HYPERTHERMIA, HEAT-SHOCK RESPONSE, AND BIRTH DEFECTS

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Hyperthermia is a well known teratogen in animals and a suspected teratogen in humans. In addition to its teratogenic effects, acute hyperthermia also induces a heat shock response characterized by alterations in transcription and translation and the synthesis of heat shock proteins (hsps). Furthermore, a variety of teratogens are capable of inducing this heat shock, or more properly, stress response. Our long range goal, therefore, is to define the relationship between teratogen- induced stress response and the induction of birth defects. One of the specific aims of this proposal is to use high resolution two-dimensional gel electrophoresis coupled with computer-assisted image analysis to examine the hypothesis that the induction of a stress response in the mammalian embryo during the critical period of organogenesis can alter the established program of activation and inactivation of genetic loci essential for normal development. Mild hyperthermia can also induce a thermotolerant state that protects cells or embryos from the toxic effects of heat and other stress-inducing agents. Although the mechanisms underlying thermotolerance are not well understood, specific hsps (hsp 27 and 72) and antioxidant defenses (glutathione, superoxide dismutase and glutathione peroxidase) have been implicated. A second specific aim, therefore, is to use antibodies, cDNAs, enzyme assays, enzyme inhibitors and inducers to examine the hypothesis that specific hsps and/or antioxidant defenses play a role in the induction of thermotolerance in rodent embryos. Finally, we will construct transgenic mice in which specific hsps are constitutively expressed under the control of a beta-actin promoter to test the hypothesis that hsps play a direct role in the induction of thermotolerance in rodent embryos.