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The Society for Integrative and Comparative Biology
Non-Traditional Targets of Endocrine Disrupting Chemicals: The Roots of Hormone Signaling1
1 Center for Ecology and Evolutionary Biology and Department of Biology, University of Oregon, 335 Pacific Hall, Eugene, Oregon 97403
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The topic of endocrine disruption and the broad range of physiological effects caused by endocrine disrupting chemicals (EDCs) can only be meaningfully framed within an ecological and evolutionary context. Environmental pollutants and EDCs operate by disrupting the "chemical communication" that coordinates signaling within an organism. Here we discuss how EDCs are also able to disrupt the chemical communication between plants and soil bacteria necessary for initiating nitrogen-fixing symbiosis. We also examine, through examples of pollutant-related impacts on a wide range of invertebrates, the need for identifying emerging targets of EDCs. We suggest broadening the defined field of endocrine disruption to encompass the effects of synthetic chemicals that interfere with signaling and communication, not only within an organism, but also between organisms and linking ecosystems. The ecological consequences of failing to recognize novel targets of chemical pollutants and EDCs may be a net loss of biological diversity and a further imbalance of the global nitrogen cycle.
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INTRODUCTION |
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A wide array of synthetic chemicals designed and produced to control insect, weed and fungal populations, plastics additives, surfactants, birth control agents, antimicrobials, pharmaceuticals, and personal care products are released into the environment intentionally or as waste products on the order of megatons per year (Daughton and Ternes, 1999
). A subset of these compounds are classified as endocrine disrupting chemicals (EDCs) based on their ability to modulate sexual development, growth, and reproduction of vertebrates by disrupting the hormone/steroid receptor signaling that initiates and maintains these processes. Such endocrine-active chemicals have been detected as unintended pollutants of water sources, including streams, groundwater, cattle feedlot effluent, water used for irrigating crops, and other key environmental sinks, at concentrations reaching as high as micrograms per liter (µg/L) (Boyd et al., 2003; Brooks et al., 2003; Downs et al., 1999; Kolpin et al., 2002; Orlando et al., 2003; Pedersen et al., 2003; Soto et al., 2003; Squillace et al., 2002; Wilson et al., 2003).
While much emphasis has been placed on monitoring vertebrate and human health effects resulting from aqueous environment contamination with synthetic pollutants and EDCs, possible deleterious effects on invertebrates have yet to be fully characterized. One reason is that the putative molecular target of EDC action, namely the estrogen receptor (ER), was not identified in any invertebrate species until recently. The report of the first invertebrate ER, and evidence that the ER is the ancestral steroid receptor from which all steroid receptors have descended, raises the possibility that such receptors are present and active components of cellular signaling pathways in many invertebrate species (Thornton, 2001; Thornton et al., 2003).
EDCs and environmental pollutants disrupt the signaling communication necessary for initiating developmental programs and maintaining growth. Table 1 presents an overview of the deleterious effects caused by EDCs, pollutants, steroid hormones, and pharmaceuticals on species ranging from bacteria to amphioxus; Figure 1 represents the phylogenetic relationships of invertebrate classes. While the ER is the most well-documented target of EDCs, these invertebrate examples illustrate that the mechanism of action of synthetic pollutants can also be via a variety of molecular players including penis morphogenic factors, heat shock proteins, ecdysteroid receptors, estrogen-binding proteins, and nodulation D (NodD) receptors (Fox et al., 2001, 2004; Guven et al., 1999; Jones et al., 1996; Madani et al., 1994; Mu and LeBlanc, 2002; Oberdorster and McClellan-Green, 2002).
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Our work has focused on signaling via the NodD receptor, which mediates chemical communication between legume plants and rhizobia soil bacteria necessary for initiating nitrogen-fixing symbiosis. Legumes describe a superfamily of dicotyledonous plants, including important crops such as soybeans, peanuts and peas as well as clover and alfalfa forage crops, which ranks them second only to rice for human nutritional importance (Grieshop et al., 2003
). Rhizobia soil bacteria are recruited for symbiosis only when flavonoid phytochemicals produced by the host plant and excreted into the soil environment are received by NodD receptors, which are constitutively expressed by the bacteria. Phytochemical signal recognition by rhizobial NodD proteins triggers expression of bacterial nod genes, which produce and send a specific signal back to the host plant allowing the soil bacteria to enter and colonize plant roots. Within these root nodules, in exchange for a steady carbon food source from the plant, rhizobia fix atmospheric nitrogen (N2) to ammonium (NH4), a usable fertilizer source for the plant. Initiation of nitrogen-fixing symbiosis requires precise timing and specific phytochemical-NodD signaling.
Rhizobial NodD proteins are ligand-dependent transcriptional activators, which act as environmental sensors that induce expression of nod genes after receiving phytoestrogen signals from the host plant. NodD receptors are the intended molecular targets of flavonoid phytoestrogen ligands, many of which also bind to and activate vertebrate ERs. Our sequence analysis (Fox et al., 2004) did not confirm reported identity shared between the ligand binding domains of Rhizobium NodD and human ER
proteins (Gyorgypal and Kondorosi, 1991). Nevertheless, ER and NodD share analogous functions and are activated by phytoestrogen ligands, which led us to question whether EDCs and environmental pollutants known to disrupt ER signaling may also disrupt NodD signaling. EDCs and phytoestrogens disrupt ER-17ß-estradiol (E2) signaling resulting in a net change (increase or decrease) in ER-induced gene expression, which can be experimentally measured using an ER-responsive reporter gene assay. Similarly, to measure possible effects of EDCs on NodD-phytoestrogen signaling, we used a strain of rhizobia, Sinorhizobium meliloti 1021pRmM57 (Mulligan and Long, 1985), containing a NodD-responsive reporter gene. As we have previously reported, forty-five different environmental pollutants and EDCs, including insecticides, herbicides, polychlorinated biphenyls (PCBs), and plasticizers, were able to significantly inhibit NodD-induced nod gene expression (Fox et al., 2001, 2004). Here we will concentrate on effects of the most environmentally long-lived groups of pollutants tested, the insecticide dichlorodiphenyltrichloroethane (DDT), DDT metabolites, and a group of PCBs.
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MATERIALS AND METHODS |
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Chemicals
Chemicals were purchased from various suppliers: AccuStandard (New Haven, CT) for the insecticides and PCBs (>99% pure), Aldrich (Milwaukee, WI) for DDT and its metabolites (99% pure), Sigma for E2 and diethylstilbestrol (DES) (98% pure), and INDOFINE (Belle Mead, NJ) for the phytochemicals (>99% pure). All chemicals were obtained neat and dissolved in dimethyl sulfoxide as a vehicle.
Bacterial strain
Sinorhizobium meliloti (S. meliloti) strain 1021 pRmM57, is a wild-type Rhizobium strain containing a plasmid-borne nodC-lacZ gene fusion and an additional copy of the nodD1gene, which was generously donated by S.R. Long, Stanford University (Mulligan and Long, 1985).
In vitro ß-galactosidase reporter gene expression assay
ß-galactosidase (ß-gal) assays were conducted to measure the level of gene expression of the nodC-lacZ reporter gene harbored by S. meliloti 1021 pRmM57, as previously described (Fox et al., 2001, 2004; Mulligan and Long, 1985). Luteolin, the natural phytochemical agonist for S. meliloti NodD, robustly induced nod gene expression. The level of nod gene expression induced by 1 µM luteolin alone was set as 100% nod induction. To challenge the level of nod gene expression induced by 1 µM luteolin, EDCs or environmental pollutants were added at concentrations ranging from 10 nM to 50 µM. All results reported are percent nod gene expression in the presence of the EDC tested plus luteolin relative to 100% nod expression induced by 1 µM luteolin alone. All data are representative of at least three independent experiments with three replicates each.
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Various EDCs and environmental pollutants inhibit nod gene induction
Environmentally relevant concentrations of EDCs, reported in Table 2, inhibit nod gene expression induced by luteolin-NodD signaling. Levels of EDCs and pesticides measured in agriculturally cultivated areas are given with the corresponding percent inhibition of nod gene expression (Table 2). Reported levels of insecticides inhibited nod gene expression by 10–75%; reported levels of herbicides inhibited nod gene expression by 10–25%; reported levels of PCBs inhibited nod gene expression by 15–70%. Results reported in Table 2 are the percent inhibition of nod reporter gene expression caused by the EDC tested, at the environmental concentration listed. Percent inhibition is in comparison to nod reporter gene expression induced by 1 µM luteolin alone (100%).
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Persistent environmental pollutants inhibit symbiotic gene expression in a dose-dependent manner
Persistent endocrine-disrupting pollutants such as DDT and its metabolites dichlorodiphenyldichloroethylene (DDE) and dichlorodiphenyldichloroethane (DDD), as well as PCBs, have soil half-lives ranging from months to decades (Table 2). The effects of these chemicals on luteolin-NodD induced nod gene expression were measured at concentrations ranging from 10–9 to 10–5 M (Fig. 2). Each chemical inhibited nod gene expression in a dose-dependent manner with maximal effects at 50 µM. For each of the chemicals tested, maximum percent of nod gene expression inhibited was: DDT, 45%; DDE, 45%; DDD, 36%; 2,3,4,5-PCB, 60%; 2,4,6-PCB, 56%. Percent inhibition is in comparison to nod reporter gene expression induced by 1 µM luteolin alone (100%). The data are representative of at least three independent experiments of three replicates each.
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Human production, distribution, and disposal of synthetic chemicals dramatically impacts reproduction, behavior, and survival. In a broader sense, pollutants and EDCs disrupt the communication systems that exist within cells, between cells, and, as we have shown, also disrupt the communication regulating symbiosis between organisms. Our results demonstrate, 1) EDCs and pollutants interfere with signaling between plant-derived phytochemicals and NodD receptors in soil bacteria, 2) it is imperative to extend the search for possible molecular targets beyond the boundaries of steroid receptors, and 3) in addition to determining how these chemicals affect signaling within an individual we must study their effects on signaling networks between organisms.
The number and scope of signaling proteins affected by EDCs as well as our findings that EDCs and pollutants can disrupt communication between organisms highlight the need for expanding research to include new or emerging molecular targets of endocrine disrupters. Although invertebrates account for 90% of extant genetic diversity and 95% of all aquatic and terrestrial species (Wilson, 1999), the effects of EDCs and synthetic pollutants on these species are not well understood. As the number of species unintentionally influenced by EDCs has grown, so has the list of molecular targets that interact with these synthetic chemicals.
The explosion of knowledge in the field of receptor-mediated crosstalk and signaling cascade networks has proven that even slight negative or positive external influences on single components of regulatory cascades can result in extensive negative consequences for the fitness of an organism (Brivanlou and Darnell, 2002; Miyata and Suga, 2001; Seiler, 2002; vom Saal et al., 1997; Welshons et al., 2003). Upon comparing the physiological and ecological effects of pollutants and EDCs on a broad range of invertebrates including prokaryotes (Table 1), a common mechanism of action of these chemicals appears to be dampening or blocking chemical communication mediated by hormones or other initiating signals necessary for controlling development, timing, and growth in an organism. In this manner, small concentrations of EDCs and pollutants that interfere with signals responsible for initiating such signaling network processes may bring about large and far-reaching changes.
Communication and signaling between organisms or species is crucial for a plethora of biological processes, including quorum sensing within populations of bacteria and between plants and microbes, intricately timed spawning events in marine worms and coral, warning signals sent from aphid-infested plants to uninfested plants, pathogen-animal interactions, signaling regulating group assemblages of Dictyostelium slime mold, and the ability of plants to attract animal pollinators (Andersson and Dobson, 2003; Atkinson et al., 2003; Guerrieri et al., 2002; LeVier et al., 2000; Newton and Fray, 2004; Ram et al., 1999; Town et al., 1976; Van Houdt et al., 2004). Our data has shown that EDCs and pollutants block signaling between plants and bacteria necessary for establishing symbiotic nitrogen fixation, a process responsible for about 60% of the Earth's available nitrogen (Lodwig et al., 2003).
Persistent pollutants and EDCs found in the soil pose a significant agricultural threat because their presence months to decades after application may result in long-term disruption of crucial symbiotic signaling. Compounds such as DDT and its metabolites (DDD and DDE) and PCBs persist in the soil environment today, although their use was banned in the United States in the 1970s. PCBs describe a class of biphenyl compounds with 2–10 chlorine substitutions that were commonly used as components of coolants, lubricants, and electrical equipment (ATSDR, 2000). PCBs are a commonly detected contaminant in groundwater, agricultural runoff, and soil in industrialized countries (Alcock et al., 1998; Backe et al., 2004; Pedersen et al., 2003; Ritter et al., 2002). PCBs inhibited NodD-phytoestrogen signaling 15–60% in a dose-dependent manner at concentrations ranging from 10–9 to 10–5 M (Fig. 2).
DDT and its metabolites are found as contaminants in the soil and groundwater of agricultural regions where they were formerly used as insecticides. Recent findings of 972 ppb (3 µM) levels of total DDT and metabolites in agricultural soil in China led researchers to conclude that either degradation of these chemicals occurs at a slower rate than previously thought, or DDT may still be in use in some areas despite being banned for more than twenty years (Gong et al., 2004). Studies measuring DDT and its metabolites in the corn belt of the U.S. have reported mean levels of total DDT/metabolites to be 10 ppb (29 nM) with maximum levels of 11,800 ppb (36 µM) (Aigner et al., 1998). The equivalent concentrations of DDT, DDD, or DDE tested in our assay resulted in a 10% and 45% reduction in NodD-phytoestrogen symbiotic signaling, respectively (Fig. 2).
The soil environment contains plant material, bacteria, fungi, and an entire microcosm of organisms in constant molecular dialogue with one another and actively receiving and assimilating environmental cues. Pesticides and other environmental pollutants are directly and indirectly introduced into this complicated soil signaling network. In addition to pesticides and synthetic fertilizers that are routinely applied in vast quantities to agricultural fields, most crops are also irrigated with either treated or untreated wastewater (Downs et al., 1999; Pedersen et al., 2003; Squillace et al., 2002). A recent study detected the presence of over 130 different pesticides, plasticizers, pharmaceuticals, personal care products, and other pollutants in surface water runoff from agricultural fields in California that had been irrigated with treated wastewater (Pedersen et al., 2003). Among the many pesticides identified were DDT, DDE, and methyl parathion, each of which have been shown to inhibit symbiotic signaling (Fox et al., 2001, 2004). Other studies measuring the chemical content of groundwater used for drinking water in the U.S. have found that 70% of sampled domestic and public water wells contained at least one of the pesticides, volatile organic chemicals, or nitrates measured (Squillace et al., 2002). Such studies point out the extent of chemical contamination or "noise" in the soil environment where Rhizobium soil bacteria and legumes are attempting to establish the communication necessary for nitrogen-fixing symbiosis.
All organisms rely on communication and signaling for maintaining cellular processes, processing external environmental cues, and for coexisting with other organisms. As stated by Thompson, "the history of evolution and biodiversity is fundamentally a history of the evolution of species interactions" (Thompson, 1999). Therefore, when assessing the effects of pollutants, contaminants, and EDCs released into the environment, it is crucial to examine a broad cross-section of organisms, both vertebrate and invertebrate, that comprise ecosystem-wide signaling webs. By recognizing that signaling and communication strategies are shared between and among organisms at every level of the evolutionary tree from bacteria to humans, we may be better able to recognize how EDCs and pollutants affect unlikely target organisms in an ecosystem.
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ACKNOWLEDGMENTS |
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I am most grateful to John A. McLachlan for mentoring and sponsoring all of the work described herein. His unflagging support has made these contributions possible. I am also grateful to the members of the environmental endocrinology laboratory at the Center for Bioenvironmental Research where this research took place. Work supported by DOE grant# 540841 and USDA grant# 586435-7019. J.E. Fox supported by National Science Foundation predoctoral fellowship.
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1 From the Symposium EcoPhysiology and Conservation: The Contribution of Endocrinology and Immunology presented at the Annual Meeting of the Society for Integrative and Comparative Biology, 5–9 January 2004, at New Orleans, Louisiana.
2 E-mail: jenfox{at}uoregon.edu
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