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GENOMIC ANALYSIS OF THE TESTICULAR TOXICITY OF HALOACETIC ACIDS
Citation:
Dix, D J. AND J C. Rockett. GENOMIC ANALYSIS OF THE TESTICULAR TOXICITY OF HALOACETIC ACIDS. Presented at Society of Toxicology, Nashville, TN, March 17 - 21, 2002.
Description:
Genomic analysis of the testicular toxicity of haloacetic acids
David J. Dix and John C. Rockett
Reproductive Toxicology Division, National Health and Environmental Effects Research Laboratory, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, NC 27711, USA.
Abstract
Gene expression profiles from testes of mice exposed to effective doses of reproductive toxicants can be used to identify genes and gene networks critical to male fertility, infer toxicant mode of action, and understand gene-environment interactions. A custom mouse cDNA microarray interrogating 950 genes was used to analyze gene expression in the testes of mice exposed to a haloactetic acid (HA). HAs are unintended byproducts of drinking water disinfection. Bromochloroacetic acid (BCA) is a commonly occurring HA that acts as a reproductive toxicant in male rodents, targeting sperm and spermatids. Adult C57BL/6N male mice were dosed via gavage with 0, 8, 24, 72 or 216 mg/kg of BCA once daily for 14 days. The mice were then used in a 40-day sequential breeding assay to determine if BCA negatively affects reproductive performance by targeting a particular phase of spermatogenesis. Decreased fecundity and infertility was observed during the first 10 days of the breeding assay, indicating that BCA was affecting post-meiotic spermatogenesis. Histological analysis of testes harvested at the end of dosing revealed spermatid retention and abnormal residual bodies, consistent with disruption of spermiation (the process of spermatid separation from Sertoli cells). DNA array analysis of these testes indicated that expression of 42 of the 950 genes interrogated was significantly altered by the higher doses of BCA. Of the 42 altered genes, 10 were cell adhesion genes, 7 stress response genes, and 4 steroid metabolism genes. These 10 cell adhesion-signaling genes included vinculin, a catenin, an integrin and tubulin. These families of proteins are components of or associated with the ectoplasmic specializations (ES) which form cell-cell junctions between Sertoli cells and between Sertolis and spermatids. Thus the gene expression results suggest that BCA exposure disrupts normal ES function and signaling cascades regulating sperm release. Further studies to examine the dose-responsiveness of these effects on gene expression are underway. (This is an abstract of a proposed presentation and does not necessarily reflect EPA policy)