Butadiene (BD) is a high production volume chemical that is currently regulated as a hazardous air pollutant. This environmental chemical is a known mutagen and human carcinogen, and possesses a wide range of hematopoietic, reproductive, and neurological toxicity, which includes bone marrow depletion, ovarian, spleen and thymus atrophy. Thus, our long-term goal is to elucidate the cellular and molecular mechanisms responsible for the toxicity of butadiene. Recent studies from our laboratory have demonstrated that butadiene's most potent active metabolite, diepoxybutane (DEB), induces p53 regulated apoptosis in human lymphocytes. The mechanisms of p53 action and p53 mediated signaling in DEB-induced apoptosis are currently unknown. Although the tumor suppressor p53 protein is a multifunctional transcription factor that mediates apoptosis in response to various forms of stress, the molecular mechanism of p53 signaling and action remain unclear, and is known to be cell type and toxicant dependent. The objective of this proposal, therefore, is to identify the DEB-induced p53-mediated apoptotic signaling pathways and determine the molecular mechanisms by which p53 regulates DEB-induced apoptosis in human lymphocytes. This study will test the central hypothesis that DEB-induced DNA damage and reactive oxygen species generation will trigger multiple signaling pathways that include p300, DNA-PK and ATM/ATR to regulate p53 abundance and apoptotic activity through post-translational modifications, resulting in the control of key specific p53 responsive genes and products that mediate DEB-induced p53 regulated apoptosis in human lymphoblasts. We expect to test our hypothesis and achieve the objective of this application by pursuing the following four specific aims. (1). Identify the initial DEB-induced cellular lesion serving as the apoptotic signal activating p53 to mediate apoptosis in human lymphoblasts exposed to DEB. (2) Identify the upstream signaling pathways induced by DEB to activate p53 into mediating DEB-induced apoptosis in human lymphoblasts. (3) Determine how p53 is activated by DEB to mediate DEB-induced apoptosis in human lymphocytes. (4) Determine how p53 regulates diepoxybutane-induced apoptosis (downstream of p53) in human lymphoblasts. At the completion of these studies, our expectation is that the mechanism of DEB-induced apoptosis will be defined and the role of p53 in this process will be better understood. This knowledge will have an important vertical impact on butadiene risk assessment as well as better means of intervention after butadiene exposure. This research is of relevance to public health due to the heavy use and accidental emissions of large volume of butadiene in petrochemical industrial areas located around the gulf coast.
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