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) Discovery/characterization of functional polymorphisms in CYP2E1 and UGT1A1 promoters (1).2) Polymorphism in the XRCC1 gene appears to be related to higher frequency of glycophorin A mutations among smokers (2). 3) XPD polymorphism was associated with greater sensitivity to X-ray induced chromatid aberrations and family history of breast cancer (4).4) We observed that among smokers GSTT1 null polymorphism results in ~2-fold higher levels of ethylene oxide-hemoglobin adducts in erythrocytes (5).5) Developed exposure model using lymphoblastoid cell lines and test with cDNA microarray analysis of gene expression following exposure to agents that initiate base excision repair and nucleotide excision repair. 6) Highly sensitive quantitative PCR methods (Taqman) have been developed to monitor CYP1A1 (PAH inducible), CYP1B1, GSTP1, COX2, GADD45, GADD153 (cell cycle arrest/damage inducible) expression and these methods will be used to independently verify inducibility (positive controls).7) Bioinformatics - A combinatorial genomic methodology for identifying unique markers from whole genomes has been developed and is the subject of an employee invention report.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.
