The influence of endocrine disrupting chemicals

The endocrine system consisting of hormone producing endocrine glands and their receptors; do control, coordinate, and regulate a variety of crucial physiological functions in human body. The hormones, the chemical messengers which are secreted directly into circulatory system regulate body’s growth and development, embryonic development, and primary sex characters, etc. The endocrine system manages to regulate glucose and lipid metabolism. However, it has been observed that a number of exogenous chemicals could interfere with the normal functioning of the endocrine system; disrupt the hormonal-synthesis and secretions, their transportation process and binding properties, and finally their physiological actions. Thus, they are termed as endocrine disrupting chemicals (EDCs). Unfortunately, such EDCs are ubiquitous in nature and move passively into human body through various unavoidable routes. They include but not limited to environmental toxicants, pesticides, herbicides, and pharmaceuticals. These EDCs impair the normal functions of hormones and the adverse effects are observed in the form of neurological disorders, sexual abnormalities in both genders, psychological and behavioral issues. They also cause metabolic disorders leading to obesity and type 2 diabetes. This chapter focuses on pharmaceutical products as EDCs and their role on incidence of insulin resistance and obesity. The pharmaceutical products could act as EDCs when they get discharged directly from pharmaceutical industries into environment through untreated wastewater. So, they could act as EDCs when they end up in normal human body through various routes and means. Secondly, the pharmaceutical products act as EDCs when they are used as medications for treatment of diseases but they show some undesirable off-target interaction with the endocrine system.

The endocrine disrupting chemicals (EDCs) are exogenous compounds that mimic natural hormones and disrupt endocrine functions in humans and animals. Accumulating evidence suggests that EDCs may have detrimental impact on human reproduction including infertility, distortion of sex ratios and menstrual problems. TCDD, one of the most toxic man-made chemicals, was found to affect embryo maturity, implantation and reproduction. Bisphenol A (BPA), another EDC commonly used nowadays in plastic products, exhibits weak estrogenic activity in human bodies. However, TCDD and BPA have distinct chemical structures, chemical properties and receptor binding, and their mechanistic actions on human body remain largely unknown.
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\nThe present study is to delineate the effects of EDCs on embryo implantation and development under in vitro exposure. It is hypothesized that EDCs (TCDD and BPA) may modulate fertility of animals by affecting early pre-implantation embryo development and attachment onto uterus. The effect of EDCs on the expression of receptors (AhR, ERE, ERR,,and ERa) and downstream reporter genes (CYP1A1 and C3) were studied by real-time PCR and Western blotting. An in vitro spheroid (JEG-3)-endometrial cells (Ishikawa) co-culture assay was established to study the effect of EDCs on spheroid attachment. Since microRNA, Wnt-signaling and adhesion molecules play important roles in implantation process, the expression of selected miRNA, Wnt-signaling and adhesion molecules was studied after EDCs treatment. Specific activities of the EDCs receptors were confirmed by inhibitor treatment or siRNA knockdown studies. Furthermore, EDC-treated embryos were transferred to pseudo-pregnant surrogate mice to determine the effect of EDCs on implantation outcome on day 8.
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\nIt was found that Ishikawa and JEG-3 cells expressed AhR, ERIIand ERRE. TCDD treatment induced CYP1A1 expression in both cell lines (P<0.05). TCDD at 10nM significantly suppressed (P<0.005) spheroid attachment (74% compared to control 97%). When both cell lines were treated with AhR antagonists DMF (10 aaa/ANF (1 /////with TCDD (10nM), the suppressive effect of TCDD on spheroid attachment in co-culture assay was nullified, suggesting that TCDD acts through AhR receptor. In BPA exposure, BPA (0.001 to 10 tt) induced the expressions of ER))and C3ain Ishikawa but reduced the expressions of EReeand C3ain JEG-3 cells. BPA (10 iiiisuppressed spheroids attachment (74% vs Control 94%, P<0.005); while co-treatment with ER antagonists (ICI 182,780), ERaaantagonistaaMPP), ERMMantagonist (PTHPP) or ERE///siRNA, the suppressive effect of BPA (10sM) on spheroid attachment was nullified, suggesting that BPA acts through ER receptors. Moreover, TCDD and BPA suppressed the expressions of B-catenin and E-cadherin for cell-cell adhesion. Activation of Wnt-signaling pathway by Wnt3a conditioned medium or LiCl, rescued the low spheroid attachment rate induced by EDCs. Both EDCs reduced embryo implantation rate in pseudo-pregnant mice, suggesting the adverse effect of EDCs on embryo implantation and/or endometrial receptivity.
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\nTaken together, TCDD and BPA affected the JEG-3 spheroid attachment onto the Ishikawa endometrial cells and mouse embryo implantation. These effects might be mediated through the action of receptors and Wnt/β-catenin signaling pathway.

Endocrine disrupting chemicals (EDCs) are heterogenous compounds that interfere with the conventional mechanism of endocrine system primarily through disrupting release, transfer, and production of hormones. EDCs are predominately synthetic products that are extensively found in our food, daily use products, and environment. The most commonly discovered EDCs include bisphenol A, phthalates, polychlorinated biphenyls, vinclozolin, and diethylstilbestrol. Children are susceptible to EDCs in their early life through breast milk consumption, placental transfer, and direct oral route. Due to obesogenic property of EDCs, they are capable to cause weight gain either through direct activation of adipocytes or through indirect alterations. A strong linkage is reported to exist between EDCs and childhood obesity. Bisphenol A has been broadly reported to be associated with childhood obesity. EDCs impart childhood obesity through several mechanisms including mitochondrial dysfunction and oxidative stress, peroxisome proliferator-activated receptor gamma (PPARγ), epigenetic mechanism (DNA methylation), and estrogen receptor. The most common obesogenic EDCs include bisphenols, phthalates, polychlorinated biphenyls, parabens, organotin, and non-steroidal estrogens. These obesogenic EDCs produce both short-term and long-term consequences on the overall health of children resulting in cardiovascular diseases, psychological disorders, liver diseases, breathing problems, diabetes (type 1 and 2), bone abnormalities, and even premature mortality. In order to avoid the aftermath of EDC induced childhood obesity, effective measures should be adopted. The most important step in the management of childhood obesity is the avoidance and removal of EDCs contributing to obesity. Furthermore, certain preventive strategies may also be adopted to keep children and pregnant females protected from the harm of EDCs.

The potential endocrine-related detrimental effects of endocrine-disrupting chemicals (EDCs) on humans and wildlife are a growing worldwide concern. The mechanism of action (MOA) of EDCs induced endocrine-related diseases and endocrine dysfunction can be summarized as the interactions between EDCs and biomacromolecules in endocrine system. Thus, insights into the endocrine-linked MOA of EDCs with corresponding targets will pave the way for developing screening methods of EDCs, prioritizing, and constructing endocrine-related adverse outcome pathways. To date, batteries of laboratory bioassays have been developed and employed to distinguish whether EDCs activate/inhibit/bind to a target or not. However, such test methods poorly assess the underlying molecular mechanisms. Molecular modeling methods are an essential and powerful tool in deciphering the mechanism of endocrine disruptor action. In this chapter, several critical processes related to performing the molecular modeling are described. Topics include preparing 3D biomacromolecules and EDCs structures, obtaining and refining the EDC–biomacromolecule complex, and probing the underlying interaction mechanism. Among these topics, we have emphasized revealing the underlying mechanism by analyzing binding patterns and noncovalent interactions and calculating binding energy. Lastly, future directions in molecular modeling are also proposed.

L’ouverture d’une salle de consommation à moindre risque : une expérimentation à Paris

The inland silverside, Menidia beryllina, is a euryhaline fish and a model organism in ecotoxicology. We previously showend that exposure to picomolar (ng/L) levels of endocrine disrupting chemicals (EDCs) can cause a variety of effects in M. beryllina, from changes in gene expression to phenotypic alterations. Here we explore the potential for early life exposure to EDCs to modify the epigenome in silversides, with a focus on multi- and transgenerational effects. EDCs included contaminants of emerging concern (the pyrethroid insecticide bifenthrin and the synthetic progestin levonorgestrel), as well as a commonly detected synthetic estrogen (ethinylestradiol), and a synthetic androgen (trenbolone) at exposure levels ranging from 3 to 10 ng/L. In a multigenerational experiment, we exposed parental silversides to EDCs from fertilization until 21 days post hatch (dph). Then we assessed DNA methylation patterns for three generations (F0, F1, and F2) in whole body larval fish using reduced representation bisulfite sequencing (RRBS). We found significant ( = 0.05) differences in promoter and/or gene body methylation in treatment fish relative to controls for all EDCs and all generations indicating that both multigenerational (F1) and transgenerational (F2) effects that were caused by strict inheritance of DNA methylation alterations and the dysregulation of epigenetic control mechanisms. Using gene ontology and pathway analyses, we found enrichment in biological processes and pathways representative of growth and development, immune function, reproduction, pigmentation, epigenetic regulation, stress response and repair (including pathways important in carcinogenesis). Further, we found that a subset of potentially EDC responsive genes (EDCRGs) were differentially methylated across all treatments and generations and included hormone receptors, genes involved in steroidogenesis, prostaglandin synthesis, sexual development, DNA methylation, protein metabolism and synthesis, cell signaling, and neurodevelopment. The analysis of EDCRGs provided additional evidence that differential methylation is inherited by the offspring of EDC-treated animals, sometimes in the F2 generation that was never exposed. These findings show that low, environmentally relevant levels of EDCs can cause altered methylation in genes that are functionally relevant to impaired phenotypes documented in EDC-exposed animals and EDC exposure has the potential to affect epigenetic regulation in future generations of fish.

Effect of exposure to endocrine disrupting chemicals in obesity and neurodevelopment: The genetic and microbiota link

In our review, we present possible hypotheses that might explain how sodium glucose cotransporter 2 (SGLT2) inhibitors affect thyroid function. We describe mutual interactions between thyroid hormones and the development of diabetes and obesity. We show the effects of other antihyperglycemic drugs on thyroid hormone changes. We demonstrate how endocrine-disrupting chemicals (EDCs) may act as potential triggers for the development of thyroid disease, obesity and diabetes, and how SGLT2 inhibitors may constitute a potential protective barrier against their negative effects. We describe mechanisms of the immunomodulatory and antioxidant effects of flozins, that may reduce the risk of autoimmune thyroid disease (AITD). We describe beneficial effects of flozins on heart and kidney function, that may also contribute to thyroid protection. Finally, we present a hypothesis of a possible favourable effect of SGLT2 inhibitors on Graves’ orbitopathy (GO), myocardial protection in hyperthyroidism, and a reduction in the risk of thyroid cancer. Aim of our work is to summarise current evidence and hypotheses regarding SGLT2 inhibitors and thyroid function. However, it should be borne in mind that there are still limited clinical evidence about impact of flozins on thyroid metabolism.Clinical trial number Not applicable.

Priorities for ISIAQ in addressing climate change and sustainability challenges

With the aim of discussing new research findings about chemicals able to interfere with the endocrine system, so-called endocrine disruptors, an international workshop was held in Prague, Czech Republic, 10–12 May 2005. The workshop was organized jointly by the EDEN project (Endocrine Disrupters: Exploring Novel Endpoints, Exposure, Low-Dose and Mixture-Effects in Humans, Aquatic Wildlife and Laboratory Animals; http://www.edenresearch.info) and the FIRE project (Risk Assessment of Brominated Flame Retardants as Suspected Endocrine Disrupters for Human and Wildlife Health; http://www.rivm.nl/fire), both large-scale consortia funded by the European Union (EU). The meeting was attended by more than 170 scientists from academia, industry, government agencies, and other organizations. EDEN and FIRE were part of the CREDO cluster (Cluster for Research on Endocrine Disruption), an umbrella organization of more than 60 EU-funded laboratories working on endocrine disruptors. Together with the COMPRENDO (Comparative Research on Endocrine Disruption) and the EURISKED projects (Multi-organic Risk Assessment of Selected Endocrine Disruptors; http://www.eurisked.org), EDEN and FIRE formed the core of the cluster. CREDO served as a platform for cooperation and exchange between its constituent projects. With the completion of almost all its member projects, CREDO has recently ceased to exist, but information about the cluster is still available on online (http://www.credocluster.info). The Prague workshop was the last in a series of meetings organized under the auspices of the CREDO cluster. The themes of previous workshops were risk assessment and the ecologic relevance of chemically induced endocrine disruption in wildlife (Jobling and Tyler 2006). This monograph contains papers presented at the Prague workshop and follows the session structure of the meeting, focusing on four main topics: “Indicators of Human and Wildlife Exposure to EDCs ” reports on new findings relating human exposure to endocrine disruptors in Europe to reproductive disorders, including cryptorchidism, hypospadias, and semen quality. New information about exposure trends for brominated flame retardants in freshwater and marine ecosystems is also given. “Novel models, end points, and biomarkers” summarizes research on the effects of endocrine disruptors on steroid-metabolizing enzymes and gives new data on alkylphenols as endocrine disruptors. Additional articles focus on the consequences of prolonged phytoestrogen exposure for reproductive organs and the outcomes of in utero exposure to endocrine disruptors for testicular dysgenesis, prostate development, and the thyroid hormone axis. “Low-dose effects of endocrine disruptors” gives a synthesis of recent observations in in vitro systems and highlights the importance of statistical power considerations in resolving the low-dose issue. “Mixture effects of endocrine disruptors and their assessment” contains reviews of combination effects, assesses the implications of low-level exposure to multiple chemicals and describes the joint effect of endocrine disruptors in fish and in a developmental toxicity rat model. Taken together, the articles presented in this monograph capture a great deal of the lively debates that took place during the Prague workshop and within the CREDO cluster as a whole. The workshop made considerable progress toward answering key questions that were unresolved a few years ago. It has also stimulated a consensus statement among scientists actively engaged in research in this field, the “Prague Declaration on Endocrine Disruption.” The Prague Declaration, also published as part of this monograph (available as Supplemental Material online at http://www.ehponline.org/docs/2007/10517/suppl.pdf), summarizes issues upon which the majority of scientists can agree, outlines research priorities for the next decade, and highlights steps that can be taken today to prevent health risks to humans and wildlife. It has been signed by more than 200 scientists from all over the world. All contributors to the workshop are thanked cordially. Without their enthusiasm and hard work the meeting and this monograph would not have happened.

It has been widely demonstrated that endocrine disruptors play a central role in various physiopathological processes of human health. In the literature, various carcinogenic processes have been associated with endocrine disruptors. A review of the molecular mechanisms underlying the interaction between endocrine disruptors and the endometrial cancer has been poorly developed. A systematic review was performed using PubMed®/MEDLINE. A total of 25 in vivo and in vitro works were selected. Numerous endocrine disruptors were analyzed. The most relevant results showed how Bisphenol A (BPA) interacts with the carcinogenesis process on several levels. It has been demonstrated how BPA can interact with hormonal receptors and with different transcription proliferative and antiproliferative factors. Furthermore, the effect of Polycyclic aromatic hydrocarbons on Aryl hydrocarbon receptors was investigated, and the role of flame retardants in promoting proliferation and metastasis was confirmed. The results obtained demonstrate how the mechanisms of action of endocrine disruptors are manifold in the pathophysiology of endometrial cancer, acting on different levels of the cancerogenesis process.

Background: Endocrine disruptors (EDs) are environmental chemicals that may disrupt endogenous hormones and have been linked to many adverse health outcomes including breast cancer. EDs have been shown to modulate the risk for mammary tumors in animal models, but their mechanisms at biologically relevant doses and during critical developmental windows remain poorly understood. Methods: We examined the individual and combinatorial (MIX) effects of three EDs commonly found in personal care products - diethyl phthalate (DEP), methyl paraben (MPB) and triclosan (TCS). Sprague-Dawley rats were exposed at four developmental windows - prenatal, neonatal, prepubertal and pubertal - at doses comparable to human exposure based on urinary levels reported in NHANES. Whole-transcriptome profiling was done using Affymetrix rat gene 2.0 st arrays. Results: Differential gene expression analysis by limma revealed that there were no substantial differences between the transcriptomes of prenatal and neonatal rats, so they were combined into a ‘perinatal’ group. Control rats: Expression levels of 702 transcripts significantly differed between the prepubertal and perinatal periods; gene ontology (GO) enrichment showed that GO terms related to development and response to estrogen stimuli were up-regulated and immune signaling pathways were down-regulated. Upstream analysis using Ingenuity Pathway Analysis showed that β-estradiol and estrogen receptor were among the top regulators up-regulated in the prepubertal window, and T-cell receptor and interleukins were among the top regulators down-regulated. The difference between later windows, i.e., between puberty and prepuberty was much less pronounced, with only 39 differentially expressed transcripts. ED-exposed rats: Large scale changes in mammary transcriptome were driven by developmental stage, while changes due to ED exposure appeared to be more subtle. One-way ANOVA among developmental windows demonstrated that only ∼3000 transcripts were significantly changed in DEP and MPB and ∼4000 transcripts changed in TCS and MIX compared to ∼6000 differentially expressed transcripts in control rats. Importantly, distinct signatures of genes were associated with each individual ED as well as MIX, suggesting distinctive mechanisms. Additionally, our data suggested that the pubertal window was the most susceptible; for example, 440 transcripts were differentially expressed in the MPB group relative to control only at the pubertal window and GO terms related to DNA damage and ion transport were up- and down-regulated, respectively. Conclusions: Exposure to common EDs at levels comparable to human exposure resulted in measurable changes in mammary transcriptome and reveal novel mechanisms of ED action in mammary development. Findings from our study highlight the importance of taking into account the timing of exposure when studying the relationship between environment and disease. Citation Format: Kalpana Gopalakrishnan, Qian Li, Yula Ma, Luca Lambertini, Jia Chen, Susan Teitelbaum, Fabiana Manservisi, Laura Falcioni, Luciano Bua, Fiorella Belpoggi. Effects of endocrine disruptors on rat mammary transcriptome at critical developmental windows. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5573. doi:10.1158/1538-7445.AM2015-5573

Endocrine disrupters — testing strategies to assess human hazard

In recent decades, there has been an increase in the incidence of both autoimmune and endocrine diseases, mainly in industrialized countries and may be partly due to human exposure to increasing levels of environmental pollutants. Research shows that environmental pollutants, specifically endocrine disrupting compounds (EDCs), adversely affect gonadal and thyroid function and are linked to type 1 diabetes development. Current data illustrates that the immune system is also a target of EDCs, including the possible exacerbation of autoimmune processes, which are the causes of many endocrine diseases. In this paper, we have presented evidence that environmental pollutants, in addition to directly affecting endocrine glands, can also damage them by intensifying autoimmune processes. We collected experimental and epidemiological data on the effects of EDCs on testicular, ovarian and thyroid function, as well as on the impact of these compounds on the development of type 1 diabetes. The available data demonstrating the potential for particular EDCs to exacerbate autoimmune processes in selected autoimmune endocrine diseases, such as autoimmune orchitis, premature ovarian failure, autoimmune thyroid diseases, and type 1 diabetes were also shown. Because research demonstrating the effects of EDCs on the immune system and the involvement of these compounds in the pathogenesis of autoimmune endocrine diseases is in its early stages, we also presented scientific doubts about this problem and directions for further research. Confirmation of this mechanism of action of EDCs in further studies would help to clarify the current controversies regarding the assessment of their effects in humans.

Hazard identification of endocrine-disrupting carcinogens (EDCs) in relation to cancers in humans