Nongenomic actions of low concentration estrogens and xenoestrogens on multiple tissues

Abstract

Nongenomic estrogenic mechanisms offer an opportunity to explain the conundrum of environmental estrogen and plant estrogen effects on cells and animals at the very low concentrations which are prevalent in our environments and diets. Heretofore the actions of these compounds have not been adequately accounted for by laboratory tests utilizing assays for actions only via the genomic pathway of steroid action and the nuclear forms of estrogen receptor alpha and beta. Membrane versions of these receptors, and the newly described GPR30 (7TMER) receptor protein provide explanations for the more potent actions of xenoestrogens. The effects of estrogens on many tissues demand a comprehensive assessment of the receptors, receptor levels, and mechanisms that might be involved, to determine which of these estrogen mimetic compounds are harmful and which might even be used therapeutically, depending upon the life stage at which we are exposed to them.

Figure 1

The two major pathways of steroid action initiate in either the membrane (nongenomic) or the nucleus (genomic). Membrane-initiated nongenomic actions generally lead to rapid actions manifesting in a seconds-to-minutes timeframe, as they usually involve the enzymatic modification of premade signaling molecules and endproducts. They are known to be mediated by three known ERs, α, β, and GPR30 (7TMER) and are also attributed to various other membrane receptors. Genomic actions usually take hours to days to effect a change, as they rely on the synthesis and processing of a series of macromolecules, and are known to be mediated by ERs α and β. The two pathways may converge where kinases and phosphatases activated at the membrane go on to modify transcription factors that control gene expression. Diverse receptors and multiple interacting proteins at both the membrane and the nucleus (see unlabeled symbols in these locations) vary the responses in different the tissues and different circumstances. Only one ligand (●) is shown here, but when the many different estrogenic ligands are considered, another layer of response diversity is to be considered.

Figure 2

Structurally diverse xenoestrogens are shown in comparison to 17β-estradiol. Diethylstilbesterol is a pharmaceutical estrogen. Coumesterol is a plant estrogen from red clover and alfalfa sprouts. Bisphenol A and nonyphenol are byproducts of plastics manufacturing. DDE is the metabolite of DDT, and is a pesticide, as are endosulfan and dieldrin.