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.
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