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. Sensitive techniques are needed 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. Previously we have developed quantitative methods to detect exposure-induced expression of CYP1A1, CYP1A2, UGT1, PAI2, and TGFa, and the oncogenic translocation in Bcl-2 t(14;18).
Aims : Develop technology and capacity for: 1) measuring exposure-induced expression 2) detecting germline polymorphism (oligoligation assay) 3) discovery of polymorphism Accomplishments: 1) Following our discovery and cloning of the rat TCDD-induced gene (25-Dx, a putative membrane bound progesterone receptor also known as mPr) collaborations were initiated to characterize the expression and function of the gene. In collaboration with M. Eddy, the mouse gene has been cloned and appears to be widely expressed during spermatogenesis. 2) Using our recently developed oligo ligation-based ELISA assay (OLA) for NAT1 polymorphisms, R. Boissy has analyzed ~3000 samples, producing for ~ 9,000 genotypes. This work will contribute to an estimated 5 manuscripts with the 1st paper in press (1) and a detailed methods manuscript being prepared. 3) Automated sample handling equipment and high throughput genotyping procedures were incorporated into the sample preparation and genotype analysis. Inventory and sample tracking systems are also being implemented. 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.
