Although the effects of 2,3,7,8-TCDD are highly species dependent, i.g. guinea pig Greater than C57BL/6J mice Greater thanrat Greater than DBA/2J mice Greater than hamster (in order of decreasing susceptibility), the hepatic cytosolic receptor protein levels in guinea pig, C57BL/6J mice, rat and hamster are similar. This study will asess the receptor binding characteristics of hepatic cytosol from these animal species using a series of PCDDs which differ with respect to their (a) Cl-substitution pattern and (b) the structure of a critically-positioned lateral substituent (i.e. a series of 7-X-2,3-dichloro and 7-X-2,3,8 trichlorodibenzo-p-dioxins where X = Cl, Br, F, H, I, OCH3, OH, NH2, CF3, CH3 and other alkyl groups). The in vitro binding affinities will be analyzed by a QSAR method to determine the species differences in the molecular interactions which facilitated receptor binding. These results will also be compared to the in vitro induction of AHH and EROD in rat hepatoma H-4-II-E cells in culture. In addition, the in vivo biologic and toxic effects of selected PCDDs and substituted PCDDs will be determined in these animals and the results compared to the in vitro receptor binding data. The second major objective will investigate the effects of modulation of receptor levels in a test animal (Wistar rats, C57BL/6J mice and hairless mice) on the biologic and toxic potencies of 2,3,7,8-TCDD. Receptor levels in these species will be increased by induction (using phenobarbitals) or depressed using a series of potential """"""""suicide"""""""" receptor ligands which have been developed in our laboratory. Preliminary experiments in our laboratory indicate that the avian is highly sensitive to the toxic and biologic effects of 2,3,7,8-TCDD, however, some of the avian responses to this toxin are unique. For example, no cytosolic receptor protein can be detected in the cytosol and 2,3,7,8-TCDD induces an unusual spectrum of monooxygenase enzyme activities. Therefore this grant proposes to further study the role of the receptor in the avian and to purify and characterize the induced cytochrome P-450 isozymes.
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