Review
Endocrine disruption via estrogen receptors that participate in nongenomic signaling pathways

https://doi.org/10.1016/j.jsbmb.2011.01.015Get rights and content

Abstract

When inappropriate (non-physiologic) estrogens affect organisms at critical times of estrogen sensitivity, disruption of normal endocrine functions can result. Non-physiologic estrogen mimetics (environmental, dietary, and pharmaceutical) can signal rapidly and potently via the membrane versions of estrogen receptors, as can physiologic estrogens. Both physiologic and non-physiologic estrogens activate multiple signaling pathways, leading to altered cellular functions (e.g. peptide release, cell proliferation or death, transport). Xenoestrogens’ mimicry of physiologic estrogens is imperfect. When superimposed, xenoestrogens can alter endogenous estrogens’ signaling and thereby disrupt normal signaling pathways, leading to malfunctions in many tissue types. Though these xenoestrogen actions occur rapidly via nongenomic signaling pathways, they can be sustained with continuing ligand stimulation, combinations of ligands, and signaling that perpetuates downstream, eventually also impinging on genomic regulation by controlling the activation state of transcription factors. Because via these pathways estrogens and xenoestrogens cause nonmonotonic stimulation patterns, they must be carefully tested for activity and toxicity over wide dose ranges. Nongenomic actions of xenoestrogens in combination with each other, and with physiologic estrogens, are still largely unexplored from these mechanistic perspectives.

Research highlights

► Compounds that have estrogenic effects can act via either genomic or nongenomic pathways. ► ERs α and β act from either the nucleus or the cell membrane; GPER acts at membranes. ► Estrogens acting on these signaling systems include a variety of physiologic metabolites, food-based estrogens, environmental contaminant estrogens, and pharmaceutical estrogens. ► Nongenomic estrogenic signaling responses often oscillate with time, and have non-monotonic concentration responses. ► Nongenomic estrogenic endpoints can be reached very rapidly, or can build up over time and be sustained.

Introduction

Estrogens are triple-edged swords. If women have too little of them they can experience problems such as reproductive failure, bone loss, hot flashes, skin changes, and some cardiovascular system vulnerabilities and cognitive declines [1]. Too much of them can result in cancers such as for the breast, uterus, colon, and pituitary [2], or other malfunctions such as blood clots [3] and nausea/eating disorders [4], [5]. Exposure to the wrong estrogens (xenoestrogenic mimetics) could result in endocrine disruption of functions normally mediated by physiologic estrogens [6]. There are many different types of estrogens to consider as candidates for estrogenic or estro-disruptive cellular actions. Since many tissues of males also have estrogen receptors, they will also respond to both physiologic estrogens and xenoestrogens. Some of these actions in both males and females could be of the organizational (nonreversible) types that occur during development [7].

Compounds that have estrogenic effects can act in several ways. Acting through an estrogen receptor (ER) in the cell nucleus, they can directly change the expression of genes via binding to DNA response elements, or binding to other transcription factors that bind to response elements [8]. Acting via an ER at the surface of the cell, they can rapidly initiate cascades of chemical signals (specific ions, lipids, cyclic nucleotides, etc.) which then percolate through a series of kinases and phosphatases to control their eventual targets by adjusting their phosphorylation levels [9], [10]. While these membrane-initiated actions generally happen rapidly, they may take some time to travel to the functional end of the pathways or to build up levels of products that change function. They may also be sustained by repeated reactivation and perpetuation down signaling cascades. Post-translational modifications brought on by nongenomic signaling can have a variety and multiplicity of downstream effects on functional molecules. Of these (and other) possible estrogen-induced mechanisms, only the genomic pathway has yet been extensively examined, and xenoestrogens are very weak via that mechanism. Data are beginning to emerge indicating that xenoestrogens may be much more potent via the non-nuclear (nongenomic, membrane-initiated) mechanisms.

Section snippets

Different kinds of ERs, their different subcellular distribution, and association with different cellular signaling mechanisms

Historically, genomic (directly transcriptional) responses to steroids acting via their nuclear receptor mediators have been the most studied and thoroughly described with respect to signaling partners, modulators, and biochemical products (RNAs and proteins) [11]. Though very rapid responses to estrogens have been observed for decades [12], [13], [14], only recently have separate nongenomic receptor-mediated signaling mechanisms been assigned to them. A variety of ERs (α, β, and GPER) have

Other physiological estrogens

Besides the most often studied estrogen – cycle-dominant estradiol (E2) – there are other prominent physiologic estrogens with significant impact at different life stages, such as E1 (estrone, elevated postmenopausally) and E3 (estriol, elevated during pregnancy). There are also many modified physiologic estrogens or metabolites, such as catechol estrogens, methoxy estrogens, sulfated estrogens, etc. [27], [28]. These other physiologic estrogens have long been labeled weak estrogens because

Nonmonotonic and oscillating responses and their causes

A curious feature typical of the actions of both physiologic estrogens and xenoestrogens via nongenomic signaling mechanisms is their oscillating time courses and nonmonotonic concentration-responses. What is the basis of these patterns characteristic of these complex responses? Possible mechanisms have been previously reviewed including different receptor levels, subpopulations, oligomerization, compartmentalization, and non-receptor-mediated effects, [9], [64], [65], [66]. However, we now

Types of nongenomic or membrane-initiated functional endpoints and their relationship to the speed of the response

Nongenomic steroid responses are often characterized as rapid responses. However, just because such responses initiate rapidly does not mean they cannot be sustained over long periods of time. In addition, some responses are very proximal to the initial signal, and others further downstream, requiring more time to reach the eventual target. Rapid initiation and response progression speed is used experimentally to rule out a genomic mechanism, but may not describe the entire course or

Combinations of physiologic estrogens with xenoestrogens

In real life xenoestrogens are rarely present by themselves; in humans and animals environmental or dietary estrogens usually signal on top of a pre-existing level of life stage-dependent physiologic estrogen signaling. Thus it is important to understand how added xenoestrogens affect endogenous physiologic estrogen signaling mechanisms. So far, we have learned that depending upon their concentration, alkylphenol and BPA xenoestrogens can either enhance or inhibit the signaling activities (ERK

Summary

We cannot extrapolate from well-behaved dose-responses to predict the actions of xenoestrogens, either by themselves, or in disrupting the actions of physiologic estrogens. Xenoestrogens do not follow the expected and simple “dose makes the poison” rules. In fact, the complexity of the signaling mechanisms makes it imperative for researchers to test the whole dose range of exposure to these compounds to decide which produce dangerous (or therapeutic) effects. In addition, these effects can vary

Acknowledgements

This work was supported by National Institutes of Health grant ES015292, the UTMB Center for Addiction Research, the UTMB Toxicology Training Grant (T32-ES07254) and the American Institute for Cancer Research. The authors acknowledge the expert skills of Dr. David Konkel, who helped with editing our manuscript.

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