Butadiene-Induced P53-Mediated Apoptotic Signaling

Southern Univ A&M Col Baton Rouge, Baton Rouge LA

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Abstract

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