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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES007026-07
Application #
6518089
Study Section
Special Emphasis Panel (ZRG1-ALTX-4 (01))
Program Officer
Heindel, Jerrold
Project Start
1996-05-01
Project End
2004-04-30
Budget Start
2002-05-01
Budget End
2004-04-30
Support Year
7
Fiscal Year
2002
Total Cost
$387,319
Indirect Cost
Name
University of Washington
Department
Pediatrics
Type
Schools of Medicine
DUNS #
135646524
City
Seattle
State
WA
Country
United States
Zip Code
98195
Prince, Lisa M; Rand, Matthew D (2018) Methylmercury exposure causes a persistent inhibition of myogenin expression and C2C12 myoblast differentiation. Toxicology 393:113-122
Jatana, Samreen; Palmer, Brian C; Phelan, Sarah J et al. (2017) Immunomodulatory Effects of Nanoparticles on Skin Allergy. Sci Rep 7:3979
Rahmani, Khatera; Dean, David A (2017) Leptomycin B alters the subcellular distribution of CRM1 (Exportin 1). Biochem Biophys Res Commun 488:253-258
Moses, Michael A; Henry, Ellen C; Ricke, William A et al. (2015) The heat shock protein 90 inhibitor, (-)-epigallocatechin gallate, has anticancer activity in a novel human prostate cancer progression model. Cancer Prev Res (Phila) 8:249-57
Resseguie, Emily A; Staversky, Rhonda J; Brookes, Paul S et al. (2015) Hyperoxia activates ATM independent from mitochondrial ROS and dysfunction. Redox Biol 5:176-85
Maduekwe, Echezona T; Buczynski, Bradley W; Yee, Min et al. (2015) Cumulative neonatal oxygen exposure predicts response of adult mice infected with influenza A virus. Pediatr Pulmonol 50:222-230
Yee, Min; Buczynski, Bradley W; O'Reilly, Michael A (2014) Neonatal hyperoxia stimulates the expansion of alveolar epithelial type II cells. Am J Respir Cell Mol Biol 50:757-66
Regal, Jean F; Lawrence, B Paige; Johnson, Alex C et al. (2014) Neonatal oxygen exposure alters airway hyper-responsiveness but not the response to allergen challenge in adult mice. Pediatr Allergy Immunol 25:180-6
Spinelli, Sherry L; Lannan, Katie L; Casey, Ann E et al. (2014) Isoprostane and isofuran lipid mediators accumulate in stored red blood cells and influence platelet function in vitro. Transfusion 54:1569-79
O'Reilly, Michael A; Yee, Min; Buczynski, Bradley W et al. (2012) Neonatal oxygen increases sensitivity to influenza A virus infection in adult mice by suppressing epithelial expression of Ear1. Am J Pathol 181:441-51

Showing the most recent 10 out of 35 publications