Hypospadias and endocrine disruption: is there a connection?

Hypospadias is one of the most common congenital anomalies in the United States, occurring in approximately 1 in 250 newborns or roughly 1 in 125 live male births. It is the result of arrested development of the urethra, foreskin, and ventral surface of the penis where the urethral opening may be anywhere along the shaft, within the scrotum, or in the perineum. The only treatment is surgery. Thus, prevention is imperative. To accomplish this, it is necessary to determine the etiology of hypospadias, the majority of which have been classified as idiopathic. In this paper we briefly describe the normal development of the male external genitalia and review the prevalence, etiology, risk factors, and epidemiology of hypospadias. The majority of hypospadias are believed to have a multifactorial etiology, although a small percentage do result from single gene mutations. Recent findings suggest that some hypospadias could be the result of disrupted gene expression. Discoveries about the antiandrogenic mechanisms of action of some contemporary-use chemicals have provided new knowledge about the organization and development of the urogenital system and may provide additional insight into the etiology of hypospadias and direction for prevention.

Significant effects of mild endogenous hormonal changes in humans: considerations for low-dose testing.

We review the significant and adverse health effects that can occur with relatively small endogenous hormonal changes in pubertal and adult humans. We discuss the effects of hormonal changes that occur within normal physiologic ranges--such as the rising levels of estrogen in peripuberty, which cause growth spurts at low levels and then the fusion of epiphyses at higher levels--and the hormonal variations during the menstrual cycle and their relation to genital phenotypic changes and intercurrent disease evolution. We turn next to adaptive changes in gonadal and other functions during aging, exercise, stress, starvation, and chronic diseases, which can serve as models for the effects of exogenous, hormonally active compounds. Then we review the states of borderline hormonal imbalances such as subclinical (having few or very mild symptoms, if any) hypothyroidism or hyperthyroidism, glucose intolerance, and other endocrine conditions. Finally, we review the deleterious systemic effects of gonadal imbalance. Information stemming from clinical observations leads to the concept of "no threshold" within the endocrine system and thus illustrates the importance of considering low-dose testing for chemicals that interfere with hormonal activity. We also urge attention to more sensitive, less visible end points such as osteoporosis, increased risk for cardiovascular disease, or cognitive changes.

Immunosuppression in mice fed on diets containing beluga whale blubber from the St Lawrence estuary and the Arctic populations.

In order to assess the immunotoxic potential of naturally relevant mixtures of PCBs and other organohalogens, C57Bl/6 mice were fed on diets in which lipids were replaced by blubber of beluga whales from the highly contaminated population of the Saint-Lawrence River, and the less contaminated population from the Arctic. Different ratios of blubber from both sources were mixed in order to allow a dose-response study. Mice were fed for a period of 90 days at the end of which their immunological status was monitored. For general parameters such as body weight, weight of the spleen and the thymus no significant effect of diets were observed. The immunological endpoints such as the blastic transformation of splenocytes and the spleen NK cell activity were not significantly affected by any of the diets compared to control diets. While the different cell subpopulations of peripheral blood and thymus were not affected by the diets, a significant decrease was noted in the CD8+ T cell population in the spleen of mice fed with most of the diets containing beluga blubber. Moreover, the ability of splenic cells to elicit humoral response against sheep red blood cells as well as the potential of peritoneal macrophages to perform phagocytosis were suppressed by all diets containing beluga blubbers. In summary, there was no differences between the groups fed with a blubber diet with low and high organochlorine contamination. However, a clear immunosuppression was demonstrated when these groups were compared to the group fed with beef oil. Despite the fact that we cannot exclude a possible contribution of the fatty acid composition of the beluga blubber to the immunosupression, these results suggest the sensitivity of mouse immune system towards organohalogens, and point out the toxic potential of contaminant mixtures as found in the less contaminated Arctic population.

Screening methods for thyroid hormone disruptors.

The U.S. Congress has passed legislation requiring the EPA to implement screening tests for identifying endocrine-disrupting chemicals. A series of workshops was sponsored by the EPA, the Chemical Manufacturers Association, and the World Wildlife Fund; one workshop focused on screens for chemicals that alter thyroid hormone function and homeostasis. Participants at this meeting identified and examined methods to detect alterations in thyroid hormone synthesis, transport, and catabolism. In addition, some methods to detect chemicals that bind to the thyroid hormone receptors acting as either agonists or antagonists were also identified. Screening methods used in mammals as well as other vertebrate classes were examined. There was a general consensus that all known chemicals which interfere with thyroid hormone function and homeostasis act by either inhibiting synthesis, altering serum transport proteins, or by increasing catabolism of thyroid hormones. There are no direct data to support the assertion that certain environmental chemicals bind and activate the thyroid hormone receptors; further research is indicated. In light of this, screening methods should reflect known mechanisms of action. Most methods examined, albeit useful for mechanistic studies, were thought to be too specific and therefore would not be applicable for broad-based screening. Determination of serum thyroid hormone concentrations following chemical exposure in rodents was thought to be a reasonable initial screen. Concurrent histologic evaluation of the thyroid would strengthen this screen. Similar methods in teleosts may be useful as screens, but would require indicators of tissue production of thyroid hormones. The use of tadpole metamorphosis as a screen may also be useful; however, this method requires validation and standardization prior to use as a broad-based screen.

Pesticide use in the U.S. and policy implications: a focus on herbicides.

This article examines herbicide use in the United States, providing estimates of poundage, land surface covered, distribution, and recent trends based on federal and state figures. Herbicides are by far the most widely used class of pesticide in the US, where 556 million lbs of herbicide active ingredients (AIs) were applied in 1995. Agriculture accounts for the majority of herbicide use, totaling 461 million lbs of AIs in 1995. Over 60% of the poundage of all agricultural herbicides consist of those that are capable of disrupting the endocrine and/or reproductive systems of animals. In addition, at least 17 types of 'inert ingredients,' which can equal 90% or more of a pesticide product, have been identified as having potential endocrine-disrupting effects. Atrazine is the predominant herbicide used according to poundage, with 68-73 million lbs of AIs applied in 1995. However, 2,4-D is the most widespread herbicide, covering 78 million acres for agricultural uses alone. Both of these herbicides are reported endocrine disruptors. Acetolactate synthase (ALS) inhibitors, namely the sulfonylureas and imidazolinones, are one of the fastest growing classes of herbicides. Many of these herbicides are 100 times more toxic to select plant species than their predecessors, so they can be applied at rates approximately 100 times lower. Consequently, they can affect plant species at concentration levels so low that no standard chemical protocol can detect them. Due in part to these more potent herbicides, the poundage of herbicides used in the US has decreased since the mid-1980s; however, the available data suggest that the number of treated acres has not significantly declined. A thorough assessment of potential exposure to herbicides by wildlife and humans is limited due to the inaccessibility of production and usage data.

Environmental neurotoxic effects: the search for new protocols in functional teratology.

Large quantities of a number of man-made chemicals with the potential to disrupt the developing endocrine and nervous systems in wildlife and humans have been released into the environment. These chemicals are particularly damaging during the embryonic, fetal, and early postnatal periods because they resemble or interfere with the hormones, neurotransmitters, growth factors, and other signaling substances that normally control development. The effects are in many cases irreversible and often are expressed as changes in function rather than as obvious birth defects or clinical diseases. Functional changes pose challenges in documenting the extent of the lesion, especially in the case of neuroendocrinological damage. In the past decade, researchers have added new dimensions to their research strategies in order to compensate for these difficulties. The new approaches reveal more about the extent of the distribution of and exposure to chemicals that interfere with the endocrine and nervous systems and strengthen the links between exposure and damage in developing wildlife and humans. Based on this new knowledge, opportunities abound for extensive multi-disciplinary research involving developmental neurotoxicity.

Epidemiological analysis of persistent organochlorine contaminants in cetaceans.

Information is provided to test the hypothesis that organochlorines introduced into the environment since the early 1940s could threaten the reproductive potential of baleen whales and other cetaceans. Comparisons are made using data on the role of organochlorines in a model system, the Great Lakes region of North America, and in model animals, including humans, pinnipeds, and other wildlife. DDT and PCB are used as model organochlorines with the caveat that there may be thousands of other chemicals in the environment also involved. Improved sensitivity in analytical quantification of synthetic chemicals in biological tissue has been accompanied by an increase in knowledge about biochemical processes that control development and function. The effects described in this review are the result of disrupted gene expression, not damage to the gene. The mechanisms of action of the organochlorines reveal their ability to affect developing organisms at very low concentrations during critical life stages: embryonic, fetal, and early postnatal. Exposure during early development can disrupt the organization of the endocrine, reproductive, immune and nervous systems, effecting irreversible damage that may not be expressed until the individuals reach adulthood. The recent discovery that human sperm count is declining worldwide at a rate of 1 x 10(6) sperm/(mL.yr) suggests common exposure to estrogen-like chemicals during prenatal and early postnatal development. This raises concern for other top predator species that also share the same exposure. Periods of intense feeding followed by long periods of fasting are common among species of baleen whales. This unique strategy places the embryonic and nursing calves in vulnerable positions, because under both situations maternal blood levels are elevated as a result of absorption from food intake or as a result of mobilization as fat is metabolized. Estimates of Toxic Equivalents (TEQs) based on the occurrence of four PCB congeners (118, 183, 153, 180) in sigma PCB reported in whales are highest for St. Lawrence belugas and Faroe Island long-finned pilot whales. This conservative approach reveals that some whale species are within the range of enzyme-induced TEQs at which effects have been associated with adverse health effects in other aquatic species. The epidemiological approach was used for analysis because it was developed to handle multiple exposure scenarios in which direct causal links are virtually impossible to isolate. The analysis includes the tenets of timeorder, strength of association, specificity of cause and effect, consistency, coherence, and predictive performance.

Pesticides--how research has succeeded and failed to translate science into policy: endocrinological effects on wildlife.

Toxicological research became institutionalized in the United States in response to society's concern about cancer and acute mortality. Driven by risk assessment, research focused on the need for data development and the standardization of testing for regulatory and management purposes in a reactive mode. Although the research community has provided evidence for over 40 years that a number of pesticides and industrial chemicals have disruptive effects on the endocrine system, little attention was given to the evidence when determining the health hazards of synthetic chemicals because of the fixation on cancer. However, recent findings concerning the effects of a number of widespread chemicals on the reproductive success and fertility of wildlife and humans has led to the call for a proactive approach using investigative research (forensic science). Suggestions are presented to modernize the research agenda of public health institutions to meet society's needs to address the problems of exposure to endocrine, nervous, and immune system disruptors.

The wildlife/human connection: modernizing risk decisions.

This article proposes that genetic and molecular ecotoxicology can play an important role in making policy and risk assessment decisions concerning xenobiotics. It calls for a greater awareness by ecotoxicologists to the effects in wildlife and humans resulting from transgenerational exposure to synthetic chemicals that interfere with gene expression and differentiation. The difficulty of recognizing these effects on the endocrine, immune, and nervous systems in developing embryos is described and suggests why effects of this nature have traditionally not been addressed when determining risk to synthetic chemicals. Specific examples are cited of environmental effects on hormonally responsive tissue in wildlife populations which could be used as models for assessing human exposure to synthetic chemicals. Evidence is presented that the environmental load of synthetic chemicals has reached critical levels at which wildlife and human health are at risk.

Developmental effects of endocrine-disrupting chemicals in wildlife and humans.

Large numbers and large quantities of endocrine-disrupting chemicals have been released into the environment since World War II. Many of these chemicals can disturb development of the endocrine system and of the organs that respond to endocrine signals in organisms indirectly exposed during prenatal and/or early postnatal life; effects of exposure during development are permanent and irreversible. The risk to the developing organism can also stem from direct exposure of the offspring after birth or hatching. In addition, transgenerational exposure can result from the exposure of the mother to a chemical at any time throughout her life before producing offspring due to persistence of endocrine-disrupting chemicals in body fat, which is mobilized during egg laying or pregnancy and lactation. Mechanisms underlying the disruption of the development of vital systems, such as the endocrine, reproductive, and immune systems, are discussed with reference to wildlife, laboratory animals, and humans.

Epidemiology of Great Lakes bald eagles.

Historical data are provided to support the hypothesis that organochlorine chemicals introduced into the Great Lakes ecosystem following World War II are the cause of reproductive loss among bald eagles (Haliaeetus leucocephalus) in the basin. This is supported with data on concurrent population fluxes of extrabasin North American bald eagle populations and the European white-tailed sea eagle (Haliaeetus albicillus) where the same chemicals were produced and released. Organochlorine chemicals appear as a unique stress on Great Lakes bald eagle populations when compared with stresses on successful populations of bald eagles continentwide. Shoreline birds bear significantly higher concentrations of these persistent toxics than inland birds. Association between contaminated prey and elevated concentrations of PCBs, DDT, and DDE in Great Lakes bald eagles are presented. A fledging ratio is used to support the hypothesis that maternal prezygotic exposure affects the viability of embryos and chicks. The ratio of the mean number of fledglings per successful territory to the mean number of fledglings per active territory, when the numerator is greater than 1.4, provides an index of exposure to contaminants by parental animals and affected offspring. When the ratio is greater than 2, parental exposure to organochlorine chemicals should be considered. The adverse effects of prezygotic exposure to the same contaminants in other animal species dependent upon Great Lakes fish, and extrabasin bald eagle populations dependent upon contaminated fish, provide consistency to the argument. The mechanism of action of the organochlorine chemicals further strengthens the causal argument indicting DDT, DDE, and PCBs. A strong association between DDT/DDE and bald eagle reproductive success is provided. However, the role of PCBs is not ruled out. Only data for total PCB concentrations in bald eagle tissue are available, and until specific PCB congeners are quantified there will be uncertainty concerning PCB's role in the Great Lakes bald eagle's lack of success.