We have developed assays for detection of toxicant exposure in rats and humans by analysis of increases in expression of specific genes. We will continue to develop and validate this assay, concentrating on the metallothionein genes as markers for exposure of humans to toxic metals. Our previous work has allowed us to optimize the technical aspects of the assay methodology for analysis of gene induction in cultured peripheral blood cells. We will now focus on issues related to application of the lymphocyte metallothionein gene induction assay (MGIA) to human populations. These issues include intra- and inter-individual variability, seasonal, dietary, gender and age effects and the relative sensitivity of the assay compared to alternative methods. The MGIA will be applied to populations with known occupational or environmental exposures to cadmium, and compared to results from control populations. The dose response and metal specificity of human lymphocyte MT mRNA induction in vitro will be investigated further to determine if individual differences in quantitative parameters of induction might be of significance for further research on interindividual differences in susceptibility to metal toxicity. Finally, we will survey both control and exposed populations for amplification and/or restriction fragment length polymorphisms in the human metallothionein genes. The goal of assessing the toxic exposure history of individuals using objective molecular biological markers will be considerably advanced by the proposed research. The preliminary field tests that we have already conducted and the proposed experiments to further develop and validate the MGIA assay, strongly support the possibility that this goal will be achieved within the next project funding period.
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