Abstract

Although a variety of environmental agents are known that can disrupt development. in animals and humans, little is known about factors that can be activated to. protect embryos from a potentially teratogenic exposure. Recent research has identified a family of genes and their respective proteins, known as heat shock proteins, that play a role in protecting cells from the toxic effects of exposure to hyperthermia and chemical insult- In this renewal proposal, we outline studies to test the following hypotheses: 1) Heat shock protein 70 (Hsp70) protects mouse embryos from the embryotoxic/teratogenic effects of hyperthermia, 2) Heat shock protein 27 (Hsp27) also protects mouse embryos from the embryotoxic/teratogenic effects of hyperthermia, and 3) Hsp70 and Hsp27 mediate their protective effects by modulating signal transduction (mitogen-activated protein kinase) pathways . To test these hypotheses we set forth 3 specific aims.
In Specific Aim 1, we propose to make and use an ecdysone-inducible Hsp70 transgenic mouse to determine whether inducible Hsp70, at sufficient levels, can protect mouse embryos from the embryotoxic/teratogenic effects of hyperthermia. In addition, we propose to use the Heat Shock Factor 1 (HSF 1) null mice, in which expression of all heat-inducible Hsps is blocked, to determine whether Hsps are necessary to protect the postimplantation mouse embryos from the embryotoxic effects of hyperthermia.
In Specific Aim 2, we propose to make and use an ecdysone-inducible Hsp27 transgenic mouse to determine whether inducible Hsp27, at sufficient levels, can protect mouse embryos from the embryotoxic/teratogenic effects of hyperthermia.
In Specific Aim 3, we propose to use transgenic mice developed in Specific Aims 1 and 2 to determine whether Hsp70 and Hsp27 exert their protective effects by modulating signal transduction pathways. Results expected from the above studies will provide mechanistic data that could lead to intervention strategies designed to decrease the frequency and/or severity of birth defects caused by developmental toxicants.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
2R01ES008744-05
Application #
6262599
Study Section
Alcohol and Toxicology Subcommittee 4 (ALTX)
Program Officer
Packenham, Joan P
Project Start
1996-12-01
Project End
2004-11-30
Budget Start
2001-01-08
Budget End
2001-11-30
Support Year
5
Fiscal Year
2001
Total Cost
$304,000
Indirect Cost

  Institution

Name
University of Washington
Department
Pediatrics
Type
Schools of Medicine
DUNS #
135646524
City
Seattle
State
WA
Country
United States
Zip Code
98195

  Publications

Hosako, Hiromi; Martin, Gail S; Barrier, Marianne et al. (2009) Gene and microRNA expression in p53-deficient day 8.5 mouse embryos. Birth Defects Res A Clin Mol Teratol 85:546-55
Barrier, Marianne; Dix, David J; Mirkes, Philip E (2009) Inducible 70 kDa heat shock proteins protect embryos from teratogen-induced exencephaly: Analysis using Hspa1a/a1b knockout mice. Birth Defects Res A Clin Mol Teratol 85:732-40
Hosako, Hiromi; Francisco, Liezl E; Martin, Gail S et al. (2009) The roles of p53 and p21 in normal development and hyperthermia-induced malformations. Birth Defects Res B Dev Reprod Toxicol 86:40-7
Mirkes, Philip E (2008) Cell death in normal and abnormal development. Congenit Anom (Kyoto) 48:7-17
Hosako, Hiromi; Little, Sally A; Barrier, Marianne et al. (2007) Teratogen-induced activation of p53 in early postimplantation mouse embryos. Toxicol Sci 95:257-69
Barrier, Marianne; Mirkes, Philip E (2005) Proteomics in developmental toxicology. Reprod Toxicol 19:291-304
Mikheeva, Svetlana; Barrier, Marianne; Little, Sally A et al. (2004) Alterations in gene expression induced in day-9 mouse embryos exposed to hyperthermia (HS) or 4-hydroperoxycyclophosphamide (4CP): analysis using cDNA microarrays. Toxicol Sci 79:345-59
Little, S A; Kim, W K; Mirkes, P E (2003) Teratogen-induced activation of caspase-6 and caspase-7 in early postimplantation mouse embryos. Cell Biol Toxicol 19:215-26
Kim, Won-Kyu; Mirkes, Philip E (2003) Alterations in mitochondrial morphology are associated with hyperthermia-induced apoptosis in early postimplantation mouse embryos. Birth Defects Res A Clin Mol Teratol 67:929-40
Soleman, Donna; Cornel, Leanne; Little, Sally A et al. (2003) Teratogen-induced activation of the mitochondrial apoptotic pathway in the yolk sac of day 9 mouse embryos. Birth Defects Res A Clin Mol Teratol 67:98-107

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