Chemical Communication Threatened by Endocrine-Disrupting

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Chemical Communication Threatened by Endocrine-Disrupting
Communication on a cellular level—defined as chemical signaling, sensing, and response—is an essential and universal component of all living organisms and the framework that unites all ecosystems. Evolutionarily conserved signaling "webs," existing both within an organism and between organisms, rely on efficient and accurate interpretation of chemical signals by receptors. Therefore, endocrine-disrupting chemicals (EDCs), which have been shown to disrupt hormone signaling in laboratory animals and exposed wildlife, may have broader implications for disrupting signaling webs that have yet to be identified as possible targets. In this article, I explore common evolutionary themes of chemical signaling (e.g., estrogen signaling in vertebrates and phytoestrogen signaling from plants to symbiotic soil bacteria) and show that such signaling systems are targets of disruption by EDCs. Recent evolutionary phylogenetic data have shown that the estrogen receptor (ER) is the ancestral receptor from which all other steroid receptors have evolved. In addition to binding endogenous estrogens, ERs also bind phytoestrogens, an ability shared in common with nodulation D protein (NodD) receptors found in Rhizobium soil bacteria. Recent data have shown that many of the same synthetic and natural environmental chemicals that disrupt endocrine signaling in vertebrates also disrupt phytoestrogen-NodD receptor signaling in soil bacteria, which is necessary for nitrogen-fixing symbiosis. Bacteria-plant symbiosis is an unexpected target of EDCs, and other unexpected nontarget species may also be vulnerable to EDCs found in the environment.

Chemical communication is a common means of endogenous and exogenous signaling for countless species. The endocrine system of vertebrates consists of an intricate web of agonistic as well as antagonistic hormone signals, which control sexual development and reproduction (McLachlan 2001). For example, circulating hormones such as 17β-estradiol (E2) control a variety of cellular processes, including developmental cues, differentiation events, and growth in organs such as breast, ovary, and uterus. The timing and concentration of estrogen signaling determine sexual maturity, ovulation, and pregnancy. In much the same way, a multitude of organisms rely on chemical cues for development and differentiation. For example, some insects and crustaceans rely on ecdysteroids to signal molting and growth (Oberdorster et al. 2001), and the slime mold Dictyostelium relies on a chlorinated alkyl phenone called DIF-1 to signal individual cells to differentiate into a multicellular sporulating stalk (Kay 1998; Town et al. 1976).

Plants produce versatile chemical signals, called phytochemicals or phytoestrogens, which serve both as endogenous signals, triggering color and scent production within the plant, and exogenous signals secreted for communication with other organisms, such as to inhibit sexual reproduction of predatory herbivores (Wynne-Edwards 2001). Leguminous plants (soybeans, clover, and alfalfa) secrete phytoestrogens into the soil as recruitment signals for symbiotic mycorrhizal fungi and Rhizobium soil bacteria, which both provide selective growth advantages to the host plant, including increased water/phosphate availability and nitrogenous fertilizer, respectively (Baker 1998; Kuiper et al. 1997; Peters et al. 1986). Although phytoestrogens serve specific signaling functions between the plants that produce them and insects, fungi, and bacteria, many chemical signals, including the fungal agent zearalenone and the phytoestrogens genistein and luteolin, are often "misinterpreted" as estrogenic signals in nontarget organisms such as vertebrates.

For chemical communication to occur within or between organisms, a receptor must have affinity for specific chemical ligands or signals, and this recognition must initiate a response. In fact, a wide variety of natural and synthetic chemicals exist in the environment that mimic hormones and disrupt endocrine signaling in vertebrates through interaction with various nuclear receptors and signal transducer proteins, including the estrogen receptor (ER), orphan receptors, and the thyroid receptor (Cheek et al. 1998; Crump et al. 2002; Ishihara et al. 2003; McLachlan 2001; Moriyama et al. 2002; Takeshita et al. 2001). Some flavonoid phytoestrogens are able to bind ER-α and ER-β and act as weak agonists (Collins-Burow et al. 2000) that compete with endogenous E2 for ER binding and activation of estrogen-responsive genes (Blair et al. 2000; Kuiper et al. 1997). Despite their ability to bind these receptors, phytoestrogens exhibit only a fraction (10-10) of the estrogenic activity of E2 (Collins-Burow et al. 2000). Nevertheless, the most active phytoestrogens found in plants have been shown to induce breast cancer cell proliferation in vitro as well as influence the in vivo endocrine function of experimental animals and livestock that consume high quantities of these phytoestrogen-laden plants (Bennetts et al. 1946; Facemire et al. 1995; Whitten and Patisaul 2001; Zava et al. 1997). The mechanism of action is defined by vertebrate ERs, which bind phytoestrogen ligands, endogenous ligands, and endocrine-disrupting chemicals (EDCs) with specific affinity. Similarly, nodulation D protein (NodD) receptors in Rhizobium soil bacteria recognize phytoestrogens as recruitment signals to initiate nitrogen-fixing symbiosis. The specific affinity for and recognition of similar natural and synthetic ligands by receptors such as ER and NodD provide an example of shared or analogous functionality (Fox et al. 2001, 2004).

In an evolutionary context, it may seem odd that phytochemical signals, produced by plants as recruiting signals for symbiotic soil bacteria, are intercepted by humans and affect estrogenic signaling by binding to ERs and influencing estrogen-responsive gene expression. Both plants and humans have the ability to synthesize steroids, and plants express proteins that are homologous in sequence and identical in function to human 5α-reductase enzymes, in that they both catalyze the reduction of steroid substrates (Li et al. 1997). Nevertheless, how is it that plants and humans, two organisms known to be derived from separate lineages (Meyerowitz 2002), both share the ability to produce and recognize steroid signals? After all, there are no ERs in plants or in their most common partners, insects. However, one intended target of phytoestrogen signaling, Rhizobium soil bacteria, does express ligand-dependent transcriptional activator proteins/receptors, called NodD proteins, which have been reported to share genetic homology with the human ER (Gyorgypal and Kondorosi 1991; Long 1989). In addition, some Nod proteins have been shown to share significant sequence homology with human steroid biochemical intermediates (Baker 1989, 1991).

Recent genetic sequence analysis has shown no significant nucleotide level homology between rhizobial NodD and human ER genes. Nevertheless, these two evolutionarily distant receptors both recognize and respond to a shared group of chemical signals and ligands, including both agonists and antagonists. A lack of homology at the nucleotide level does not preclude the possibility that NodD and ER are receptors with analogous signaling functions. In fact, recent advances in X-ray crystallography have helped uncover many examples of proteins that share little or no nucleotide level homology and yet, when crystallized, have been shown to share significant homology in three-dimensional protein folding, domains, and structural characteristics (Benner et al. 2000; Lai et al. 2000; Rives and Galitski 2003; Suel et al. 2003). The emerging proteomics field is based on the principle that the structural characteristics of proteins are more telling determinants of a protein's function and evolutionary origin than is simple nucleotide-level homology (Koonin et al. 2002; Meyerowitz 2002; Todd et al. 2001). Although the crystal structure of the NodD protein has not yet been solved, based on the similar ligand-binding profiles (both natural and synthetic ligands) and DNA-binding ability of NodD and ER, these two proteins may share some degree of structural identity.

Although they share no common evolutionary ancestor, NodD and ER recognize and respond to a similar profile of chemical signals found in the environment. Convergent evolution may explain the shared ligand recognition properties common to both ER and NodD proteins. Convergent evolution is demonstrated when two species that do not share a common ancestor exhibit similar traits that have arisen, through natural selection, as adaptations to similar ecologic and environmental conditions or signals (Thompson 1999). I contend that NodD and ER may have separately evolved, in lineages leading to Rhizobium bacteria and vertebrates, to adapt to the presence of natural estrogenic ligands, such as those produced by vertebrates, fungi, and plants (phytoestrogens). Recent evolutionary analysis has found that some invertebrates express an ER, and phylogenetic analysis of these sequences has demonstrated that the ER is the earliest ancestral receptor of the entire steroid receptor family (Thornton 2001; Thornton et al. 2003). Conversely, the endogenous natural ligand for ER, E2, is the terminal product of the steroid biochemical pathway. Therefore, when compared on an evolutionary time scale, the ER may have arisen long before its endogenous ligand, E2, was produced. In this absence of E2, ancestral ERs may yet have functioned as receptors for exogenous/environmental signals. At the time of the evolutionary emergence of the ER, organisms such as insects, fungi, bacteria, and plants existed and may have been actively producing chemical signals that served, then as they do today, as potent ER ligands. These environmental signals may have included a wide variety of phytoestrogens, including those that signal through rhizobial NodD receptors to initiate symbiosis.

In addition to having specific affinity for and being activated by many of the same ligands and phytoestrogens, vertebrate ER proteins and rhizobial NodD proteins can also be affected by many of the same environmental cues and ligands. ER and NodD both require chaperone proteins, hsp70 and GroESL, respectively, for proper folding and full activation of transcription (Cheung and Smith 2000; Nair et al. 1996; Takayama and Reed 2001; Yeh et al. 2002). Specific ligand binding to ER and NodD results in either activation or inhibition of responsive gene transcription; therefore, both receptors exhibit ligand-concentration-dependent activity. Moreover, ligand binding to ER and NodD results in both receptors binding to highly conserved consensus sequences of DNA, the estrogen response element and the Nod box, respectively, in the promoter regions of responsive genes. ER- or NodD-induced transcription of responsive genes is responsible for growth and differentiation events (Fisher and Long 1993; Katzenellenbogen et al. 2000; McLachlan 2001; van Rhijn and Vanderleyden 1995). ER can also be activated in a ligand-independent manner via cross-talk with growth factor signaling pathways (Bjornstrom and Sjoberg 2002; Frigo et al. 2002; Klotz et al. 2002). For example, ER can be activated via mitogen-activated protein kinase (MAPK) phosphorylation cascade members (Weinstein-Oppenheimer et al. 2002; Weldon et al. 2002). Interestingly, a member of the MAPK eukaryotic signal transduction pathway, Raf (MAPK kinase) protein, has a homologous protein in plants that also functions in signal transduction of the plant hormone ethylene (Clark et al. 1998). ER's ability to signal in the absence of ligand and be influenced by multiple signal transduction pathways, as well as ER's promiscuous binding of an array of environmental compounds, has led to hypotheses that the original signaling function of ER may have been as a receiver and translator of many varied environmental signals and cues.

On the basis of the functional similarities listed above and their shared affinity for similar chemical signals, I propose that the evolutionarily distinct ER and NodD receptors are functionally analogous in their response to and mediation of chemical signaling. Therefore, it follows that both of these signaling systems are vulnerable to disruption by EDCs present in their shared environment.

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