Species, interindividual, and tissue specificity in endocrine signaling

The activity of endocrine-active agents exhibits specificity at many levels . Differential responsiveness to these agents has been observed between dif ferent species and extends to interindividual differences within a species and between different tissues as well. In cases where they have been identi fied, the biologic and molecular mechanisms underlying this specificity are quite diverse. Determinants of species specificity include differences tha t exist in receptor binding, gene transcription, and cellular responses to endocrine-active compounds between species. Interindividual differences in responsiveness may be determined at the level of genetic polymorphisms in h ormone-metabolizing enzymes, hormone receptors, and in those genes that are transactivated by these receptors, as well as during changing windows of s usceptibility that occur as a function of age, such as prenatal and postmen opausal exposures. Extrinsic factors such as diet can also impact individua l susceptibility to endocrine-active agents. Tissue-specific determinants o f susceptibility are well documented, but little is known regarding the mec hanisms underlying these different responses. Differences in the expression of accessory proteins for steroid hormone receptors and different patterns of receptor expression, estrogen receptor a and estrogen receptor beta for example, may contribute to tissue specificity as may differences in the pa ttern of expression of other genes such as hormone-metabolizing enzymes. Th e use of animal model systems and development of appropriate mathematical m odels has the potential to yield additional valuable information for elucid ating the role of these determinants of specificity at low-dose exposures a nd for improved risk assessments for the adverse health effects of endocrin e-active compounds.