Many if not all, developmental toxicants induce an episode of cell death as part of the pathogenesis that culminates in recognizable birth defects. More importantly, different tissues within the early postimplantation mammalian embryo exhibit vastly different sensitivities to developmental toxicant-induced cell death. Over the past 10 years we have shown that a variety of developmental toxicants induce a profound episode of cell death in the developing CNS and a complete absence of cell death in the developing heart and the visceral yolk sac. The fact that developmental toxicants operating through widely different mechanisms induce cell death in the CNS but not the heart and visceral yolk sac suggests that a common factor (s) is involved in determining whether a cell lives or dies. Recent research has shown that both PCD and toxicant-induced cell death are active processes requiring specific gene products. moreover, one of the key factors controlling whether a cell lives or dies is the oncogene Bcl-2. Bcl-2 has been shown to block cell death induced by a variety of drugs, chemicals and physical agents. In addition , Bcl02 is the structural and functional homolog of the ced-9 gene in the round worm, C. elegans, where it functions as a negative regulator of programmed cell death. To investigate the role of Bcl-2, and Bcl-2 related genes in the control of developmental toxicant-induced cell death, we will investigate the following hypotheses associated with our three specific aims; 1) the sensitivity of murine embryonic cells to the cell-death-inducing potential of developmental toxicants (cadmium chloride, cyclophosphamide, hyperthermia, lindane, menadione) is regulated by the expression of Bcl-2 and/or Bcl-2 family members, and 2) developmental toxicants may further alter the sensitivity of embryonic cells by altering the expression of Bcl- 2 and/or Bcl-2-family members. To investigate these hypotheses we will pursue the following three specific aims; 1) correlate endogenous levels of Bcl-2,Bax,Bcl-x and Bad mRNA/protein with tissue sensitivity; 2) correlate developmental toxicant-induced alterations in Bcl-2,Bax,Bcl-x and/or Bad expression with tissue sensitivity; 3) use transgenic embryos that are either deficient in Bcl-2-or overexpress Bcl-2 to assess the functional role of Bcl-2 in determining tissue sensitivity.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES007026-03
Application #
2701320
Study Section
Toxicology Subcommittee 2 (TOX)
Project Start
1996-05-01
Project End
1999-04-30
Budget Start
1998-05-01
Budget End
1999-04-30
Support Year
3
Fiscal Year
1998
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
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

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