Core--Protein modulators of toxicity

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The research activities in the Core emphasize biologically active proteins that function as critical regulatory molecules in normal cell processes. These research projects are making contributions toward understanding risk associated with exposures to particular chemicals and to knowledge of the molecular and cellular processes involved in certain diseases. Several sub-themes are included under this central theme: Receptor proteins as molecular sensors, post-transcriptional modification of RNA, proteins involved in Glutathione homeostasis and the role of these in xenobiotic transport and metabolism, and proteins involved in cell cycle regulation as targets for xenobiotics. The investigations are organized into seven projects: 1) Cellular and Molecular Responses to Dioxins Mediated by the Ah Receptor (T. A. Gasiewicz). This project is directed at understanding the molecular and cellular basis by which the Ah receptor mediates the toxicity of structurally-related halogenated hydrocarbons. A secondary objective is to advance knowledge of Ah receptor function especially the role of AhR phosphorylation. Collaborative projects include studies using an AhR-responsive reporter mouse model and molecular actions of AhR and cellular and functional alterations in the immune system. 2) Causes and Consequences of Thymic Atrophy Induced by TCDD and Estrogens (A. E. Silverstone). A major objective of this work is the identification of the cell type(s) that contain the estrogen receptor (ER) and AhR and are activated by TCDD or estrogen to cause thymic atrophy and immunosuppression. These studies will examine either cell cycle arrest, apoptosis, and/or altered cellular differentiation are involved and identification of the gene products involved. A second objective is to use a mouse model of a lupus-like nephritis to identify estrogen and TCDD-induced alterations in T-cell development. 3) Cellular and Molecular Toxicology of Heme Degradation (M. Maines). This research focuses on the heme metabolic pathway enzymes, heme oxygenase (HO) and biliverdin reductase (BVR) to elucidate the physiological functions of the heme degradation products. These studies are examining the biological functions of HO in the brain and cardiovascular system. One hypothesis being tested is that modulation of HO activity by exogenous and endogenous sensors may be involved in steroid-mediated degradation of neurons in brain areas involved in memory and learning. Other studies indicate that CO generated via HO may be a component of the cardiovascular system defense against impairment induced by nephrotoxic agents. The role of BVR as a defense mechanism against oxidants in the brain. 4) Alteration in RNA processing by Alcohol and its Role in Atherogenic Diseases (H. Smith). This research involves the purification and molecular cloning of auxiliary protein genes involved in RNA editing. Additional studies are testing the hypothesis that ethanol stimulation of apoB mRNA editing results from alteration of enzymes/factors involved in mRNA editing, 5) Glutathione-dependent Metabolism and Plasma Membrane Transport of Xenobiotics (N. Ballatori). The focus of this research is the identification and characterization of cell membrane proteins that mediate the export of GSH adducts, related organic anions and GSH. This group has shown that oatp1, a sinusoidal organic solute transporter in liver functions as a GSH/organic solute exchanger and elucidates a pathway for GSH release in blood plasma. Other studies are defining the role of the y-glutamyl cycle in a mercapturic acid biosynthesis. N-acetylcysteine has been identified as an antidote for methyl mercury. 6) Bioactivation of Halogenated Hydrocarbons (M. W. Anders). A major objective of this research is to investigate the GSH-dependent bioactivation of haloalkanes and the GSH- and b-lyase-dependent bioactivation of haloalkenes. Mechanisms of cysteine S-conjugate induced cytotoxicity and activation of transcription factors in response to changes in cellular redox as a possible step is being considered. The role of mitochondria as an intracellular target is being assessed. 7) Radiation Sensitivity and G2M Delay in Lung Tumor Cells (P. Keng). The central hypothesis to be tested is that IFN-b modulates DNA repair capacity of irradiated human lung tumor cells. The repair of DNA strand breaks is the focus of these studies and the impact of IFN-b on accumulation of cells in G2M following irradiation is being investigated.