Molecular determinants of hormone mimicry: Halogenated aromatic hydrocarbon environmental agents

The potential of ostensibly structurally diverse environmental chemicals to modulate endocrine processes in biological systems has been recognized. Difficulty in classifying endocrine system modulators by chemical structure may in large part be due to lack of understanding of mechanisms of action. New developments in understanding nuclear receptor mechanisms of hormone action support a more complex mechanism, possibly involving dimerization/aggregation events leading to multimeric receptor complexes in agonist action. Because of the requirement for high structural specificity in agonist action, it is suggested that most environmental chemicals of concern are likely to function as imperfect hormones with partial agonist-antagonist properties, especially at environmentally realistic concentrations. In the absence of having appropriately placed molecular recognition domains to affect agonist action, partial agonism-antagonism may be associated with favorable low-energy conformational flexibility and complementary receptor protein flexibility. The halogenated aromatic hydrocarbons are of particular concern as hormone mimics since they often have (1) similar molecular recognition factors but in many cases relatively more flexible structures, (2) similar bulk physicochemical properties controlling uptake and distribution in biological systems, and (3) are relatively more resistant to metabolism and elimination. Some important molecular reactivity properties underlying thyromimetic and estrogenic actions of some of these chemicals are identified and described in terms of structure-activity relationships (SARs). It is proposed that specificity of hormone action in the nucleus could be associated with differential interaction of ligand-bound receptor dimeric forms with other transcription factors specific to the target cell. The small-molecule ligand can be viewed as playing a central, multifunctional role in nuclear receptor action as an organic unmasking and reclustering agent for critical macromolecules. Evidence is discussed in support of a nuclear heterodimerization model for dioxin and related compound action involving a structural transition mechanism. These models with some molecular detail also have utility in understanding the different structural properties of agonists and antagonists. There would appear to be ample opportunities for environmental chemicals to act as antagonists for multiple receptor systems with little more than anchor-ring similarities in structure. The application of three-dimensional quantitative structure-activity (3D QSAR) models incorporating such structural information should be a useful adjunct for identifying endocrine system modulating chemicals. This data has implications for (1) improved drug design, (2) understanding of chemical interaction toxicity, (3) removing undesirable chemicals from our environment, and (4) reducing their chemical release.