Although both 3-methylcholanthrene (MC) and 2,3,7,8-TCDD bind to the hepatic receptor protein from several species with comparable affinities there are important major differences in their in vivo AHH induction activities. For example, the 2,3,7,8-TCDD (maximally) induced AHH activities in responsive and nonresponsive mice are comparable, however higher levels of the inducer are required to elicit this response in non-responsive DBA/2 mice compared to more responsive strains. In contrast, the maximal induction response by MC in genetically inbred mice appears to be dependent upon the number of cellular receptors. MC does not significantly induce AHH in DBA/2 mice whereas the maximum AHH induction response in several strains of mice increases with increasing hepatic Ah receptor levels (i.e. C57BL/6 greater than B6D2F1 greater than C3H/HeJ greater than C3D2F1). Preliminary studies in our laboratory have demonstrated that treatment of immature male C57BL/6 mice with 2,2',4,4',5,5'-HCBP results in a 250% increase in hepatic Ah receptor levels as determined by competitive binding studies with [3H]-2,3,7,8-TCDD. However it has not been shown if the """"""""population"""""""" of increased receptors is homogeneous with respect to ligand affinities and this provides an excellent opportunity to probe for the possible presence of a heterogenous population of Ah receptors using multiple radioligands. This will be determined using [3H]-2,3,7,8-TCDD, [3H]-MC, [3H]- benzo[a]pyrene and [3H-2,3,7,8-TCDF as radioligands and hepatic cytosol from inbred strains of mice (as indicated above). The effects of 2,2',4,4',5,5'-HCBP-modulated hepatic receptor levels in inbred mice with different """"""""control"""""""" levels of this receptor protein (see above) on the AHH induction activities of both submaximal and maximal inducing doses of both MC and 2,3,7,8-TCDD will also be investigated. These studies will determine whether increased receptor levels result in increased activities of these inducers at submaximal induction doses or whether increased receptor levels results in higher absolute levels of AHH induction in the inbred strains of mice. The role of receptor modulation and receptor antagonists on the biologic and toxic effects of 2,3,7,8-TCDD will also be determined in C57BL/6 and DBA/2 mice. These studies will aid in the design of future experiments which will probe the (as yet) unknown steps involved in the overall mechanisms of toxicity for this class of compounds.
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