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The Society for Integrative and Comparative Biology
The Study of Endocrine-Disrupting Compounds: Past Approaches and New Directions1
1 Department of Biological Sciences, Box 5640, Northern Arizona University, Flagstaff, Arizona 86011
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 SYNOPSIS INTRODUCTIONENDOCRINE DISRUPTORS:...IS THERE A LITERATURE...A LITERATURE BIAS IN...CONSERVATION IMPLICATIONSReferences |
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Over the last decade, evidence has mounted demonstrating that human-made compounds released into the environment are disrupting endocrine systems of animals. Research has centered largely on direct steroidogenic or antisteroidogenic effects of these compounds with a recent focus on development of rapid in vitro assays employing estrogen receptors. A literature search and analysis confirms attention placed on estrogen and anti-estrogen-like aspects of endocrine disruption at the receptor level. Non-steroidal components of the hypothalamic-pituitary-end gland axes have received much less attention in the published endocrine disruption literature. Furthermore, aspects of endocrine physiology, such as the ability of animals to cope with stress or communicate chemically, have also received relatively less literature attention when compared to disruption of development and reproduction. As researchers continue to investigate complex mixes of human-synthesized compounds in the environment, it is critical to broaden the spectrum of hormonal disruption investigated beyond estrogenic and androgenic actions and to determine how exposure to mixes affects physiological function beyond reproduction. Last, in the field of endocrine disruption, it also important to begin to use data on individuals for development of hypotheses regarding fitness risks, changes in population dynamics, and the potential for ecosystem level disruption.
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INTRODUCTION |
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SYNOPSISINTRODUCTIONENDOCRINE DISRUPTORS:...IS THERE A LITERATURE...A LITERATURE BIAS IN...CONSERVATION IMPLICATIONSReferences |
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In their environments, organisms are exposed to a wide variety of naturally occurring chemicals. In the last 100 years, humans have introduced hundreds of new, synthetic compounds into the environment. Many of these compounds are known, and even were specifically developed to influence microbial, plant, and animal physiological function. Some have had unintended physiological consequences on non-target species. How these compounds ultimately influence physiology and fitness of individual organisms, dynamics of populations, and ultimately functioning of ecosystems, is not well understood.
Many human-introduced compounds influence the endocrine system of animals (Colborn et al., 1993
; Oberdorster and Cheek, 2001) and have been termed "endocrine disrupting compounds" (EDCs). By interfering at multiple levels of the endocrine pathways, these compounds disrupt physiological processes including development, reproduction, general metabolism and behavior. Given that there are thousands of human-introduced compounds now mixing in our environment, and the complexity of even a single organism's physiology, the possible mechanisms for disruption and range of physiological outcomes are enormous. Yet, only a small fragment of this potential physiological disrupting capacity has been investigated. I will provide definitions of endocrine disruption and then review the distribution of literature involving the 1) hormone investigated as being targets for disruption, 2) biochemical mechanisms of endocrine disruption, and 3) physiological systems that are effected by EDCs. This search will test the hypotheses that the disruptor literature focuses on first, estrogens and androgens as the targets of disruption, second, on receptor binding as the mechanism of disruption and third on reproduction and development as a physiological focus in the literature. I will discuss how bias in the literature may drive our research into mixes of compounds known to exist in our environment.
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ENDOCRINE DISRUPTORS: DEFINITIONS |
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In part, because of the complex political and regulatory climate, defining what an "endocrine disruptor" is has been difficult. The United States Environmental Protection Agency (USEPA), as of February 2004, has accepted with qualifications Kavlock et al.'s 1996
(p. 715) definition of an endocrine disruptor as "an exogenous agent that interferes with the synthesis, secretion, transport, binding, action, or elimination of natural hormones in the body which are responsible for the maintenance of homeostasis, reproduction, development and or behavior." The current agency position goes on to state it "...does not consider endocrine disruption to be an adverse effect per se, but rather to be a mode or mechanism of action potentially leading to other outcomes, for example carcinogenic, reproductive, or developmental effects, routinely considered in reaching regulatory decisions. Evidence of endocrine disruption alone can influence priority setting for further testing and the assessment of the results of this testing could lead to regulatory action if adverse effect are shown to occur" (http://www.epa.gov/scipoly/oscpendo/edsparchive/2–3attac.htm). Therefore, the USEPA's working statement regarding endocrine disruption does not make any statement regarding whether such disruption has negative impacts on an individual's ability to function, but leaves open the possibility of introducing regulatory statutes based on results of specific testing regimes. The USEPA's Endocrine Disruptor Screening Program now outlines these tests (http://www.epa.gov/scipoly/oscpendo/edspoverview/index.htm). Alternatively, a European Commission Report, less mechanistic in its definition, makes clear potential negative outcomes of exposure to EDCs. This report states "an endocrine disruptor is an exogenous substance that causes adverse health effects in an intact organism, or its progeny, secondary to changes in endocrine function. A potential endocrine disruptor is a substance that possesses properties that might be expected to lead to endocrine disruption in an intact organism" (European Commission, 1997). The e.hormone website follows more along the European Commission report; it defines endocrine disruption as "the process by which an exogenous substance causes adverse health effects consequent to changes in endocrine function" (http://e.hormone.tulane.edu/learning/learning.html). Note that all definitions include the focus that an endocrine disruptor is a compound that interferes with endogenous endocrine function. Sources for environmental contamination are numerous. Pesticides, industrial compounds, heavy metals, phytoestrogens, and pharmaceutical compounds have been detected in the environment. The level and form of contamination at any one site varies. Rivers downstream of municipal wastewater effluent will have a different mix of compounds compared to areas adjacent to agricultural fields. Nevertheless, it is critical to understand the physiological outcomes to exposed wildlife and human populations.
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IS THERE A LITERATURE BIAS? |
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Using a uterine assay, Bitman et al. in 1968
found that the pesticide, dichlorodiphenyltrichloroethane (DDT), was estrogenic. In 1974, Nelson demonstrated DDT and its metabolites displace estrogen from its receptor, providing a mechanism for its estrogenicity. Since then numerous studies have determined that many compounds disrupt endogenous estrogen signaling processes by competing for the estrogen receptor (see Orchinik and Propper, 2005). Because estrogens are essential to overall reproductive development and function, researchers began focusing on estrogenic disruption of a wide variety of compounds. However, research on the disruption of other hormones or aspects of the endocrine system may have been neglected. To test the hypothesis that there is a literature bias in favor of estrogenic disruption, I collected data on the number of publications regarding endocrine disrupting compounds using specific sets of key words. First, I collected data from three search engines found in the Cambridge Scientific Abstracts (CSA) under the "Medline," Biological Sciences," and "Toxline" search engine databases and limited the timeline of the search to papers published between 1990 and the present. To retrieve published research involving endocrine disruptors, I used 3 sets of key word descriptors: "endocrine disrupting," "endocrine disruptor," or "pesticide," and determined the number of papers published for these key words that was also linked to individual hormones (see Table 1). The key word descriptor "endocrine disruption" was not used in the analysis because it generated a number of papers with no relevance to the field of environmental endocrine disruption. First, the hypothesis that there are differences in results that depended on the type of search engine used was tested using a Chi-square contingency test across all three search engines. Though there are differences in the total number of papers found under the different search engines (total Medline results for all three set of key words representing endocrine disruption = 406; Biological Sciences = 342; Toxline = 244), there are no significant differences among the three different search engines for any of the key word descriptors (key words: "endocrine disrupting," P = 0.99, Table 1; "endocrine disruptor," P = 0.99, data not shown; "pesticide," P = 0.99, data not shown). These results indicate that using data generated from Medline, which gave the highest number of papers in the field, will provide sufficient data for the analyses described below. Therefore, the other analyses were conducted solely within "Medline" via the CSA website.
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Next, I determined whether the literature distribution is different across different key word descriptors describing environmental endocrine disruption. Within Medline, a Chi-squared contingency test determined that there were no significant differences among the distribution of literature across hormone types when the descriptors "endocrine disrupting," "endocrine disruptor," or "pesticide" were used as key words (P = 0.21; Table 2). For the rest of the analysis, I analyzed data using the descriptor key words "endocrine disrupting" as they gave the largest data set in this analysis.
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Is the literature biased towards investigation of environmental endocrine disruption of one or a few hormone systems, specific mechanisms of disruption, and/ or physiological outcome? To determine whether there is a hormonal bias, expected values for an even distribution of the literature was derived by dividing the total number of papers found for the hormones by the number of hormones used in the search. A Chi-squared contingency test comparing the actual results to the "expected" results if the literature were evenly distributed supports the hypothesis of an unequal literature distribution (Table 2, column 1; P < 0.001). The distribution confirms that much of the research focuses on estrogen and androgen-related studies (60% using keywords "endocrine disrupting"); other hormones are less prominent in this literature. For example, thyroxine (T4) represents only 3.4% of the total literature in this search. Given recent studies by Zoeller (Zoeller et al., 2000
; Zoeller, 2003) and Howdeshell (2002) demonstrating that thyroid hormone disruption (by influencing T4 levels or T4 binding to its receptor) can have profound effects on the developing nervous system, it becomes critical to gain a better understanding of which EDCs may impact the thyroid hormone system. Also of importance is that the hormones from the "end-point" glands of the hypothalamic-pitiutary-gonad/adrenal/thyroid axes make up most of the literature. End-gland hormones (estradiol, testosterone, the glucocorticoids and T4) account for 79% of the literature presented in Table 2, while less than 4% is represented by the hypothalamic neurohormones. However, there is evidence that disruption may be occurring at higher levels along these axes. For example, (Gore et al., 2002) has demonstrated that exposure to polychlorinated biphenyls (PCBs) influences function of GnRH-containing neurons. This survey demonstrates that there is evidence for disruption of multiple hormones and hormonal systems. It is clear that disruption of estrogenic and androgenic systems occurs. We need to better understand whether disruption of other hormone systems is a rare or common outcome of EDC exposure.
To determine whether the literature is unevenly distributed for the types of biochemical mechanisms of disruption, another literature search was conducted using the key words "receptor," "enzyme," or "binding globulin" + "binding protein" as key words along with "endocrine disrupting" in Medline. The literature was not evenly distributed (P < 0.0001, Table 3) with a majority of papers emphasizing receptor mechanisms (70%). Depending on the EDC, an exogenous compound may activate a receptor inappropriately or it may block activity of the receptor by preventing available endogenous hormone binding. Historically, Nelson (1974) first determined DDT and its metabolites bind to the estrogen receptor. Since then numerous compounds, commonly found in the environment, have been shown to bind either to estrogen or androgen receptors with either agonist or antagonistic properties (see review by Orchinik and Propper, 2005). Exposure to EDCs at significant concentrations can influence the cellular and ultimately the physiological function of an organism by competing with endogenous hormones for their receptors.
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A smaller number of papers were found utilizing the key word "enzymes." These studies have demonstrated that EDCs affect hormone levels by influencing the action and/or expression of the enzymatic machinery involved in hormone synthesis. For example, in alligators exposed in ovo, the pesticide atrazine increases activity of aromatase, the enzyme that converts the hormone testosterone to estradiol (Crain et al., 1997
, 1999). EDCs affect hormone synthesis by influencing production of key transcription factors involved in enzyme synthesis. For example, exposure of bullfrogs (Rana catesbeiana) to the industrial compound, 4-tert octylphenol, leads to elimination of the sexually dimorphic pattern of steroidogenic factor-1 (SF-1) expression (Mayer et al., 2003). SF-1 is an orphan nuclear receptor and is part of the promoter region machinery involved in expression of multiple enzymes necessary for steroid hormone production (Parker and Schimmer, 1995). Changes in SF-1 expression, therefore could lead to dramatic shifts in the expression of enzymes central to steroidogenesis during development or in the adult. Furthermore, EDCs can act by changing metabolic breakdown or clearance of hormones via changes in production of appropriate enzymes. Such changes may ultimately induce shifts in concentrations of plasma hormones. For example, polybromiated diethers (PBDEs), used as flame retardants, are widely distributed in the environment, and are found in wildlife and human populations (Darnerud, 2003). Increases in expression of liver enzymes involved in T4 metabolism and clearance is induced by exposure to PBDEs in rats leading to reduced T4 plasma levels (Hallgren and Darnerud, 2002).
Other papers were found demonstrating that EDCs can influence binding of hormones to their plasma binding proteins. These carriers protect hormones from enzymatic breakdown in the liver and act as a plasma buffering system for free hormone levels. PBDEs bind competitively with transthyretin, the binding globulin that carries thyroxin in plasma (Hallgren and Darnerud, 2002). The physiological implications of this form of disruption are still unclear.
EDCs may influence post-receptor mechanisms. Bisson and Hontela (2002) examined the effects of four common pesticides on interrenal cell function. Interrenal secretion of glucocorticoids is activated by stimulation from adrenocorticotropin hormone (ACTH). ACTH acts via a cAMP-dependent pathway. Two pesticides induced changes in glucocorticoid secretion without influencing ACTH-induced cAMP production. Their results suggest that there are endocrine disrupting mechanisms occurring via a post-receptor mechanism.
The outcome of disruption-induced changes in binding, synthesis, transport, and breakdown ultimately leads to changes in overall plasma hormone levels in organisms not only in the laboratory, but also in the wild. Guillette and Gunderson (2001) reviewed the specific changes in synthesis and metabolic pathways that can determine disrupted plasma hormone levels, and they provided an example of how this can affect a wild population of alligators. Male juvenile alligators from a pesticide-contaminated lake have higher androgen and lower estrogen levels than do animals from a reference lake (Guillette et al., 1999). Correlated with these hormone level differences between highly contaminated and reference sites were changes in activity of liver enzymes involved in androgen biotransformation (Gunderson et al., 2001). All of these studies demonstrate that EDCs may influence physiology in ways that are not directly related to their actions at their own receptors.
To determine whether the literature was evenly distributed among different physiological systems, I used the Medline search engine and the descriptor key words "endocrine disrupting" and several physiological systems. Again, the literature was unevenly distributed (Table 4; P < 0.0001). Notably, when "development, reproduction, and sex differentiation" are combined, these aspects of physiological function constitute 70% of the literature in this survey. Metabolism comprises another 11% of the literature and the remaining 19% of the literature is spread over the rest of the physiological systems employed in the search. Recently, two published reviews state that behavior has been underrepresented in the endocrine disruption literature (Clotfelter et al., 2004; Zala and Penn, 2004). Other physiological systems, like digestion, calcium and water balance are largely ignored. Although this method of surveying the literature inevitably misses some published investigations (including work from my laboratory on disruption of pheromonal communication [Park et al., 2001]), it does confirm that there is a critical dearth of endocrine disrupting literature in many areas of physiological function.
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A LITERATURE BIAS IN THE INVESTIGATION OF ENVIRONMENTAL MIXES |
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Purdom et al. (1994)
noted that many fish in wastewater effluent lagoons from a specific wastewater treatment facility were hermaphroditic. They hypothesized that compounds in the wastewater were acting like estrogens. To test this hypothesis, they placed trout into effluent lagoons from this plant, and then also treated animals with effluent from 15 other plants in England. They assayed the fish plasma for the estrogenic biomarker, vitellogenin, the major egg-yolk protein under synthesis control of endogenous estradiol. Not only did the original effluent lagoons induce vitellogenin synthesis, but effluent from all the other plants in the study also demonstrated estrogenic activity.
In order to determine whether estrogen-like compounds in the effluent were getting into local river systems, Jobling et al. (1998) surveyed fish in rivers receiving effluent upstream and downstream from wastewater treatment facilities output regions. They examined the gonads for intersexuality and found that males downstream from the plants had a higher level of gonadal abnormalities than did those upstream. Furthermore, fish from reference streams receiving no effluent had lower levels of intersexuality compared to fish from sites near the plants. This result critically demonstrates that chemical contamination at levels found in the environment affects vertebrate developmental processes.
In the United States the United States Geological Survey (USGS) has undertaken a study to evaluate organic wastewater contaminants (OWCs) in water around the country (Kolpin et al., 2002). They deliberately biased their sample by examining stream and river systems downstream from urban or intense agricultural areas. This significant study found that many pesticides, industrial compounds and pharmaceuticals are in river systems, sometimes at levels that have been demonstrated to be endocrine disrupting even for individual compounds. In Europe, there is a strong understanding of the potential impact of contaminants found in sewage sludge and wastewater. Results from many sites in Europe are summarized in a recently published volume Endocrine Disrupters in Wastewater and Sludge Treatment Processes (Birkett and Lester, 2002). These studies demonstrate the need and interest not just to investigate compounds as individually endocrine disrupting, but to better understand how environmental mixes influence overall organismal physiology. Wastewater provides a strong "Model Chemical Mix" to begin such investigations.
As a result of the above studies, a number of labs have begun to evaluate the endocrine disrupting potential of water downstream of effluent plants; but, as demonstrated above for individual compounds, the bias has been towards investigating the estrogenic or antiestrogenic effects. Using the same methods as above to determine whether the literature is unevenly distributed in investigations of waste systems, a survey of the literature using hormonal terms in Table 2 and the key word descriptors "sewage" and "wastewater" was conducted. For this survey, published results were found for only those hormones shown in Table 5. The results demonstrate an unequal distribution in the published investigations (Chi-squared analysis: expected values were calculated only for those hormones listed; P < 0.0001, Table 5) with estradiol being the keyword that garnished the most number of published papers.
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Why the bias towards estrogens, androgens and reproduction? One hypothesis is that the bias is a historic function of the environmental endocrine disruption field. Estrogenic disruption was the first well-defined form of disruption, and receptor mechanisms were the first clearly defined means through which disruption occurs. Therefore, a scientific research "band wagon effect" may have occurred. An alternative hypothesis is that other non-estrogen or reproductive outcomes are investigated, but the results generated are negative making them difficult to publish. In the case of endocrine disruption research, however, it could be argued that having access to negative data is valuable. The development of a government-managed database (through the Public Health Service, the USEPA, or USGS) accessible to researchers in the field would be useful. In one such example, one could list the compounds studied, the basic outcome investigated, and the status of the project along with contact information. Researchers could log onto the system and make appropriate contacts. The success of such a program would depend upon openness. Such a database would help direct future studies and provide valuable information about the endocrine disrupting (or lack thereof) potential of tested compounds.
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CONSERVATION IMPLICATIONS |
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Previous work examining one hormone or receptor and one compound at a time has been exceedingly useful in defining the potential for disruption of physiological function. Endocrine disruption, though initially found to provide inappropriate ligands for receptors, is now known to influence physiology through a variety of mechanisms. It is exciting that many papers at this symposium presented work regarding EDCs that went beyond estrogen-based physiology. It is now critically important to begin to determine whether disruption of hormonal or physiological systems has long-term biological meaning important to conservation efforts. To do so, it is vital to understand how disruption can influence fitness outcomes and relevant population parameters. Furthermore, also unanswered is the question of how endocrine disruption can directly or indirectly have ecosystem level repercussions. Our work on the red-spotted newt demonstrated a decrease in mating success when either males or females were exposed to a common pesticide, endosulfan (Park et al., 2001
; Park and Propper, 2002). Jobling et al. (2002) have demonstrated a reduction in fertility in wild-caught intersex fish whose gonadal development was endocrine disrupted. Bayley et al. (2003) have also found that exposure to a fungicide decreases male reproductive success in guppies. In all of these studies there was no indication of overt toxicity, but negative individual fitness outcomes could be realized.
Few studies demonstrate the potential for population level impacts, though the implication for such potential is clear if reproductive success among a significant portion of individuals in a population is affected. One study used population-level endpoints to determine that musk fragrances at environmental levels were probably not affecting specific life table parameters, although they were overtly toxic at high concentrations (Breitholtz et al., 2003). The methods for investigating population level effects of endocrine disruption used in this study could be a powerful tool.
Last, the overall ecosystem level potential for disruption is rarely addressed. Of course, indirect effects on the ecosystem could be initiated by changes in population dynamics of individual species within an ecosystem. Jennifer Fox's work presented in this symposium reveals the fascinating possibility that known endocrine disrupting compounds can influence complex species interactions. Her work demonstrates that plant/ microbial symbiotic interactions may be influenced by numerous environmental contaminants (Fox et al., 2001, 2004). Disruption of these interactions could influence nutrient cycling. The above studies help define the need to translate endocrine disruption effects at the individual level into fitness effects, population impacts and ecosystem outcomes in order to gain conservation-relevant interpretations.
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ACKNOWLEDGMENTS |
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I would like to thank three anonymous reviewers who gave clear and appropriate critiques of an earlier version of this manuscript. I appreciate Dr. Amy Whipple for her statistical advice, and I thank the members of my laboratory group, Angela Schwendiman, Priyanka Shah, Maureen Maloney, and Elizabeth Allen, for their careful reading and thoughtful input.
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FOOTNOTES |
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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: Catherine.Propper{at}nau.edu
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References |
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