Although a variety of physical and chemical agents disrupt development in animals and humans, little is known about factors that determine whether a particular animal or human will be sensitive to a potentially developmentally toxic exposure. Recent research has identified a family of genes and their respective proteins, known as 70 kilodalton heat shock protein (Hsp 70) family, that plays a role in protecting cells and organs from the toxic effects of exposure to hyperthermia and chemical insult. In addition, research from the author's laboratory and other laboratories has implicated these heat shock proteins as modulators of developmental toxicity in mammalian embryos. To determine more precisely the role of specific heat shock proteins in modulating developmental toxicity, three specific aims are proposed.
In specific aim 1, it is proposed to use transgenic mice that overexpress specific heat shock proteins to test the hypothesis that overexpression of inducible Hsp70 will decrease the sensitivity of early postimplantation mouse embryos to the teratogenic effects of selected developmental toxicants.
In specific aim 2, it is proposed to use transgenic mice in which the Hsp 70-1 and Hsp 70-3 genes have been inactivated by homologous recombination to test the hypothesis that loss of Hsp 70-1/3 will increase the sensitivity of early postimplantation mouse embryos to the transgenic effects of selected developmental toxicants.
In specific aim 3, it is proposed to use these gain-of-function and loss-of-function transgenics to investigate the hypothesis that Hsp 70-1/3 exerts its modulating activity by interacting with the cell cycle machinery, thereby preventing inappropriate cell death. In the work proposed the developmental toxicants will be hyperthermia and cyclophosphamide.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES008744-03
Application #
2838228
Study Section
Special Emphasis Panel (ZES1-CKS-B (02))
Project Start
1996-12-01
Project End
2000-11-30
Budget Start
1998-12-01
Budget End
1999-11-30
Support Year
3
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of Washington
Department
Pediatrics
Type
Schools of Medicine
DUNS #
135646524
City
Seattle
State
WA
Country
United States
Zip Code
98195
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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