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GENE EXPRESSION PROFILING TO IDENTIFY MECHANISMS OF MALE REPRODUCTIVE TOXICITY
Citation:
Dix, D J. GENE EXPRESSION PROFILING TO IDENTIFY MECHANISMS OF MALE REPRODUCTIVE TOXICITY. Presented at Toxicogenomics International Forum 2001, Juntendo University, Tokyo, Japan, October31-November 1, 2001.
Description:
Gene Expression Profiling to Identify Mechanisms of Male Reproductive Toxicity
David J. Dix
National Health and Environmental Effects Research Laboratory, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, NC, 27711, USA.
Abstract
With the advent of sequence information for entire mammalian genomes, it is now possible to analyze gene expression and gene polymorphisms on a genomic scale. We have used cDNA microarrays to define the testicular transcriptomes of mice and humans and develop microarrays appropriate for monitoring testicular gene expression. Profiling gene expression in the testis of fertile, subfertile, and infertile mice and humans has been used to highlight genes critical to fertility and responsive to toxicant exposures. Gene expression profiling offers the ability to identify pre-clinical effects of exposure and provide mechanistic data useful for risk assessments, and could ultimately provide a vehicle for developing early diagnostic and preventative measures in at-risk populations or individuals. In animal models, we have used DNA microarrays to identify toxicant mode-of-action as indicated by effects on gene expression relevant to testis histopathology and fertility. After a series of experiments utilizing commercial human and mouse arrays defined the testis transcriptome and identified gene expression changes linked to fertility, we selected 950 mouse genes and created a custom cDNA microarray focused on testicular gene expression. This array has been used to characterize testicular gene expression following exposure of mice to the water disinfectant by-product bromochloroacetic acid in a regimen that induces subfertility at the higher doses. This type of toxicogenomic data has already provided mechanistic data useful for identifying toxicant mode-of-action. In future studies we plan to identify common changes in gene expression between chemicals, tissues, strains and species in order to characterize cumulative and aggregate risks and assist harmonized non-cancer and cancer risk assessments.