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.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
1R01HD022095-01A1
Application #
3321433
Study Section
Human Embryology and Development Subcommittee 2 (HED)
Project Start
1987-08-01
Project End
1992-07-31
Budget Start
1987-08-01
Budget End
1988-07-31
Support Year
1
Fiscal Year
1987
Total Cost
Indirect Cost
Name
University of Washington
Department
Type
Schools of Medicine
DUNS #
135646524
City
Seattle
State
WA
Country
United States
Zip Code
98195
Mirkes, P E; Cornel, L M; Wilson, K L et al. (1999) Heat shock protein 70 (Hsp70) protects postimplantation murine embryos from the embryolethal effects of hyperthermia. Dev Dyn 214:159-70
Thayer, J M; Mirkes, P E (1997) Induction of Hsp72 and transient nuclear localization of Hsp73 and Hsp72 correlate with the acquisition and loss of thermotolerance in postimplantation rat embryos. Dev Dyn 208:227-43
Mirkes, P E; Cornel, L M; Park, H W et al. (1997) Induction of thermotolerance in early postimplantation rat embryos is associated with increased resistance to hyperthermia-induced apoptosis. Teratology 56:210-9
Bratton, S L; Jardine, D S; Mirkes, P E (1997) Constitutive synthesis of heat shock protein (72 kD) in human peripheral blood mononuclear cells: implications for use as a clinical test of recent thermal stress. Int J Hyperthermia 13:157-68
Mirkes, P E; Little, S A; Cornel, L et al. (1996) Induction of heat shock protein 27 in rat embryos exposed to hyperthermia. Mol Reprod Dev 45:276-84
Little, S A; Mirkes, P E (1995) Clusterin expression during programmed and teratogen-induced cell death in the postimplantation rat embryo. Teratology 52:41-54
Thayer, J M; Mirkes, P E (1995) Programmed cell death and N-acetoxy-2-acetylaminofluorene-induced apoptosis in the rat embryo. Teratology 51:418-29
Cunningham, M L; Mac Auley, A; Mirkes, P E (1994) From gastrulation to neurulation: transition in retinoic acid sensitivity identifies distinct stages of neural patterning in the rat. Dev Dyn 200:227-41
Fujinaga, M; Park, H W; Shepard, T H et al. (1994) Staurosporine does not prevent adrenergic-induced situs inversus, but causes a unique syndrome of defects in rat embryos grown in culture. Teratology 50:261-74
Mirkes, P E; Doggett, B; Cornel, L (1994) Induction of a heat shock response (HSP 72) in rat embryos exposed to selected chemical teratogens. Teratology 49:135-42

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