Background: Accurate risk assessment for carcinogens requires an understanding of the link between the presence of the chemical in human tissues and the resulting biological effects of the exposure. New methods are being developed to measure the phenotypic effects of exposure and for studying genetic changes that may be directly in the pathway of the disease process. In addition, discovery of new genes in environmental response pathways and new polymorphisms in these response pathways has become an important focus.
Aims : Develop technology and capacity for: 1) discovery of genes expressed as a result of exposure, 2) quantitative measurement of exposure-induced expression 3) detection of germline polymorphism 4) genotype/phenotype comparisons 5) Bioinformatic derived genetic markers. Accomplishments: 1. Human COX1, and COX2 have been resequenced 2. Preliminary evidence suggested that several COX2 polymorphisms potentially influence expression or alter the active site of NSAIDS binding. Thorough functional analysis of these polymorphisms indicates they have little impact on COX2 activity or inhibition 3. Human UGT1A1 polymorphisms, which alter serum bilirubin levels, have been detected in various population samples. We hypothesize that these may be linked with susceptibility to oxidative damage. Significance: Development of these biomarker techniques will allow us to test hypotheses concerning the role of environmental and genetic factors in understanding the etiology of human disease.
