HYPERTHERMIA, HEAT SHOCK RESPONSE, AND BIRTH DEFECTS

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Hyperthermia (elevated temperature) is a well known animal and quite possibly human teratogen, producing primarily malformations of the central nervous system. In addition to its teratogenic effects, acute hyperthermia has been shown to induce the so-called heat shock response in cells of a variety of organisms from bacteria to man. The heat shock response is characterized by alterations in transcription and translation and the synthesis of several heat shock proteins (HSPs). Recent research has documented that in addition to hyperthermia a variety of other physical and chemical agents, many of which are also teratogens, is capable of inducing what has come to be called the stress response, hyperthermia being the best studied example. The long-term objective of the proposed research is too determine whether the stress response, characterized by altered transcription and culminating in the synthesis of specific stress proteins, plays a role in the teratogenic process initiated by hyperthermia and other teratogens. The specific aims of this proposal focus on several aspects of the relationship between the stress response and stress-induced abnormal development in mammalian (rat) embryos. Preliminary results from our laboratory indicate that hyperthermia-induced abnormal development is correlated with the induction of eight heat shock proteins and one specific aim is to characterize further the rat embryo heat shock response using the techniques of in vitro culture, radioisotopic labeling and two-dimensional gel electrophoresis. A second specific aim is to examine the hypothesis that the stress response, i.e., altered transcription and/or heat shock proteins, constitutes a basic mechanism of teratogenesis. This hypothesis will be tested using a multifaceted approach including: 1/ a direct assessment of whether the developmental program of transcription is altered by heat, 2/ whether a correlation exists between stage of development, induction of HSPs and abnormal development, 3/ a genetic analysis of sensitivity to heat-induced exencephaly and HSPs, 4/ modulation of HSP synthesis with inhibitors and 5/ whether other known teratogens induce a heat shock response. Based upon recent evidence indicating that specific stress proteins may play a role in providing protection from the effects of specific stress proteins may play a role in providing protection from the effects of hyperthermia, a third specific aim is to determine whether specific stress proteins play a role in protecting embryos from the teratogenic effects of heat and other teratogens.