Monograph
Endocrine Disruptors
Descriptions of endocrine disruption have been associated with wildlife and driven by documented estrogenic, androgenic, antiandrogenic, and antithyroid actions. These actions, in response to exposure to ecologically relevant concentrations of various environmental contaminants, have now been established in numerous vertebrate species. However, many potential mechanisms and endocrine actions have not been studied. Guillette (p. 9) contends that future studies must broaden the basic science approach to endocrine disruption, thereby expanding the mechanisms and endocrine end points examined. This goal should be accomplished even if the primary influence and funding continues to emphasize a narrower approach based on regulatory needs.
Population Decline and Imposex in Babylonia Japonica
Horiguchi et al. (p. 13) examined gonads and organotin compounds in tissues of the ivory shell Babylonia japonica. Imposex (a superimposition of male-type genital organs on females) occurred in approximately 80-90% of the specimens, with the penis and vas deferens well developed. No oviduct blockage by vas deferens formation was observed. Ovarian spermatogenesis and suppressed ovarian maturation were observed in females, although no abnormalities were found in males. Tissue distributions of tributyltin (TBT), triphenyltin (TPhT) strongly suggest that reproductive failure in adult females accompanied by imposex, possibly induced by TBT and TPhT from antifouling paints, may have caused the marked decline of B. japonica populations in Japan.
Association between Genotoxicity and Imposex
Reports of endocrine disruption describe changes in the normal development of organs and tissues that are consistent with genetic damage. Recent studies confirm that many chemicals also possess carcinogenic and mutagenic potential. Hagger et al. (p. 20) provide the first evidence of DNA damage associated with imposex (the masculinization of female gastropods considered to be the result of alterations to endocrine mediated pathways) in the dog whelk Nucella lapillus. A strong association was found between tributyltin body burden and the prevalence of abnormal growths, providing evidence to support the hypothesis that environmental chemicals that affect reproductive processes do so partly through DNA damage.
Vitellogenin and Sex Steroids in Flounder
High concentrations of vitellogenin (VTG) and gonadal abnormalities, including intersex, have been observed in male flounder (Platichthys flesus) from U.K. estuaries. Although ascribed to the presence of estrogenic endocrine-disrupting compounds (EDCs), there is no firm evidence that these two findings are causally linked or that the presence of EDCs has any adverse population effects. Scott et al. (p. 27) examined the relationship between concentrations of VTG and the sex steroids (11-oxotestosterone in males and 17β-estradiol in females). When matched by capture month and stage of maturation, both 17β-estradiol in females and 11-ketotestosterone in males were significantly lower in those years when VTG concentrations were higher.
Predicted Exposures to Estrogens Correlate with Endocrine Disruption in Wild Fish
Steroidal estrogens likely play a major role in causing widespread endocrine disruption in wild populations of the roach Rutilus rutilus in rivers contaminated by treated sewage effluents. Risk assessment models that predict the location and severity of endocrine disruption in river catchments and identify areas where regulation of sewage discharges to remove these contaminants is needed. Jobling et al. (p. 32) attempt to correlate the extent of endocrine disruption with their predicted exposure to human steroid estrogens. The results support the hypothesis that steroidal estrogens play a major role in causing intersex in wild river fish in England and that the endocrine-disrupting effects can be predicted.
Pesticide Mixtures and Amphibians
Amphibian populations are declining globally and pesticides are among the proposed causes for the declines. A sizable pesticides database on amphibians exists; however, the vast majority of these studies focus on toxicologic effects at relatively high doses. Hayes et al. (p. 40) examined nine pesticides used on cornfields in the United States Although it cannot be determined whether all of the pesticides contributed to the adverse effects, the present study revealed that estimating ecologic risk and the impact of pesticides on amphibians using studies that examine only single pesticides at high concentrations may lead to gross underestimations of the role of pesticides in amphibian declines.
Testis-Antler Dysgenesis in Deer on Kodiak Island, Alaska
It had been observed that many male Sitka black-tailed deer (Odocoileus hemionus sitkensis) on Kodiak Island, Alaska, had abnormal antlers, were cryptorchid, and presented no evidence of hypospadias. To better understand the problem, Veeramachaneni et al. (p. 51) investigated 171 male deer for phenotypic aberrations and 12 for detailed testicular histopathology. They hypothesize that the testis-antler dysgenesis resulted from continuing exposure of pregnant females to an estrogenic environmental agent, thereby transforming testicular cells, affecting development of primordial antler pedicles, and blocking transabdominal descent of fetal testes. A browse favored by deer in this locale might carry the putative estrogenic agent.
PCB Exposure in Bottlenose Dolphins
Marine mammals are susceptible to the effects of anthropogenic contaminants. Hall et al. (p. 60) examined the effect of different polychlorinated biphenyl (PCB) accumulation scenarios on potential population growth rates using data obtained for the population of bottlenose dolphins from Sarasota Bay, Florida. It is suggested that the current estimated annual PCB accumulation rate for the Sarasota Bay dolphin population is depressing the population growth rate. However, the predictions are limited both by model naivety and parameter uncertainty. Such data require continued efforts directed toward long-term studies of known individuals in wild and semi-wild populations.
Trenbolone Metabolites in Feedlot Runoff
Little is known concerning the ecological effects of hormonally active substances associated with discharges from animal feeding operations. Trenbolone acetate is a synthetic anabolic steroid widely used in the United States to promote beef cattle growth. Trenbolone metabolites are stable in animal wastes and are relatively potent androgens in fish and mammals. Durhan et al. (p. 65) evaluated the occurrence of these metabolites in feedlot discharge and in river water. Water samples from the discharge caused a significant androgenic response in CV-1 cells and contained detectable concentrations of metabolites. Additional work to ascertain the degree to which synthetic androgens contribute to androgenic activity is needed.
Water Quality Affects Female Gambusia
Contamination of freshwater ecosystems with nitrate is a growing global concern. Although nitrate pollution is recognized as a cause of aquatic eutrophication, few studies have examined the possible physiological impacts of nitrate exposure. Edwards et al. (p. 69) surveyed several reproductive variables of viviparous female Gambusia holbrooki (Poeciliidae) captured from eight springs in Florida. The eight springs represent a gradient of nitrate contamination. The study provides evidence that maternal support of the embryo occurs at least during the first two-thirds of gestation and that female fecundity is affected by an apparent tradeoff between embryo size and embryo number.
Endocrine-Disrupting Chemicals and Arctic Climate Change
The effects of global change on biodiversity and ecosystems encompass complex dynamic processes. Climate change and exposure to endocrine-disrupting chemicals (EDCs) are regarded as two of the most serious anthropogenic threats to biodiversity and ecosystems. Jenssen (p. 76) expresses concern about the effects of EDCs on the ability of marine mammals and seabirds to adapt to environmental alterations caused by climate change. Even though behavioral and morphological effects of persistent organic pollutants are consistent with endocrine disruption, no direct evidence exists for such relationships.
Health Effects of Wastewater Treatment Works Effluent
Reproductive disorders may not necessarily arise as a result of estrogenic effects alone, and a better understanding of the relative importance of endocrine disruption in relation to other forms of toxicity is needed. Liney et al. (p. 81) report that genotoxic and immunotoxic effects occur at concentrations lower than those required to induce recognizable changes. Their findings emphasize the need for multiple end points for assessing the potential health effects and suggest that for some effluents, genotoxic and immune end points may be more sensitive than estrogenic end points.
Predicting Mixture Effects of Estrogens in Effluents
The effects of simple mixtures of chemicals, with similar mechanisms of action, can be predicted using the concentration addition model. The ability of this model to predict the estrogenic effects of more complex mixtures such as effluent discharges, however, has yet to be established. Thorpe et al. (p. 90) analyzed effluents from 43 U.K. wastewater treatment works (WwTW) for the presence of the principal estrogenic chemical contaminants estradiol, estrone, ethinylestradiol, and nonylphenol. The data support the use of bioassays for determining the estrogenic potency of WwTW effluents, and they highlight the associated problems for modeling approaches that are reliant on measured concentrations of estrogenic chemicals.
COMPRENDO--Comparative Research on Endocrine Disrupters
Because endocrine-disrupting chemicals (EDCs) can affect the body's signaling system in many ways, unraveling the mechanisms of action is difficult. A major concern of Schulte-Oehlmann et al. (p. 98) is that some EDCs are biologically active at extremely low concentrations. Evidence indicates that the guiding principle of traditional toxicology that "the dose makes the poison" may not always be the case. The European Union COMPRENDO Project aims to develop an understanding of potential health problems posed by androgen and antiandrogen-mimicking substances (AACs) by focusing on the commonalities and differences in responses to AACs across the animal kingdom.
Application of Ecotoxicogenomics to Endocrine Disruption
Developing organisms are particularly sensitive to estrogenic chemicals. Exposure to estrogens or estrogenic chemicals during critical periods of development induces persistent changes, including persistent molecular alterations, in both reproductive and nonreproductive organs, Toxicogenomics/ecotoxicogenomics, defined as the integration of genomics (transcriptomics, proteomics, metabolomics) into toxicology and ecotoxicology, are needed as powerful tools for research. Iguchi et al. (p. 101) are identifying estrogen-responsive genes in mouse reproductive tracts using cDNA microarrays and are trying to establish microarray systems in the American alligator, roach, medaka, and Daphnia magna.
Biomarkers as Signposts
Biomarkers are currently best used as mechanistic "signposts" rather than as "traffic lights" in the environmental risk assessment of endocrine-disrupting chemicals (EDCs) suggests Hutchinson et al. (p. 106). In field studies, biomarkers of exposure are powerful tools for tracking single substances and mixtures of concern and should be mechanistically relevant and reproducible. An established historical control database is needed to help differentiate between statistically detectable versus biologically significant responses. Environmental decision-making needs to move forward, and it is proposed that the "biomarkers-as-signposts" approach is a pragmatic way forward in the current risk assessment of EDCs.
Stickleback Antiandrogen Assay
Exposure to exogenous androgens causes female sticklebacks (Gasterosteus aculeatus) to produce the glue protein, spiggin, in their kidneys. This protein can be quantified by an enzyme-linked immunosorbent assay (ELISA). Katsiadaki et al. (p. 115) report the development of an in vivo test for the detection of environmental antiandrogens. The results provide the first evidence of in vivo antiandrogenic activity of both linuron and fenitrothion in teleosts. Although there are other suggested fish species that could be used for this purpose, the stickleback is the only widely available species in which it is now possible to study both estrogenic and antiandrogenic end points in the same individual.
Demographic Models with Endocrine Disruption
Gurney (p. 122) describes a series of strategic models of populations and individuals subject to challenge by endocrine disrupters. The models are not designed to be fitted to detailed data on specific species but rather to provide general insights on the relative importance of different demographic mechanisms in the population context. In many circumstances endocrine disruptors produces deleterious effects on female fecundity at levels far below those required to reduce male fertility. A simple model is formulated of individual energetics, which can form the basis of a discussion of the sensitivity of female demographic parameters to chemically induced changes in physiological function.
Bisphenol A Effects in Marisa Cornuarietis
Previous investigations have shown that bisphenol A (BPA) induces a superfeminization syndrome in the freshwater snail Marisa cornuarietis. Superfemales are characterized by the formation of additional female organs, enlarged accessory sex glands, gross malformations of the pallial oviduct, and a stimulation of egg and clutch production, all of which contribute to increased female mortality. Based on challenges of incomplete experimentation, Oehlmann et al. (p. 127) attempt to bridge several gaps in knowledge by conducting additional experiments. The results emphasize that prosobranchs are affected by BPA at lower concentrations than other wildlife groups. The findings also highlight the importance of exposure conditions.
Atrazine and Hermaphroditism
Atrazine is a potent endocrine disruptor that both chemically castrates and feminizes male amphibians. It depletes androgens in adult frogs and reduces androgen-dependent growth of the larynx in developing male larvae. It also disrupts normal gonadal development and feminizes the gonads of developing males. Hayes et al. (p. 134) describe the frequencies at which these malformations occur and compare them with morphologies induced by estrogens and androgens. The experimental findings suggest that atrazine-induced gonadal malformations result from the depletion of androgens and production of estrogens, perhaps subsequent to the induction of aromatase by atrazine, a mechanism established in fish, amphibians, reptiles, and mammals (rodents, and humans).
Protecting Wildlife from Endocrine Disruptors
Man-made endocrine-disrupting chemicals (EDCs) present a threat to biodiversity, even in remote areas. To date, numerous wildlife species have been affected by EDCs in the environment, but it is likely that many more species are suffering effects that have not yet been reported. Lyons (p. 142) reports that the World Wildlife Fund (WWF) considers that sufficient information is already available to merit action on several such substances. WWF maintains that any effect that could reasonably be expected to affect the population level should be taken forward in environmental risk characterization, in particular, behavioral effects should be given more consideration.
Environment Agency Assessment of Feminization of Male Fish
Gross-Sorokin et al. (p. 147) report that regulators grow increasingly concerned over the ability of substances discharged into the environment to disrupt the normal endocrine function of wildlife. In particular, the widespread feminization of male fish. United Kingdom and European data demonstrate that the occurrence is associated with effluent discharges, and the incidence and severity is positively correlated with the proportion of treated sewage in receiving waters. Based on the available information, the Environment Agency (England and Wales) has concluded that the weight of evidence for endocrine disruption in fish is sufficient to develop a risk management strategy for estrogenically active effluents that discharge to the aquatic environment.
Late Lessons from Early Warnings for Endocrine-Disrupting Substances
The histories of selected public and environmental hazards, from the first scientifically based early warnings about potential harm, to the subsequent precautionary and preventive measures, have been reviewed by the European Environment Agency. Gee (p. 152) relates the "late lessons" from these early warnings to the current debates on the application of the precautionary principle to the hazards posed by endocrine-disrupting substances (EDSs). Scientific methods need to reflect the realities of multicausality, mixtures, timing of dose, and system dynamics. This improved science could provide a more robust basis for the use of the precautionary principle in the assessment and management of the threats posed by EDSs.
