, in the near future flow cytometry may be used for evaluating 10,000 or more cells per animal. Thus, we are examining pilot data from this counting method, as well.
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