Steroid Hormones and Endocrine Disruptors: Recent Advances in Receptor–Mediated Actions

It has been accepted that receptor-mediated action of steroid hormones depends on both the receptor and the hormonal level. The mechanism of transcription by steroid receptors is mediated by cofactors, which function as co-activators or co-repressors, while their non-genomic actions depend on receptors localized to the cell membrane. Recently, a number of environmental chemicals, which are now termed as endocrine disruptors, have been identified, and their unwanted effects on our lives have become serious problems all over the world. Their adverse effects on endocrine systems in animals, mostly estrogenic or anti-estrogenic, have resulted in reproductive malfunction and developmental disorders. Although aryl hydrocarbons exhibit estrogenic or anti- estrogenic activity through specific interaction with aryl hydrocarbon receptors, other chemicals seem to interact directly with estrogen receptors, α and β forms. In this paper, we surveyed the most recent understanding of endocrine disruptors from the viewpoint of steroid receptor systems. We suggest two potential mechanisms of action for endocrine disruptors. Endocrine distruptors i) directly associate with steroid receptor systems and/or ii) associate with the growth factor or the neurotransmitter receptor systems, and then upregulate the mitogen-activated protein kinase signaling cascades, leading to the ligand-independent activation of steroid receptor systems. Using these steroid receptor-dependent mechanisms, it appears that endocrine disruptors disorder our endocrine systems. We have proposed future suggestions to further understand endocrine disruptors from the viewpoint of steroid receptor systems. Key words: endocrine disruptors; receptor-mediated actions; steroid hormone

Steroid Hormones and Endocrine Disruptors: Recent Advances in Receptor–Mediated Actions

It has been accepted that receptor-mediated action of steroid hormones depends on both the receptor and the hormonal level. The mechanism of transcription by steroid receptors is mediated by cofactors, which function as co-activators or co-repressors, while their non-genomic actions depend on receptors localized to the cell membrane. Recently, a number of environmental chemicals, which are now termed as endocrine disruptors, have been identified, and their unwanted effects on our lives have become serious problems all over the world. Their adverse effects on endocrine systems in animals, mostly estrogenic or anti-estrogenic, have resulted in reproductive malfunction and developmental disorders. Although aryl hydrocarbons exhibit estrogenic or anti- estrogenic activity through specific interaction with aryl hydrocarbon receptors, other chemicals seem to interact directly with estrogen receptors, α and β forms. In this paper, we surveyed the most recent understanding of endocrine disruptors from the viewpoint of steroid receptor systems. We suggest two potential mechanisms of action for endocrine disruptors. Endocrine distruptors i) directly associate with steroid receptor systems and/or ii) associate with the growth factor or the neurotransmitter receptor systems, and then upregulate the mitogen-activated protein kinase signaling cascades, leading to the ligand-independent activation of steroid receptor systems. Using these steroid receptor-dependent mechanisms, it appears that endocrine disruptors disorder our endocrine systems. We have proposed future suggestions to further understand endocrine disruptors from the viewpoint of steroid receptor systems. Key words: endocrine disruptors; receptor-mediated actions; steroid hormone

Endocrine disruptors in bottled mineral water : total estrogenic burden and migration from plastic bottles

Background, aim, and scope Food consumption is an important route of human exposure to endocrine-disrupting chemicals. So far, this has been demonstrated by exposure modeling or analytical identification of single substances in foodstuff (e.g., phthalates) and human body fluids (e.g., urine and blood). Since the research in this field is focused on few chemicals (and thus missing mixture effects), the overall contamination of edibles with xenohormones is largely unknown. The aim of this study was to assess the integrated estrogenic burden of bottled mineral water as model foodstuff and to characterize the potential sources of the estrogenic contamination. Materials, methods, and results In the present study, we analyzed commercially available mineral water in an in vitro system with the human estrogen receptor alpha and detected estrogenic contamination in 60% of all samples with a maximum activity equivalent to 75.2 ng/l of the natural sex hormone 17beta-estradiol. Furthermore, breeding of the molluskan model Potamopyrgus antipodarum in water bottles made of glass and plastic [polyethylene terephthalate (PET)] resulted in an increased reproductive output of snails cultured in PET bottles. This provides first evidence that substances leaching from plastic food packaging materials act as functional estrogens in vivo. Discussion and conclusions Our results demonstrate a widespread contamination of mineral water with xenoestrogens that partly originates from compounds leaching from the plastic packaging material. These substances possess potent estrogenic activity in vivo in a molluskan sentinel. Overall, the results indicate that a broader range of foodstuff may be contaminated with endocrine disruptors when packed in plastics. Keywords Endocrine disrupting chemicals - Estradiol equivalents - Human exposure - In vitro effects - In vivo effects - Mineral water - Plastic bottles - Plastic packaging - Polyethylene terephthalate - Potamopyrgus antipodarum - Yeast estrogen screen - Xenoestrogen

Exposure to polybrominated diphenyl ethers (PBDEs) suppresses the release of pro-inflammatory products by alveolar macrophages in vitro

Endocrine disrupting chemicals have adverse effects on immune function that may result in respiratory conditions. Inhalation of dust is a major route of exposure to PBDEs; however, the impact of PBDEs on the immune response is unclear. The objective of this in vitro study was to determine the impact of PBDEs on the release of pro-inflammatory cytokines by activated alveolar macrophages. Porcine alveolar macrophages were grown in RPMI growth media supplemented with 10% porcine serum and incubated for 24-hours. After 24-hours, cells were activated by inoculation with PMA. In addition to PMA, different concentrations of the PBDE mixture DE-71 were introduced to the wells. After 6-hour incubation, conditioned media was removed and analyzed. Cells exposed to PMA and PBDEs released significantly less pro-inflammatory cytokines compared to controls. Suppression of pro-inflammatory cytokines---characteristic of a compromised immune system---suggests that persistent exposure to PBDEs may increase the susceptibility to respiratory conditions

New approaches for estimating risk from exposure to diethylstilbestrol.

A subgroup from a National Institute of Environmental Health Sciences, workshop concerned with characterizing the effects of endocrine disruptors on human health at environmental exposure levels considered the question, If diethylstilbestrol (DES) were introduced into the market for human use today and likely to result in low-dose exposure of the human fetus, what would be required to assess risk? On the basis of an analysis of the quality of data on human DES exposure, the critical times and doses for inducing genital tract malformations and cancer must be determined. This would be facilitated through analysis of the ontogeny of estrogen receptor expression in the developing human genital tract. Models of low-dose estrogenic effects will have to be developed for human and rodent genital tract development. Mouse models offer many advantages over other potential animal models because of the wealth of the earlier literature, the availability of sensitive end points, the availability of mutant lines, and the possibility of generating genetically engineered model systems. Through multidisciplinary approaches, it should be possible to elucidate the cellular and molecular mechanisms of endocrine disruption elicited by estrogens during development and facilitate an assessment of risk to humans

Dining Cryptographers with 0.924 Verifiable Collision Resolution

The dining cryptographers protocol implements a multiple access channel in which senders and recipients are anonymous. A problem is that a malicious participant can disrupt communication by deliberately creating collisions. We propose a computationally secure dining cryptographers protocol with collision resolution that achieves a maximum stable throughput of 0.924 messages per round and which allows to easily detect disruptors.Comment: 11 pages, 3 figure

Conclusions of the French Food Safety Agency on the toxicity of bisphenol A

Since more than 10 years, risk assessment of bisphenol A (BPA) is debated at the international level. In 2008, the U.S. National Toxicology Program (NTP) expressed some concern for adverse effects, at current level of exposure to BPA, on developmental toxicity. In this context, the French Food Safety Agency (AFSSA) decided to review the toxicity data on BPA with a special focus on this endpoint at doses below 5mg/kg bw/day (the no observed adverse effect level set by different regulatory bodies). This paper summarizes the conclusions of a collective assessment conducted by an expert Working Group from AFSSA. Studies were classified into 3 groups: (i) finding no toxicity, (ii) reporting results not considered to be of concern and (iii) indicating warning signals. The term "warning signal" means that no formal conclusion can be drawn regarding the establishment of a health based guidance value but the study raises some questions about the toxicity of BPA at low doses. It was concluded that studies are needed to ascertain the significance for human health of these warning signals and to be able to propose new methodologies for assessing the risks associated with low doses of BPA and more generally of endocrine disruptors

Assessing the carcinogenic potential of low-dose exposures to chemical mixtures in the environment: the challenge ahead.

Lifestyle factors are responsible for a considerable portion of cancer incidence worldwide, but credible estimates from the World Health Organization and the International Agency for Research on Cancer (IARC) suggest that the fraction of cancers attributable to toxic environmental exposures is between 7% and 19%. To explore the hypothesis that low-dose exposures to mixtures of chemicals in the environment may be combining to contribute to environmental carcinogenesis, we reviewed 11 hallmark phenotypes of cancer, multiple priority target sites for disruption in each area and prototypical chemical disruptors for all targets, this included dose-response characterizations, evidence of low-dose effects and cross-hallmark effects for all targets and chemicals. In total, 85 examples of chemicals were reviewed for actions on key pathways/mechanisms related to carcinogenesis. Only 15% (13/85) were found to have evidence of a dose-response threshold, whereas 59% (50/85) exerted low-dose effects. No dose-response information was found for the remaining 26% (22/85). Our analysis suggests that the cumulative effects of individual (non-carcinogenic) chemicals acting on different pathways, and a variety of related systems, organs, tissues and cells could plausibly conspire to produce carcinogenic synergies. Additional basic research on carcinogenesis and research focused on low-dose effects of chemical mixtures needs to be rigorously pursued before the merits of this hypothesis can be further advanced. However, the structure of the World Health Organization International Programme on Chemical Safety 'Mode of Action' framework should be revisited as it has inherent weaknesses that are not fully aligned with our current understanding of cancer biology

COMPRENDO: Focus and approach

Tens of thousands of man-made chemicals are in regular use and discharged into the environment. Many of them are known to interfere with the hormonal systems in humans and wildlife. Given the complexity of endocrine systems, there are many ways in which endocrine-disrupting chemicals (EDCs) can affect the body’s signaling system, and this makes unraveling the mechanisms of action of these chemicals difficult. A major concern is that some of these EDCs appear to be biologically active at extremely low concentrations. There is growing evidence to indicate that the guiding principle of traditional toxicology that “the dose makes the poison” may not always be the case because some EDCs do not induce the classical dose–response relationships. The European Union project COMPRENDO (Comparative Research on Endocrine Disrupters—Phylogenetic Approach and Common Principles focussing on Androgenic/Antiandrogenic Compounds) therefore aims to develop an understanding of potential health problems posed by androgenic and antiandrogenic compounds (AACs) to wildlife and humans by focusing on the commonalities and differences in responses to AACs across the animal kingdom (from invertebrates to vertebrates)

Effect of age and cytoskeletal elements on the indentation-dependent mechanical properties of chondrocytes.

Articular cartilage chondrocytes are responsible for the synthesis, maintenance, and turnover of the extracellular matrix, metabolic processes that contribute to the mechanical properties of these cells. Here, we systematically evaluated the effect of age and cytoskeletal disruptors on the mechanical properties of chondrocytes as a function of deformation. We quantified the indentation-dependent mechanical properties of chondrocytes isolated from neonatal (1-day), adult (5-year) and geriatric (12-year) bovine knees using atomic force microscopy (AFM). We also measured the contribution of the actin and intermediate filaments to the indentation-dependent mechanical properties of chondrocytes. By integrating AFM with confocal fluorescent microscopy, we monitored cytoskeletal and biomechanical deformation in transgenic cells (GFP-vimentin and mCherry-actin) under compression. We found that the elastic modulus of chondrocytes in all age groups decreased with increased indentation (15-2000 nm). The elastic modulus of adult chondrocytes was significantly greater than neonatal cells at indentations greater than 500 nm. Viscoelastic moduli (instantaneous and equilibrium) were comparable in all age groups examined; however, the intrinsic viscosity was lower in geriatric chondrocytes than neonatal. Disrupting the actin or the intermediate filament structures altered the mechanical properties of chondrocytes by decreasing the elastic modulus and viscoelastic properties, resulting in a dramatic loss of indentation-dependent response with treatment. Actin and vimentin cytoskeletal structures were monitored using confocal fluorescent microscopy in transgenic cells treated with disruptors, and both treatments had a profound disruptive effect on the actin filaments. Here we show that disrupting the structure of intermediate filaments indirectly altered the configuration of the actin cytoskeleton. These findings underscore the importance of the cytoskeletal elements in the overall mechanical response of chondrocytes, indicating that intermediate filament integrity is key to the non-linear elastic properties of chondrocytes. This study improves our understanding of the mechanical properties of articular cartilage at the single cell level