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A DOUBLE KNOCKOUT; A NOVEL APPROACH TO UNDERSTANDING STRESS-INDUCIBLE 70 KDA HEAT SHOCK PROTEINS (HSP70S) ON DEVELOPMENT AND REPRODUCTION
Garges, J B., J C. Rockett, J. C. Luft, AND D J. Dix. A DOUBLE KNOCKOUT; A NOVEL APPROACH TO UNDERSTANDING STRESS-INDUCIBLE 70 KDA HEAT SHOCK PROTEINS (HSP70S) ON DEVELOPMENT AND REPRODUCTION. Presented at Society of Toxicology, San Francisco, CA, March 25 - 29, 2001.
Heat and chemical toxicants which disrupt spermatogenesis and cause male infertility are thought to induce the expression of Hsp70-1 and 70-3, the major inducible heat shock proteins of the 70kDa family. Previous studies from several laboratories including our own have characterized the expression of Hsp70-1 and 70-3 in rodent testes and embryos exposed to heat and chemicals. For example, we have shown that inhibiting expression of Hsp70-1 and 70-3 during preimplantation embryogenesis heightens embryo sensitivity to arsenic. In the testis, heat exposure leads to transient infertility, apoptosis and expression of Hsp70-1 and 70-3 in spermatocytes. We now hypothesize that these stress proteins protect both adult and juvenile reproductive tissues exposed to heat and chemicals. This protection is likely afforded by the ability of Hsp70s to chaperone the re-folding and reassembly of denatured proteins. In order to begin testing this hypothesis, gene knockout mice have been created that constitutively lack both Hsp70-1 and 70-3. Matings of heterozygous mice and initial phenotype analysis during the first eight weeks postnatal revealed no difference in body weight, gross physical appearance, or behavioral vigor between litter-mates of all genotypes. Furthermore, the homozygous null (hsp70-1/3-/-) genotype does not appear to be embryonic lethal, as the knockout allele is transmitted according to Mendelian ratios. Further characterization of the phenotype will include mating studies with hsp70-1/3-/- male and female mice to test for effects on fertility, followed by analysis of the effects of heat shock and chemical exposure in the testis. (This is an abstract of a proposed presentation and does not necessarily reflect EPA policy)