Authors
Cheryl Walker, S. Ansar Ahmed, Terry Brown, Shuk-Mei Ho, Leslie Hodges, George Lucier, Jose Russo, Nancy Weigel, Tom Weise, John Vandenbergh,

Title
Species, interindividual, and tissue specificity in endocrine signalling

Journal
Environmental Health Perspectives 107(Suppl 4):619-624. 1999.

Differential responsiveness to endocrine disrupting chemicals has been identified between different species, individuals within a species, and tissues. At the species level, differences exist in receptor binding, gene transcription, and cellular response to endocrine-active agents. Factors that are differentially expressed in different species and can affect receptor binding to hormonally active agents include: i) serum-binding proteins (SBPs) that sequester and/or transport hormones to target cells, ii) the ligand-binding domain of steroid hormone receptors, and iii) ligand-independent receptor activation. In terms of gene transcription, the working group discussed the possibility of developing a hormone-responsive gene chip that could monitor changes in gene expression in different species in response to endogenous and exogenous hormones. Species-specific differences also exist in terms of hormone responses to endocrine-disrupting chemicals. In addition, the window of susceptibility to the effects of exogenous chemicals also varies between species.

Interindividual differences in responsiveness to endocrine disruptors may exist for prenatal, postnatal, peripubertal, adult, and aged subpopulations. Genetic factors that can predispose to adverse health effects from endocrine disruptors include polymorphisms in steroid hormone-metabolizing genes and polymorphisms in target genes. The working group identified several research needs related to factors responsible for interindividual differences in susceptibility. In particular, investigations into receptor polymorphisms and the impact this has on receptor activation by endocrine disruptors are of primary importance. In addition, further research is required to confirm and/or resolve the present literature on the relationship between genetic polymorphisms and increased risk for a particular disease. Extrinsic factors such as diet, socioeconomic status, and obesity can also impact individual susceptibility to hormonally related diseases.

Several tissue-specific factors can influence the response of different tissues to endocrine disruptors. Tissue receptor distribution and number exhibit tissue-specific patterns of expression (i.e., ER-a and ER-b). Differences in the pattern of gene expression may also contribute to tissue-specific response (i.e., hormone-metabolizing enzymes). In addition, receptor activity can have different effects in different tissues and in different species. These tissue-specific differences suggest that endocrine disrupting agents may use multiple cellular mechanisms to produce an adverse cellular response. Thus, it will be important to identify which pathways are used in response to various endocrine disruptors at different dose levels.

The use of in vivo and in vitro models and the development of mathematical models will be useful in determining the role of species, interindividual, and tissue specificities related to adverse health effects from low-dose exposures of endocrine disruptors.

>Go to next summary in this workshop