Environmental signaling: what embryos and evolution teach us about endocrine disrupting chemicals

The term "endocrine disrupting chemicals" is commonly used to describe environmental agents that alter the endocrine system. Laboratories working in this emerging field-environmental endocrine research-have looked at chemicals that mimic or block endogenous vertebrate steroid hormones by interacting with the hormone's receptor. Environmental chemicals known to do this do so most often with receptors derived from the steroid/thyroid/retinoid gene family. They include ubiquitous and persistent organochlorines, as well as plasticizers, pharmaceuticals, and natural hormones. These chemicals function as estrogens, antiestrogens, and antiandrogens but have few, if any, structural similarities. Therefore, receptor-based or functional assays have the best chance of detecting putative biological activity of environmental chemicals. Three nuclear estrogen receptor forms-alpha, beta, and gamma-as well as multiple membrane forms and a possible mitochondrial form have been reported, suggesting a previously unknown diversity of signaling pathways available to estrogenic chemicals. Examples of environmental or ambient estrogenization occur in laboratory experiments, zoo animals, domestic animals, wildlife, and humans. Environmentally estrogenized phenotypes may differ depending upon the time of exposure-i.e., whether the exposure occurred at a developmental (organizational and irreversible) or postdevelopmental (activational and reversible) stage. The term "estrogen" must be defined in each case, since steroidal estrogens differ among themselves and from synthetic or plant-derived chemicals. An "estrogen-like function" seems to be an evolutionarily ancient signal that has been retained in a number of chemicals, some of which are vertebrate hormones. Signaling, required for symbiosis between plants and bacteria, may be viewed, therefore, as an early example of hormone cross-talk. Developmental feminization at the structural or functional level is an emerging theme in species exposed, during embryonic or fetal life, to estrogenic compounds. Human experience as well as studies in experimental animals with the potent estrogen diethylstilbestrol provide informative models. Advances in the molecular genetics of sex differentiation in vertebrates facilitate mechanistic understanding. Experiments addressing the concept of gene imprinting or induction of epigenetic memory by estrogen or other hormones suggest a link to persistent, heritable phenotypic changes seen after developmental estrogenization, independent of mutagenesis. Environmental endocrine science provides a new context in which to examine the informational content of ecosystem-wide communication networks. As common features come to light, this research may allow us to predict environmentally induced alterations in internal signaling systems of vertebrates and some invertebrates and eventually to explicate environmental contributions to human reproductive and developmental health.