Field Of Endocrine Disruption Research Articles

From Wingspread to CLARITY: a personal trajectory.

In the three decades since endocrine disruption was conceptualized at the Wingspread Conference, we have witnessed the growth of this multidisciplinary field and the accumulation of evidence showing the deleterious health effects of endocrine-disrupting chemicals. It is only within the past decade that, albeit slowly, some changes regarding regulatory measures have taken place. In this Perspective, we address some historical points regarding the advent of the endocrine disruption field and the conceptual changes that endocrine disruption brought about. We also provide our personal recollection of the events triggered by our serendipitous discovery of oestrogenic activity in plastic, a founder event in the field of endocrine disruption. This recollection ends with the CLARITY study as an example of a discordance between 'science for its own sake' and 'regulatory science' and leads us to offer a perspective that could be summarized by the motto attributed to Ludwig Boltzmann: "Nothing is more practical than a good theory".

Perinatal exposure to Bisphenol A disturbs the early differentiation of male germ cells

Understanding the effects of Bisphenol A (BPA) on early germ cell differentiation and their consequences in adult life is an area of growing interest in the field of endocrine disruption. Herein, we investigate whether perinatal exposure to BPA affects the differentiation of male germ cells in early life using a transgenic mouse expressing the GFP reporter protein under the Oct4 promoter. In this model, the expression of GFP reflects the expression of the Oct4 gene. This pluripotency gene is required to maintain the spermatogonial stem cells in an undifferentiated stage. Thus, GFP expression was used as a parameter to evaluate the effect of BPA on early germ cell development. Female pregnant transgenic mice were exposed to BPA by oral gavage, from embryonic day 5.5 to postnatal day 7 (PND7). The effects of BPA on male germ cell differentiation were evaluated at PND7, while sperm quality, testicular morphology, and protein expression of androgen receptor and proliferating cell nuclear antigen were studied at PND130.We found that perinatal/lactational exposure to BPA up-regulates the expression of Oct4-driven GFP in testicular cells at PND7. This finding suggests a higher proportion of undifferentiated spermatogonia in BPA-treated animals compared with non-exposed mice. Moreover, in adulthood, the number of spermatozoa per epididymis was reduced in those animals perinatally exposed to BPA.This work shows that developmental exposure to BPA disturbed the normal differentiation of male germ cells early in life, mainly by altering the expression of Oct4 and exerted long-lasting sequelae at the adult stage, affecting sperm count and testis.

Plastic bodies in a plastic world: multi-disciplinary approaches to study endocrine disrupting chemicals

In the 1950's and 60's, there was significant development of synthetic materials for use in consumer products. Plastics of all kinds were produced and have since been incorporated into countless materials. Producers of these chemicals and materials have assumed that they would not have effects on humans or wildlife if exposures remained low. Yet evidence from field studies, controlled laboratory animal experiments and epidemiology has challenged this assumption. Many compounds used in plastics have been characterized as endocrine disrupting chemicals (EDCs), chemicals that interfere with the proper functioning of the endocrine system. EDCs present new challenges to both the industries that produce chemicals and manufacture consumer products, as well as the agencies that are tasked to protect public health. This review will address the issue of developmental plasticity – the concept that developing organisms can adapt to various environmental insults to allow the individual to survive. Studies of EDCs have revealed that developing organisms have tremendous capacity to adapt, but not without significant costs to the individual. We will also address recent efforts by environmental health scientists and green chemists to work collaboratively to solve some of the biggest problems in the field of endocrine disruption. We argue that the use of 21st Century tools and sustainability frameworks will help to avoid ‘regrettable replacements’ and provide society with workable solutions to the issue of endocrine disruption. Further, we conclude that a truly sustainable future demands that exposures to EDCs should be eliminated whenever possible.

AB0681 Bisphenol A Levels in Patients with Ankylosing Spondylitis and Its Correlation with Disease Activity

BackgroundAnkylosing spondilitis (AS) is a systemic chronic inflammatory disorder of unidentified etiology. Bisphenol A (BPA) which act as a protective lining on the inside of metal-based food and beverage cans,...

17α-Ethinylestradiol and nonylphenol affect the development of forebrain GnRH neurons through an estrogen receptors-dependent pathway

There is growing evidence that neuroendocrine circuits controlling development and reproduction are targeted by EDCs. We have previously demonstrated that low concentrations of 17α-ethinylestradiol (EE2) disrupt the development of forebrain GnRH neurons during zebrafish development. The objectives of the present study were to determine whether the weak estrogenic compound, nonylphenol (NP), could elicit similar effects to EE2 and to what extent the estrogen receptors are involved in mediating these effects. Using immunohistochemistry, we confirmed that EE2 exposure induces an increase in the number of GnRH-ir neurons and we demonstrated that NP is able to produce similar effects in a concentration-dependent manner. The effects of both NP and EE2 were shown to be blocked by the estrogen receptors (ERs) antagonist ICI 182-780, demonstrating the involvement of functional ERs in mediating their effects.Altogether, these results highlight the need to consider neuroendocrine networks as critical endpoints in the field of endocrine disruption.

Bisphenol-A and the great divide: a review of controversies in the field of endocrine disruption.

In 1991, a group of 21 scientists gathered at the Wingspread Conference Center to discuss evidence of developmental alterations observed in wildlife populations after chemical exposures. There, the term "endocrine disruptor" was agreed upon to describe a class of chemicals including those that act as agonists and antagonists of the estrogen receptors (ERs), androgen receptor, thyroid hormone receptor, and others. This definition has since evolved, and the field has grown to encompass hundreds of chemicals. Despite significant advances in the study of endocrine disruptors, several controversies have sprung up and continue, including the debate over the existence of nonmonotonic dose response curves, the mechanisms of low-dose effects, and the importance of considering critical periods of exposure in experimental design. One chemical found ubiquitously in our environment, bisphenol-A (BPA), has received a tremendous amount of attention from research scientists, government panels, and the popular press. In this review, we have covered the above-mentioned controversies plus six additional issues that have divided scientists in the field of BPA research, namely: 1) mechanisms of BPA action; 2) levels of human exposure; 3) routes of human exposure; 4) pharmacokinetic models of BPA metabolism; 5) effects of BPA on exposed animals; and 6) links between BPA and cancer. Understanding these topics is essential for educating the public and medical professionals about potential risks associated with developmental exposure to BPA and other endocrine disruptors, the design of rigorously researched programs using both epidemiological and animal studies, and ultimately the development of a sound public health policy.

Environmental Review: Trenbolone and Other Cattle Growth Promoters: Need for a New Risk-Assessment Framework

The “six-pack” of hormone growth promoters used in feedlot cattle deserves closer investigation from researchers and policy makers. The potential effects of exposure to such compounds are of particular interest in the field of endocrine disruption, which focuses on the effects these compounds can have during sensitive developmental periods, rather than using a carcinogenesis model. Steroid hormones participate in a delicate balance during fetal development. Interference with that balance can lead to disruptions that manifest as health problems at birth and later in life. Although we need more studies of the effects of feedlot compounds on human and wildlife development, some industry and government literature leads consumers to conclude that all the data are in. Governmental reviews of the literature from the European Union (where hormone use is banned) and Australia (where hormones are used) reveal different attitudes and conclusions about the same body of research, and these differences may relate to a different understanding of the value of the endocrine-disruption model. It is important to approach examinations of the effects of trenbolone and other growth promoters without bias and to acknowledge that cattle growth promoter research in the context of endocrine disruption has just begun. The scientific jury is still out regarding whether introducing these compounds into the human food supply and ecosystems—research suggests that hormonally active feedlot effluent may harm wildlife—can be deleterious.

Endocrine Disrupters in the Aquatic Environment: An Overview

Although a relatively new area of environmental research, the field of endocrine disruption has grown very rapidly, and currently many hundreds, perhaps even a few thousand, papers are published annually on the many different aspects covered by the field. As far as endocrine disruption in wildlife is concerned, most attention has been focused on aquatic organisms, for two reasons. Firstly, the aquatic environment receives most of the pollutants intentionally released into the environment, through effluents from wastewater treatment plants, and secondly because many of the best documented examples of endocrine disruption in wildlife are of partially or completely aquatic species. These two reasons are probably not unconnected, of course. Hence, aquatic organisms can receive continuous exposure to endocrine-disrupting chemicals throughout their lives, albeit usually to low concentrations of these chemicals. Analysis of effluents has identified many of the endocrine-disrupting chemicals present, and shown that these are both natural and man-made, and vary greatly in potency. Most attention has been directed to identifying the main estrogenic chemicals, because many of the effects reported in wildlife appear to be a consequence of ‘feminization’ of males. However, chemical analysis of effluents has also demonstrated that chemicals with other types of endocrine activity are present, such as androgens, anti-androgens, progestagens, etc. The effects (if any, of course) of such chemicals on aquatic organisms are unknown, and largely uninvestigated, presently. Much of the biological research has centred on the effects of estrogenic chemicals, especially to fish. These effects, such as elevated vitellogenin concentrations and intersexuality, have to date been studied almost exclusively at the level of the individual, and hence whether endocrine-disrupting chemicals cause population-level consequences is largely unknown (the undeniable effects of TBT on molluscs, leading to local extinctions, being the exception). It is my opinion that rather too much of the recent research has not advanced our understanding of endocrine disruption a great deal, and we are probably not much further forward now than we were five years or so ago. It is surely time to tackle some of the outstanding, unresolved issues, such as the impact of endocrine disruption at the population level, and the issue of how organisms respond when exposed to complex mixtures of endocrine active chemicals. Such research will not be easy, and will require multidisciplinary teams, including people with expertise in areas not yet involved in the field of endocrine disruption, such as mathematical modellers. However, until such research is done, it will not be possible to decide how important an issue endocrine disruption is to wildlife, and how that importance compares to the other factors adversely affecting wildlife, such as habitat loss, climate change, and the introduction of exotic species and novel diseases.

The Study of Endocrine-Disrupting Compounds: Past Approaches and New Directions

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.

Endocrine disruption in marine fish

This topic reviews the whole field of endocrine disruption (ED) in marine fish and compares this with our knowledge of the situation in freshwater species. In broad terms, similar types of ED have been observed in the two groups, although effects in the marine environment tend to be less marked, presumably due to dispersion and dilution. There are, however, some data which suggest that marine fish that are top-predators can experience ED due to biomagnification of organochlorines. Processes such as smoltification, metamorphosis, and hermaphroditism, which are common in some marine species, may be particularly susceptible to ED, but have as yet been scarcely studied. As with freshwater fish, firm links to population-level effects have not yet been demonstrated, although it is not unreasonable to suppose that they are occurring in some locations. The topic concludes with some recommendations for future research.

4- n-Nonylphenol and 17-β estradiol may induce common DNA effects in developing barnacle larvae

There is a growing concern over the potential effects of environmental endocrine disrupters on both human and wildlife populations. However, to date, minimal research has been conducted to determine the effect of estrogens and xenoestrogens at the DNA level. In this study, we used the random amplified polymorphic DNA (RAPD) assay to evaluate the effects on the genomic DNA of barnacle larvae that had been exposed to 17β-estradiol (E 2) and low concentrations of 4- n-nonylphenol (NP). DNA effects include DNA damage as well as mutations and possibly other effects at the DNA level that can be induced by chemical or physical agents that directly and/or indirectly interact with genomic DNA. Not only did exposure to NP and E 2 induce changes in RAPD profiles in the exposed barnacle larvae when compared to control patterns, but also, and more importantly, there were similarities in the RAPD modifications in the exposed populations that had been treated to either chemical. We propose that NP and E 2 induced some common DNA effects in barnacle larvae and that these specific modifications in RAPD patterns may arise as a consequence of hot spot DNA damage (e.g. DNA adducts) and/or mutations (point mutations or genomic rearrangements). This could help to explain how xenoestrogens mimic the effects produced by natural estrogens. In conclusion, in the field of endocrine disruption, the study of DNA effects induced by estrogens and/or xenoestrogens warrants further investigation. Indeed, changes at the DNA level may be the precursors of some of the numerous effects reported at higher levels of biological organisation such as the feminization of males, developmental abnormalities, and infertility.

Possible androgenic/anti-androgenic activity of the insecticide fenitrothion.

To date, within the field of endocrine disruption, much focus has been placed on chemicals that mimic oestrogens (so-called xenoestrogens), and the number of such chemicals apparently detected continues to grow steadily. Less effort has been expended on investigating chemicals that mimic, or antagonize, other hormones. Nevertheless, a number of chemicals have been reported to have a weak affinity for the androgen receptor, all of which have, to date, been found to have anti-androgenic activity in vivo. In this report, we present evidence that the insecticide fenitrothion can interact with the androgen, but not with the oestrogen, receptor. Using recombinant yeast expressing the human androgen receptor, we found that fenitrothion behaved as an androgen agonist in vitro when tested alone, and that it could antagonize the androgen DHT when both chemicals competed for the androgen receptor in vitro. In vivo studies using both intact and castrated male rats showed no conclusive androgenic or anti-androgenic responses. Changes in organ weights suggestive of anti-androgenic effects were mitigated against by the reduced body weights of fenitrothion-treated rats. The toxicity of the compound precluded the use of higher dose levels to substantiate any tentative findings. Interestingly, fenitrothion (and related insecticides) is structurally similar to flutamide, an anti-androgen used clinically that gives clearly positive responses in both intact and castrated rats.