Understanding the mechanism of carcinogens present in the workplace and the environment has become increasingly important because of the use of mechanism-based approaches to extrapolate results from laboratory animals to humans for risk assessments. This is especially true when tumor response in laboratory animals at dose levels that are much greater than environmental exposure are used to estimate the risk to human. Hence, knowledge of the mechanism of carcinogens will improve low dose and interspecies extrapolation. We hypothesize that dibromoacetic acid (DBA) will be carcinogenic in mouse liver, that bromodichloromethane (BDCM) will be carcinogenic in rat colon and mouse liver and that 3-chloro-4- (dichloromethyl)-5-hydroxy-2(5H)- furanone (MX) being a very potent mutagen will be a carcinogen. Furthermore, we hypothesize that the mechanism for the carcinogenic activity of BDCM and DBA in mouse liver will be non-genotoxic while the mechanism of BDCM in rat colon and MC will be genotoxic.
Specific Aim 1 is to determine in mouse and rat liver and colon the ability of DBA and BDCM to decrease the methylation of the promoter regions of the protooncogenes, insulin-growth factor-2, c-jun and c-myc and to increase the expression of their mRNA and proteins.
This aim will test the hypothesis that DBA and BDCM have non-genotoxic and non-genotoxic mechanisms for DBA and BDCM including the determination of biomarkers in tumors induced by them in MX. This includes mutations in the ras oncogene.
Specific Aim 3 is to characterize the pathogenesis of DBA and BDCM-induced mouse liver tumors for comparison to other non-genotoxic mouse liver carcinogens including dichloroacetic acids and trichloroacetic acid. hence, this grant by improving the understanding of the mechanism of these likely carcinogens in drinking water will have great relevance in the performance of more scientifically based risk assessment of them.
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| Tao, Lianhui; Wang, Wei; Li, Long et al. (2004) Effect of dibromoacetic acid on DNA methylation, glycogen accumulation, and peroxisome proliferation in mouse and rat liver. Toxicol Sci 82:62-9 |
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