Toxicity of endogenous and environmental estrogens: what is the role of elemental interactions?

Many naturally occurring and man-made chemicals present in the environment possess estrogenic activity. Examples include plant and fungal products, pesticides, plasticizers, and other agricultural and industrial chemicals. These environmental estrogens as well as endogenous ovarian estrogens are thought to initiate their physiological actions in target tissues largely via interactions with a nuclear receptor system. The resultant estrogen-receptor complex in turn affects transcription via its interactions with nucleotide sequences known as estrogen response elements (EREs) present in the regulatory regions of hormone responsive genes. A "consensus" ERE sequence GGTCAnnnTGACC was originally identified in the vitellogenin genes of birds and amphibians, but it is now clear that most naturally occurring EREs differ from this sequence in one or more bases. We and others have obtained both in vivo and in vitro data suggesting a differential interaction of receptor complexes containing different ligands with the multiple EREs present in mammalian systems. This raises the possibility that the toxicity of environmental estrogens may arise in part from a differential pattern of ERE activation by environmental compounds relative to endogenous ovarian estrogens. The experimental basis for such a paradigm and its toxicological implications are discussed in this paper.