FEATURE
Monitoring EndocrineDisrupting Chemicals O M O W U N M I A. SADIK AND DIANE M. WITT
he effect of endocrine-disrupting chemicals (EDCs) on human health and wildlife is receiving growing attention from the scientific community, regulatory agencies, and the public at large. Exposure to EDCs (see Table 1) can mimic or interfere with mechanisms of naturally occurring hormones responsible for regulating reproductive and developmental bodily processes of the body (1-3). The chemicals can also dramatically alter normal physiological functioning of the endocrine system and can affect formation (synthesis) of hormones in the body or target tissues where the hormones exert their effects. Driven by this increasing awareness of possible EDC impacts, a recent government-wide effort is stimulating innovative, multidisciplinary research that addresses scientific uncertainties concerning potential adverse effects of the chemicals. The collaborative effort involves experts from EPA, the U.S. Department of Interior, the National Institute of Environmental Health Sciences, National Oceanic and Atmospheric Administration, the U.S. Department of Agriculture, the U.S. Department of Energy, the Centers for Disease Control and Prevention, and the U.S. Food and Drug Administration. Undertakings in the areas of human health, ecological effects, and exposure assessment are considered priority research needs essential to the larger goal of determining the extent and magnitude of endocrine distrupter impacts. The most critical step toward achieving this goal is to determine which pollutants can definitely be characterized as environmental endocrine disrupters. Unfortunately, although endocrine-disrupting chemicals are of great interest to agencies responsible for determining their potential effects on humans and wildlife, currently, no suitable characterization method exists for evaluating most EDCs in
T
Novel strategies are providing a more comprehensive and refined basis for understanding the occurrence and effects of endocrine disrupters.
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© 1999 American Chemical Society
biota or biological media. Moreover, monitoring and surveillance studies of EDCs are difficult undertakings. In addition, screening (or testing) of the wide variety of syntiietic EDCs and their metabolites involves substantial costs and time. Adding to these complexities is that, unlike most toxic substances, EDCs generally exhibit unusual "dose-response" behaviors, thus rendering the threshold concept of toxicology inapplicable for EDC studies. The dose-response behaviors for most toxic substances usually increase with increasing levels of chemical compounds, which eventually level off. In contrast, the response curves for environmental estrogens exhibit an inverted U-shape—the greatest response is produced at extremely low doses. There are also concerns that the effects of different EDCs are additive, or even synergistic, such that regulating individual compounds may be inadequate. Moreover, the process of enabling estrogenic activities in some tissues, while completely blocking these activities in others, could result in an increase in estrogenic activities of certain EDCs found in tissues. This phenomenon is known as an "agonistic and antagonistic" effect. Issues such as these are being addressed through the development of novel monitoring strategies that involve use of bioaffinity sensors, cell-based assays, acute slice explants, and hyphenated techniques. The monitoring strategies can be based on combinations of short-term screening, highperformance testing, long-term behavioral testing, and animal testing. Such approaches seek to capitalize on advantages of and surmount limitations of existing analytical techniques. Taken together, these approaches should provide viable strategies for characterizing potential environmental estrogens.
Exposure and impact Exposure to EDCs can occur during pregnancy through the transfer of blood-borne agents from the mother to the fetus, which can cause hormonal imbalance or changes in receptor sensitivities in the fetus, ending in reproductive abnormalities. It is already well established mat environmental factors can directly influence genes and physiological mechanisms underlying sexual differentiation of brain structures, genitalia, and behavioral characteristics. Prenatal or postnatal exposure to EDCs can permanendy alter the neuroendocrine properties of the central nervous system, interfering with the feedback systems that are normal features of the pituitary, gonads, adrenal, and thyroid axes in males and females. EDCs may also indirectly affect plasma steroid levels by altering hormonal activities in the gonads or adrenals or by modifying die second messenger systems in the brain. For example, polychlorinated biphenyls (PCBs) appear to interfere with gonadotropin secretion because of changes in neurotransmitter activity in the hypothalamus (4). Many EDCs compete with estradiol for the estrogen receptor, whereas omers compete with dihydrotestosterone for the androgen receptor (5). Therefore, EDCs are capable of altering the endocrine system by affecting hormone synthesis or degradation, transport, receptor binding properties, and gene transcription. EDCs may even eliminate the natural-borne hormones responsible for regulating homeostasis, as well as developmental and reproductive processes {1, 2).
Testing and surveillance requirements Prompted by this new awareness of potential impacts of EDCs, scientists are looking for efficient, lowcost screening strategies capable of identifying and
TABLE 1
Selected endocrine-disrupting chemicals Endocrine-disrupting chemicals, most of which are present at parts-per-billion levels, include compounds such as bioaccumulative organochlorines, pesticides, industrial chemicals, and phytoestrogens—naturally occurring EDCs. uiuup o
Group 1 Chlorinated organics
Group 2 Industrial chemicals
Polymers with molecular weights 1000 or less
Group 4 TSCA
Group 5 Pesticides
2,4,5-Trichlorophenol (S)
Hydrazine* (P)
Fluoropolyol
PAHs (K)
Malathion (S)
PCBs (K)
Bisphenol A (P) Transplatin (S) Benzoflumethiazide Propanthelinebromide (S)
Methoxypolysiloxane (P)
Triazines (K) Kepone(S)
1,2-Dibromo-3chloropropane Aldicarb nitrofen (S)
2,3,7,8-TCDD (K)
Butyl benzyl pthalate (S) Polyethylene oxide (S)
Lead (K)
Pyrethroids (S)
Pentachlorophenol (K)
p-Nitrotoluene
Poly(isobutylene)
Mercury (K)
Dicamba (S)
Obidoxime chloride (S)
Polyurethane (S)
Endosulfans
Aldicarb (P)
* Currently no available EPA method. P denotes probable EDC; S denotes suspected EDC; K denotes known EDC
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classifying all EDCs, as well as potentially contaminated sites within the environment. Once these screening methods are developed, further laboratory reanalysis, including confirmation and longterm studies, will be necessary to identify endocrinedisrupting characteristics among the population. The amount of screening that will be required is enormous, given the wide range of EDCs, metabolites, and potential environmental estrogens. According to a recent EPA advisory committee on endocrine disrupters, several commercial chemicals, including nearly 87,000 mixtures, should be screened to assess and determine their effects on the endocrine system (6). The relative potencies of synthetic and natural EDCs include highly target, organspecific species, and the differences could complicate hazard assessment (7). Development and deployment of screening techniques are important prerequisites for determining the behavioral effects of EDCs, an area that has been largely neglected by researchers. Understanding both the phar macokinetics and mechanisms of action, while localizing the specific effects of EDCs on target tissue, may be equally vital for developing biochemical interventions capable of diminishing the impact of EDCs.
Most important, such studies should generate the detailed information needed to avoid synthesizing similar compounds that could have ill effects on the endocrine system. This task will not be easy. The unusual dose-response behavior of EDCs complicates testing and surveillance: Results obtained for both estradiol and diethylstilbestrol in prostrate indicated a response that first decreased with dose, then increased, producing the inverted U-shaped dose-response relationship (8). Moreover, the use of threshold inference is difficult in the case of many xenobiotics, because these compounds readily mimic the endogenous actions of steroidal compounds essential for development. Thus, the threshold is automatically exceeded with continued exposure to these substances. Also posing a challenge for monitoring is that the effects of different EDCs can be additive, or even synergistic. A typical range of synergistic endocrine receptor binding, which includes the induction of reporter gene activity compared with that observed for the compounds alone, is between 160- and 1600fold. In one yeast-based assay, the binary mixtures of weak estrogenic pesticides, including dieldrin, chlordane, toxaphene, and endosulfan, exhibited greater than a 90-fold effect (9).
TABLE 2
Current monitoring methods for endocrine-disrupting chemicals There are specific advantages and disadvantages of techniques used for characterizing endocrine-disrupting chemicals. 1Reference
Characterization method
Principle
Advantages
Disadvantages
Bioassays
Quantitation of the response following the application of a stimulus to a biological system
Similar to living situation/ incorporates the effects of metabolism, serum binding, and pharmacokinetics
Large-scale screening requires faster and less expensive alternatives.
[7,8)
Receptor-binding assays
Principle similar to immunoassays in which antibody is replaced with enzyme-linked estrogen receptor
Useful for pharmacologically and toxicologically relevant substances in unknown samples; adaptable to f l o w injection analysis mode; easy to perform; allows identification; rapid analysis time
Unable to differentiate the binding of agonist and antagonist EDCs
(6)
DNA-binding assays
DNA binding of estrogen receptor by suitable ligands
Suitable for studying important biological effects of active compounds through the cell membrane
May be unsuitable for the detection of synergistic effects of natural and environmental estrogens
(6)
Cell-based assays
Proliferation of cells on incubation with estrogenic compounds
Suitable for primary identification of estrogenic activities of several compounds
Length of assays is about 4-6 days, making it less attractive for large-scale screening.
Chromatographic methods
Separating components of materials between t w o immiscible phases on the basis of differences in their molecular size, charge, mass, polarities, and redox potentials.
Structure confirmation and analysis of estrogenic compounds (particularly GC/MS)
Potential loss in specificity and high cost; GC/MS requires derivatization of the estrogenic compounds in order to be volatile; Low levels in biological matrices make quantitation using UV-vis difficult.
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Current monitoring techniques Most studies involving the analysis of EDCs have focused on estrogens using bioassay techniques. Bioassay involves the quantitation of a biological response that follows the application of a stimulus to a living organism. The quantitative response can be seen in some aspects of the biological system, producing a positive or negative signal such as an increased activity, a negative response (inhibition), or even death to the biological system. The response obtained provides information on the biological activity that is normally attributed to the analyte. One major advantage of the bioassay is its specificity. Specificity is particularly attractive for any characterization in which the mixture of agonist and antagonist forms is present but cannot be separated effectively. Bioassays are often very sensitive and can distinguish very small differences in analyte activities, particularly when insufficient material is available. The use of animal bioassays is becoming less frequent because of improvements in both the purification and alternative analytical techniques and because of the advent of sophisticated tools in molecular biology for detecting and accurately measuring biological products. In addition, large-scale screening using bioassays requires faster and less expensive alternatives. Other modifications of bioassays for in vitro analyses commonly used for the characterization of EDCs include receptor-binding assays, biosensors, DNA-binding assays, cellbased assays and recombinant yeastscreen assays (see Table 2). For example, enzyme-linked receptor assays (ELRAs) have been used to investigate estrogenic activities in vitro involving estrogen receptors (6). Experiments conducted on 17|}-estradiol resulted in a detection limit of 0.1 ng/mL. Although an ELRA is simple to perform (and can identify all of the EDCs that act through estrogen receptors), the major limitation lies in its inability to differentiate the functional binding activities of agonist or antagonist EDCs. Well-known synthetic EDCs are generally assayed using conventional analytical techniques, including liquid chromatography, gas chromatography, and hyphenated
FIGURE 1
Biosensor surface preparation Biosensors can be designed with predefined functionality for the analysis of specific endocrine-disrupting chemicals (EDCs). The sensor consists of an artificial interface located on the surface of a transducer. This interface can be engineered to have a predefined affinity for target analytes (such as EDCs). Sensor preparation requires immobilization of two types of molecules. The first molecule serves as a "template," having a shape similar to the analyte of interest and contains an additional functional group that is capable of strongly binding with the transducer surface. The second molecule acts as a "substrate" capable of strong adsorption on the surface and forms a monolayer thicker than itself. Because of coadsorption of the two molecules on the transducer surface, a mixed monolayer matrix, consisting of template and substrate, forms. This resulting monolayer contains template-shaped cavities that do not undergo lateral diffusion and exhibit a pronounced affinity for the analyte molecule of interest. Such predefined affinity interfaces can also be prepared by techniques other than adsorption, for example, covalent binding, cross-linking, entrapment, or microencapsulation.
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FIGURE 2
Operation of a whole-cell biosensor Bacterial cells used in this application are grown on a single carbon or nitrogen source. These cells, thus grown, contain a very large amount of a particular enzyme (significant for its selectivity). The presence of analytes (such as endocrine-disrupting chemicals (EDCs)) often leads to substantial increases in the metabolic activities that cause production of electroactive species generating as a result, a large potentiometric signal. Mediator molecules facilitate the transfer of electrons from the cells to the surface of the indicator electrode, by interacting at certain sites along the electron transfer chain. The effect of this interaction causes the mediators to become reduced as the chain progresses—this causes the mediator molecules to act like terminal electron acceptors. Subsequent reoxidation of the reduced mediator molecules at the working electrode results in a steady flow of current that can be measured by an external circuitry. The magnitude of this current is proportional to the activity of the bacterial organisms, so that any perturbation in the ensuing current time curve indicates the presence of an EDC pollutant.
techniques such as gas chromatography and mass spectrometry (GC/MS). The advantages of these techniques include their accuracy and precision. Gas chromatography (GC) and liquid chromatography (LC) techniques are used generally for structure confirmation and the validation of environmental samples. A wide range of available analytical methods can be used to analyze other known EDCs, such as those listed in Table 1. These techniques have known limitations. Using GC-based techniques for analysis of potential EDCs requires derivatization to increase their volatility prior to mass spectroscopic identification. LC methods require the use of ultrasensitive detectors for monitoring dynamic events and low levels of EDCs usually found in biological matrices. These techniques are costly, generally have low analytical throughputs, and require more complex instrumentation. Extensive validation studies are required to eliminate interference problems. Multidimensional GCs, including fast GCs and high-resolution MS, are capable of overcoming these limitations. However, for biomonitoring purposes, in particular, the analysis of EDCs, the potential resulting loss in specificity (such as coelution of peaks), and issues of resolution and sensitivity must be addressed. To ascertain estrogenic activities of a compound using classical chromatographic techniques, these methods must be combined with bioassays or other receptor-based techniques. For these reasons, researchers are looking at the relevance of existing methodologies in providing unam3 7 2 A • SEPTEMBER 1, 1999 / ENVIRONMENTAL SCIENCE & TECHNOLOGY / NEWS
biguous analysis results, or in some cases, are simply seeking new approaches for the characterization of potential EDCs. Novel monitoring methods Sophisticated biosensors are used for rapid and reliable measurement of harmful substances and biochemical compounds, including triazines, phenols, polyaromatic hydrocarbons, and others that are of military interest or are relevant to the food industry. The evolution of tiiese novel sensors has brought about a growth in environmental measurement technique capabilities and has accelerated understanding of biochemical reactions. A typical biosensor consists of a biologicalsensing element (such as an antibody), whole cells, and receptors, which are in close proximity to a transducer (such as an electrode, an optical fiber, or a piezoelectric or mass transducer). The biological element may be connected directly to or integrated within the transducer. Measurement of a target analyte (such as an EDC) can be achieved by selectively converting the molecular recognition occurring at the analyte-sensor interface from a nonelectrical domain to an electrical signal. Several bioaffinity reagents can be used to construct a sensor, including receptors, binding proteins, and nucleic acids immobilized on the surface of the transducer. It is possible to couple the receptor to the sensor surface using an antibody that can recognize the binding site distinctly from the active site. Care must be taken to ensure that the antibody binding causes no conformational change in the receptor in a way that could alter the function of the active site. Once the purified receptor has been coupled to the sensor surface, the binding of the EDCs can be detected through a change in the physical property at the sensing surface. In our laboratories the renewable immunosensors and electrochemical microassembly technologies have been used to analyze a range of suspected EDCs, including PCBs, chlorinated phenols, atrazines, and heavy metals [10-12). In bioaffinity sensors, the ability of EDCs to interfere with the hormone system is a major factor used to develop a (rapid) detection method. The architecture of these sensors is similar to those commonly used in immunoassays. In this case, the endocrine disrupter of interest is permitted to compete with and displace a fluorescent (or enzymelabeled) receptor. The quantity of the endocrine disrupter is then determined using the standard curve obtained from the quantity of the fluorescent molecule remaining after the system reaches equilibrium, which requires only 1-3 minutes. Bioaffinity sensors provide two ways of differentiating target from interfering compounds. The first is associated with construction of the sensing device—differentiation is realized by preparing an artificial template with a predefined affinity. A second level of discrimination is realized through the use of relative binding affinities. These sensors (see Figure 1) are capable of separating an individual component or a selected range of components from com-
plex mixtures of biomolecules (on the basis of their chemical structures and biological functions).
structing these biosensors, the cells are immobilized onto the surface of bacteriological filters that allow the diffusion of the toxicant (such as an EDC) and the mediator molecules to the cells, as well as New monitoring strategies On the basis of EPA's advisory committee's testing re- the diffusion of the reduced mediator molecules to gime for various chemicals (see Table 1), a strategy the electrode. Immunocytochemical methods and long-term anbased on three levels of screening has been recommended for addressing the wide range of possible EDCs, imal studies. If and when positive or equivocal results are obtained in any of the above regimes, those metabolites, and potential environmental estrogens. Prescreening of EDCs using biological assays. Bi- chemicals should undergo further detailed in vitro ological assays such as ELRAs, DNA-binding as- analyses of the effects of EDCs on the central nersays, and biosensors that can provide rapid "yes or vous system prior to long-term animal studies. An no" answers should first be carried out, preferably example of suitable techniques includes immunoon site. This step can eliminate chemicals that do not cytochemical methods for localizing the brain reexhibit endocrine characteristics. For example, af- gions responsive to the tested EDCs. Another method finity biosensors can be used to successfully screen is simulated in situ histochemistry for measuring the chemical compounds provided a suitable antibody alterations in receptor messenger RNA. To characor receptor is available. Alternatively, cells can be terize the direct effects of EDCs on the physiology grown in an appropriate medium for in situ screen- of an organism, we must specifically determine how ing of EDCs. The performance of these sensors is di- the EDCs "reorganize" neural substrates underlying rectly linked to their sensitivity, limit of detection, pre- reproductive physiology and behavior. The determicision, and accuracy. The most important of these nation of the specific neural mechanisms involved factors is sensor specificity, including minimal in- in EDC exposure is clearly limited by the complexterference from other structurally similar com- ities of the in vivo environment in the brain, which pounds and metabolites. If the screening studies re- consists of a multitude of neural networks and feedsult in any significant amount of interference, the back circuits. chemical can be classified as an endocrine disThe specific cellular responses following EDC exrupter and subsequently assigned a quantitative en- posure are particularly difficult to analyze in vivo, and docrine-disrupting index based on a combination of such phenomena should be examined initially in vitro, its IC50 values (a measure of incapacitation effect), under highly controlled conditions. We have develrate constants, and known chemical structure. oped a screening technique to isolate and identify inMultidimensional bioassay, chromatographic, and tact neuroanatomic structures that might be highly reflow injection analysis techniques. The next level of sponsive to EDCs. Information derived from these screening should involve methods that use renew- studies will be instrumental in identifying specific brain able surfaces for rapid, high-performance, and on- regions most often affected by EDC exposure and deline screening assays. This can further test the abil- termining cellular phenotypes that might be directly ity of a chemical to attach to a nominated receptor involved in EDC-mediated physiological and behavand provide information derived from cultured cells. ioral responses. These data will delineate which brain Affinity chromatography, high-throughput GCs, flow areas should be the primary focus of subsequent studies and will eliminate wasted time and effort on sysinjection analysis, two-dimensional GCs, highresolution MS, and LC techniques are examples of tematic in vivo searching for a myriad of neural strucanalytical methods that could be integrated with bi- tures that may respond to EDCs. osensors to provide this second level of EDC screening. These methods provide the necessary selectiv- Future research areas ity, as well as continuous monitoring capabilities. In vitro studies ofEDC actions in humans and wildSuitable detectors include arrays of cell-based senlife. An in vitro system provides the opportunity to sors and receptor-based assays that incorporate a net- extensively characterize the effects of EDCs in spework of intact biological cells as the detection- cific brain nuclei. Current in vitro models allow premeasurement elements. cision in timing, concentrations, and length of exCell-based biosensors can provide alternative tem- posure, but they also have their limitations. The plates for screening EDCs because animals are not primary culture of brain cells, for long-period in vitro, suitable for continuous monitoring, quantitative anal- often alters normal neuronal properties. Typically, the ysis, or any screening in hostile environments. Cell mechanisms affecting receptor synthesis or activabiosensors are also suitable for studying the cellu- tion are studied in homogenate preparations of prilar (and molecular) mechanism of interactions be- mary dissociated neurons or cultures of transtween EDCs and steroids of the central nervous sys- formed cell lines. In such preparations, the tem. By responding to a wide range of chemicals fundamental neuroanatomic specificity and synapthrough biological reaction sequences, cells can be tic organization are absent, and therefore many of used to promote optimum analyte-receptor activi- the regulatory mechanisms that operate within the ties. Such sensors can provide a low-cost alterna- interneuronal circuits in vivo may not be adetive for in situ monitoring of EDCs. In whole cell- quately represented. based assays, indicator electrodes are used in To circumvent some of the problems usually asconjunction with immobilized bacteria entrapped in sociated with long-term in vitro tissue culture, fua gel or membrane support (see Figure 2). In con- ture areas of research must involve the developSEPTEMBER 1, 1999 / ENVIRONMENTAL SCIENCE & TECHNOLOGY / NEWS • 3 7 3 A
ment of viable alternatives that can provide important insights into the in vivo effects of EDCs on gene expression. For example, we have made a novel adaptation to an existing slice explant technology typically used for electrophysiological studies and developed an in vitro method to study gene expression, referred to as the acute slice explants (ASE) technique {13, 14). Quantitative structure-activity relationships (QSAR). Research in this area is expected to deepen understanding of the nature of EDC actions in humans and wildlife. QSAR represents an empirical way of connecting the functional binding affinity of a series of structurally related EDCs to its endocrinedisrupting action. Simple QSAR relationships may exist between the binding energies of an EDC molecule and estradiol. Other important parameters may include hydrophobicity, binding constant, d o s e response behaviors, and polarity of the chemical groups. The QSAR concept may be refined by assigning empirical values to structural features of a molecule such as size, shape, electron distribution, and hydrogen bond capability. Multiple linear regression should produce a quantitative structureactivity relationship; the magnitudes of which coefficient and regression parameters could reveal which structural features are important in determining the endocrine-disrupting characteristics. This information could be extracted from the three-level monitoring strategies discussed above.
References (1) Colborn, T.; Dumanoski D.; Myers J. P. Our Stolen Future. Dutton: New York, NY, 1996. (2) Keith, L. H. Environmental Endocrine Disruptors:A Handbook of Property Data, Wiley & Sons: New York, 1997. (3) Hilleman, B. Chem. Eng. News 1998, 76(6), 7-8. (4) Kahn, I. A.; Thomas, P. Neurotoxicology 1997,18, 553-560. (5) Danzo, B. J. Environ. Health Perspect. 1997,105, 294-301. (6) Oosterkamp, A. J.; Hock, B.; Seifert, M.; Irth, H. Trends Anal. Chem. 1997, 16, 544-553. (7) Safe, S.; Connor, K.; Ramamoorthy, K.; Gaido, K.; Mannes S. Regul. Toxicol. Pharmacol. 1997, 26, 52-58. (8) vom Saal, F. S.; Timms, G.; Nagel, S.; Dhar, M.; Ganjum, V; Parmigiani, S.; Weldshons, W. Proc. Natl. Acad. Sci. U.SA. 1997, 94, 2056-2061. (9) Arnold, S.; Klotz, D.; Collins, B.; Vonier, P.; Guilette, L. Jr.; McLachlan, J. Science 1996, 272, 1489-1492. (10) Sadik, O. A.; Van Emon, J. M. Biosens. Bioelectron. 1996, 11(8), 1-11. (11) Sadik, O. A; Van Emon, J. M. CHEMTECH 1997, 27(6), 38-46. (12) Bender S.; Sadik, O. A. Environ. Sci. Technol. 1998,32(6), 788-797. (13) Witt, D. M.; Gainer, H. Soc. Neurosci. Abstr. 1998, 639(19), 1632. (14) Witt, D. M. Regulatory Mechanisms of Oxytocin-Mediated Sociosexual Behavior. In The Integrative Neurobiology of Affiliation; Carter, C. S., Kirkpatrick, B., Lederhendler, 1.1., Eds.;
Annals NY. Acad. Sci. 1997, 807, 287-301.
Omowunmi A. Sadik is an assistant professor in the Department of Chemistry, and Diane M. Witt is an assistant professor in the Department of Psychology, Behavioral Neuroscience Program, at the State University of New York-Binghamton.
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