In this project we propose to study the biochemical changes 2, 3, 4, 7, 8-TCDD (tetrachlorodibenzo-p-dioxin) and related chlorinated aromatics cause in experimental animals. The major emphasis will be placed on their effects on plasma membrane-bound enzymes and receptors. Preliminary experiments have revealed that the hepatic plasma membrane from TCDD-treated rats in vivo has unusually low levels of various ATPases, binding capabilities towards concanavalin A, insulin and low density lipoprotein. As a result there is a possibility that many biochemical lesions which are observed in TCDD-treated animals such as body weight loss, thymic involution, reduction in cell-mediated immune response and tumor promotion may be explained on the basis of the changes in the function of the cell surface membrane. Specific projects proposed are: (1) Studies on the relationship between TCDD-induced changes in the hepatic plasma membrane functions and hepatotoxicity and carcinogenicity, (2) interspecific differences in susceptibility of the hepatic plasma membrane functions toward TCDD treatment in vivo, (3) TCDD effects on lipoprotein regulation in the guinea pig liver, (4) the changes induced in the plasma membrane from the adipose tissues of the guinea pig by TCDD treatment, (5) effects of reduced lipoprotein-receptor interaction on extra-hepatic functions, and (6) studies on increased protein kinase activities as the cause for pleiotropic alteration of plasma membrane receptors and enzymes.
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