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APPLICATION OF GENOMICS TO REPRODUCTIVE TOXICOLOGY: WORKING FROM RESEARCH TOWARDS RISK ASSESSMENT
Citation:
Dix, D J. APPLICATION OF GENOMICS TO REPRODUCTIVE TOXICOLOGY: WORKING FROM RESEARCH TOWARDS RISK ASSESSMENT. Presented at American College of Toxicology, Hershey, PA, November 10-13, 2002.
Description:
Genomic technologies are available to examine the expression of thousands of genes simultaneously. These technologies represent a paradigm shift from single-gene approaches fundamentally altering the practice of toxicology. The goal of toxicogenomic studies is to improve human health risk assessment by delineating toxicant mode of action and identifying useful biomarkers indicative of exposure and predictive of effect. We performed gene expression profiling (GEP) in the testes and sperm of humans and rodents in order to characterize normal, fertile mRNA populations and begin examining differential gene expression in four exposure and infertility models. First, GEP in mouse testes following exposure to the drinking water disinfection byproduct bromochloroacetic acid (BCA) identified 53 genes differentially expressed in a dose-responsive fashion. Analysis of the 53 genes identified biological functions consistent with BCA targeting of post-meiotic spermatids and Sertoli cells, a first step in deriving the toxicogenomic fingerprint of BCA and perhaps other haloacetic acids in the testis. Second, GEP in mouse testes following hyperthermic exposure identified numerous genes encoding proteins with functions concordant with the observed disruption of spermatogenesis and germ cell apoptosis. Third, GEP in testes of mice and humans identified candidate biomarkers characterizing the etiology of a range of male infertility models and cases. And fourth, we defined the spermatozoal RNA profiles of normal fertile men. The discovery of mRNAs in ejaculated sperm makes it possible to catalogue transcripts from the male germ lineage using a non-invasive procedure, and the 2,780 unique mRNAs identified provide a window into spermatogenesis and testicular gene expression. Sperm mRNA could be used to identify and diagnose idiopathic infertilities, or to monitor effects of environmental exposures on sperm and male fertility. The application of such toxicogenomic data to risk assessments will rely on increased involvement and understanding by regulatory agencies such as EPA.
This is an abstract of a proposed presentation and does not necessarily reflect EPA policy.