Available data indicates that 2-3% of all human neonates have clinically identifiable birth defects at term, this percentage increases to 7-10% if the assessment is made at one year of age. Data also indicate that birth defects constitute the leading cause of infant mortality in the U.S., accounting for approximately one out of every five infant deaths. Although the etiology of birth defects is often unknown, accumulated evidence from animal and human studies indicates that environmental exposures play a significant role. These studies also demonstrate that tissue specific cell death is a common event in the pathogenesis of developmental toxicant-induced abnormal development. Recent work from the investigator's laboratory shows that activation of one of the key components of the apoptotic pathway, caspace-3, is directly correlated with this tissue specific cell death in early post-implantation murine embryos. Thus, this proposal addresses two inter-related long-term objectives: 1) elucidation of the molecular pathways activated by developmental toxicants and 2) elucidation of the mechanism(s) by which developmental toxicants induce tissue-specific cell death in early post- implantation murine embryos. To accomplish these objectives, the investigators will investigate the following specific aims: 1) Bcl-2 family members regulate developmental toxicant-induced cell death and play a role in neuroepithelial cell sensitivity/heart cell resistance, 2) caspases """"""""upstream"""""""" of caspase-3 are activated by selected developmental toxicants and tissue specific expression or activation of these caspases contribute to neuroepithelial cell sensitivity/heart cell resistance, 3) caspase inhibitors determine the embryo's response to developmental toxicants and contribute to neuroepithelial cell sensitivity/heart cell resistance, and 4) mitochondria play a role in developmental toxicant-induced cell death and in neuroepithelial cell sensitivity/heart cell resistance.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
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Special Emphasis Panel (ZRG1-ALTX-4 (01))
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University of Washington
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