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Special Issue "Advances in the Research of Endocrine Disrupting Chemicals"

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Toxicology".

Deadline for manuscript submissions: closed (28 February 2018).

Special Issue Editor

Prof. Dr. Hideko Sone
E-Mail Website
Guest Editor
1 Yokohama University of Pharmacy, Environmental Health and Drug Department, 601 Matano-cho, Totsuka, Yokohama 2450066, Japan
2 Guest Researcher, National Institute for Environmental Studies, Center for Health and Environmental Risk Research, 16-2 Onogawa, Tsukuba, Ibraki 3058506, Japan
Interests: health and disease in humans and animals; risk assessment of cancer; reproduction; child development; objective methods for epidemiology; in vivo, in vitro and in silico; mechanism sciences; exposure sciences for food and drinking; use and application of stem cells in toxicology

Special Issue Information

Dear Colleagues,

Advanced sciences for endocrine disrupting chemicals (EDCs) now allow the deep concerns about how EDCs affect health and disease in humans and animals. Exciting work from the US, Europe and Asia have shown that they have potential risks for cancer, reproduction, development, obesity and allergy by intake food, drinking and air in daily life. However, objective methods are still needed for integrating the multiple streams of evidence, such as epidemiology, in vivo, in vitro, and in silico analyses that are relevant in assessing EDCs, and for elucidating mechanisms of EDC’s biological properties. We have the pleasure of inviting research scientists to submit original research, mini and full reviews for this Special Issue of the International Journal of Molecular Sciences, entitled “Advances in the Research of Endocrine Disrupting Chemicals”, dedicated to providing a comprehensive overview of the identified risks of the EDCs, covering new advances in elucidation of their adverse and biological properties, the discovery of new properties, or research on human health and animal health. Original research and reviews on these and related topics in this area are welcome.

Dr. Hideko Sone
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All papers will be peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Health, disease
  • humans
  • animals
  • cells
  • risk assessment
  • cancer
  • reproduction
  • development
  • obesity
  • allergy
  • food
  • drinking
  • objective methods
  • epidemiology
  • in vivo
  • in vitro
  • in silico
  • mechanism
  • exposure sciences

Published Papers (12 papers)

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Research

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Open AccessArticle
Comparative Analysis of Zearalenone Effects on Thyroid Receptor Alpha (TRα) and Beta (TRβ) Expression in Rat Primary Cerebellar Cell Cultures
Int. J. Mol. Sci. 2018, 19(5), 1440; https://doi.org/10.3390/ijms19051440 - 11 May 2018
Cited by 2
Abstract
Thyroid receptors play an important role in postnatal brain development. Zearalenone (ZEN), a major mycotoxin of Fusarium fungi, is well known to cause serious health problems in animals and humans through various mechanisms, including the physiological pathways of thyroid hormone (TH). In the [...] Read more.
Thyroid receptors play an important role in postnatal brain development. Zearalenone (ZEN), a major mycotoxin of Fusarium fungi, is well known to cause serious health problems in animals and humans through various mechanisms, including the physiological pathways of thyroid hormone (TH). In the present study, we aimed to investigate the expression of thyroid receptors α (TRα) and β (TRβ) in primary cerebellar neurons in the presence or absence of glia and following ZEN treatment, using quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and Western blot. Primary cerebellar granule cells were treated with low doses of ZEN (0.1 nM) in combination with physiologically relevant concentrations of l-thyroxine (T4), 3,3′,5-triiodo-l-thyronine (T3) and 17β-estradiol (E2). Expression levels of TRα and TRβ at mRNA and protein levels were slightly modified by ZEN administered alone; however, along with thyroid and steroid hormones, modelling the physiological conditions, expression levels of TRs varied highly depending on the given treatment. Gene expression levels were also highly modulated by the presence or absence of glial cells, with mostly contrasting effects. Our results demonstrate divergent transcriptional and translational mechanisms involved in the expression of TRs implied by ZEN and hormonal milieu, as well as culturing conditions. Full article
(This article belongs to the Special Issue Advances in the Research of Endocrine Disrupting Chemicals)
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Open AccessArticle
Allosteric Activation of GDP-Bound Ras Isoforms by Bisphenol Derivative Plasticisers
Int. J. Mol. Sci. 2018, 19(4), 1133; https://doi.org/10.3390/ijms19041133 - 10 Apr 2018
Cited by 2
Abstract
The protein family of small GTPases controls cellular processes by acting as a binary switch between an active and an inactive state. The most prominent family members are H-Ras, N-Ras, and K-Ras isoforms, which are highly related and frequently mutated in cancer. Bisphenols [...] Read more.
The protein family of small GTPases controls cellular processes by acting as a binary switch between an active and an inactive state. The most prominent family members are H-Ras, N-Ras, and K-Ras isoforms, which are highly related and frequently mutated in cancer. Bisphenols are widespread in modern life because of their industrial application as plasticisers. Bisphenol A (BPA) is the best-known member and has gained significant scientific as well as public attention as an endocrine disrupting chemical, a fact that eventually led to its replacement. However, compounds used to replace BPA still contain the molecular scaffold of bisphenols. BPA, BPAF, BPB, BPE, BPF, and an amine-substituted BPAF-derivate all interact with all GDP-bound Ras-Isoforms through binding to a common site on these proteins. NMR-, SOScat-, and GDI- assay-based data revealed a new bisphenol-induced, allosterically activated GDP-bound Ras conformation that define these plasticisers as Ras allosteric agonists. Full article
(This article belongs to the Special Issue Advances in the Research of Endocrine Disrupting Chemicals)
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Open AccessArticle
The Influence of High and Low Doses of Bisphenol A (BPA) on the Enteric Nervous System of the Porcine Ileum
Int. J. Mol. Sci. 2018, 19(3), 917; https://doi.org/10.3390/ijms19030917 - 20 Mar 2018
Cited by 9
Abstract
Bisphenol A, used in the production of plastic, is able to leach from containers into food and cause multidirectional adverse effects in living organisms, including neurodegeneration and metabolic disorders. Knowledge of the impact of BPA on enteric neurons is practically non-existent. The destination [...] Read more.
Bisphenol A, used in the production of plastic, is able to leach from containers into food and cause multidirectional adverse effects in living organisms, including neurodegeneration and metabolic disorders. Knowledge of the impact of BPA on enteric neurons is practically non-existent. The destination of this study was to investigate the influence of BPA at a specific dose (0.05 mg/kg body weight/day) and at a dose ten times higher (0.5 mg/kg body weight/day), given for 28 days, on the porcine ileum. The influence of BPA on enteric neuron immunoreactive to selected neuronal active substances, including substance P (SP), vasoactive intestinal polypeptide (VIP), galanin (GAL), vesicular acetylcholine transporter (VAChT—used here as a marker of cholinergic neurons), and cocaine- and amphetamine-regulated transcript peptide (CART), was studied by the double immunofluorescence method. Both doses of BPA affected the neurochemical characterization of the enteric neurons. The observed changes depended on the type of enteric plexus but were generally characterized by an increase in the number of cells immunoreactive to the particular substances. More visible fluctuations were observed after treatment with higher doses of BPA. The results confirm that even low doses of BPA may influence the neurochemical characterization of the enteric neurons and are not neutral for living organisms. Full article
(This article belongs to the Special Issue Advances in the Research of Endocrine Disrupting Chemicals)
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Open AccessArticle
Roles of Aryl Hydrocarbon Receptor in Aromatase-Dependent Cell Proliferation in Human Osteoblasts
Int. J. Mol. Sci. 2017, 18(10), 2159; https://doi.org/10.3390/ijms18102159 - 17 Oct 2017
Cited by 3
Abstract
Aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor and its expression is influenced by environmental compounds, such as 3-methylcholanthrene (3-MC) and β-naphthoflavone (β-NF). AhR and its downstream genes, such as CYP1A1, are considered to play a pivotal role in xenobiotic responses. [...] Read more.
Aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor and its expression is influenced by environmental compounds, such as 3-methylcholanthrene (3-MC) and β-naphthoflavone (β-NF). AhR and its downstream genes, such as CYP1A1, are considered to play a pivotal role in xenobiotic responses. AhR signaling has also been proposed to mediate osteogenesis in experimental animals, but its details have remained unclear. Therefore, in this study, we examined the possible roles of AhR in human bone. Immunohistochemical analysis revealed that AhR was detected in both osteoblasts and osteoclasts. We then screened AhR-target genes using a microarray analysis in human osteoblastic hFOB cells. Results of microarray and subsequent PCR analysis did reveal that estrogen metabolizing and synthesizing enzymes, such as CYP1B1 and aromatase, were increased by 3-MC in hFOB and osteosarcoma cell line, MG-63. The subsequent antibody cytokine analysis also demonstrated that interleukin-1β and -6 expression was increased by 3-MC and β-NF in hFOB cells and these interleukins were well known to induce aromatase. We then examined the cell proliferation rate of hFOB and MG-63 cells co-treated with 3-MC and testosterone as an aromatase substrate. The status of cell proliferation in both hFOB and MG-63 cells was stimulated by 3-MC and testosterone treatment, which was also inhibited by an estrogen blocker, aromatase inhibitor, or AhR antagonist. These findings indicated that AhR could regulate estrogen synthesis and metabolism in bone tissues through cytokine/aromatase signaling. Full article
(This article belongs to the Special Issue Advances in the Research of Endocrine Disrupting Chemicals)
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Open AccessArticle
Interference of Paraben Compounds with Estrogen Metabolism by Inhibition of 17β-Hydroxysteroid Dehydrogenases
Int. J. Mol. Sci. 2017, 18(9), 2007; https://doi.org/10.3390/ijms18092007 - 19 Sep 2017
Cited by 7
Abstract
Parabens are effective preservatives widely used in cosmetic products and processed food, with high human exposure. Recent evidence suggests that parabens exert estrogenic effects. This work investigated the potential interference of parabens with the estrogen-activating enzyme 17β-hydroxysteroid dehydrogenase (17β-HSD) 1 and the estrogen-inactivating [...] Read more.
Parabens are effective preservatives widely used in cosmetic products and processed food, with high human exposure. Recent evidence suggests that parabens exert estrogenic effects. This work investigated the potential interference of parabens with the estrogen-activating enzyme 17β-hydroxysteroid dehydrogenase (17β-HSD) 1 and the estrogen-inactivating 17β-HSD2. A ligand-based 17β-HSD2 pharmacophore model was applied to screen a cosmetic chemicals database, followed by in vitro testing of selected paraben compounds for inhibition of 17β-HSD1 and 17β-HSD2 activities. All tested parabens and paraben-like compounds, except their common metabolite p-hydroxybenzoic acid, inhibited 17β-HSD2. Ethylparaben and ethyl vanillate inhibited 17β-HSD2 with IC50 values of 4.6 ± 0.8 and 1.3 ± 0.3 µM, respectively. Additionally, parabens size-dependently inhibited 17β-HSD1, whereby hexyl- and heptylparaben were most active with IC50 values of 2.6 ± 0.6 and 1.8 ± 0.3 µM. Low micromolar concentrations of hexyl- and heptylparaben decreased 17β-HSD1 activity, and ethylparaben and ethyl vanillate decreased 17β-HSD2 activity. However, regarding the very rapid metabolism of these compounds to the inactive p-hydroxybenzoic acid by esterases, it needs to be determined under which conditions low micromolar concentrations of these parabens or their mixtures can occur in target cells to effectively disturb estrogen effects in vivo. Full article
(This article belongs to the Special Issue Advances in the Research of Endocrine Disrupting Chemicals)
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Open AccessArticle
Alteration of Mammary Gland Development and Gene Expression by In Utero Exposure to Cadmium
Int. J. Mol. Sci. 2017, 18(9), 1939; https://doi.org/10.3390/ijms18091939 - 09 Sep 2017
Cited by 5
Abstract
Environmental exposure to estrogens and estrogen like contaminants during early development is thought to contribute to the risk of developing breast cancer primarily due to an early onset of puberty; however, exposure during key developing windows may also influence the risk of developing [...] Read more.
Environmental exposure to estrogens and estrogen like contaminants during early development is thought to contribute to the risk of developing breast cancer primarily due to an early onset of puberty; however, exposure during key developing windows may also influence the risk of developing the disease. The goal of this study was to ask whether in utero exposure to the metalloestrogen cadmium alters mammary gland development due to acceleration of puberty onset or to an effect on early development of the mammary gland. The results show that, in addition to advancing the onset of puberty, in utero exposure to the metalloestrogen cadmium altered mammary gland development prior to its effect on puberty onset. In utero exposure resulted in an expansion of the number of mammosphere-forming cells in the neonatal mammary gland and an increase in branching, epithelial cells, and density in the prepubertal mammary gland. In the postpubertal mammary gland, there was a further expansion of the mammary stem/progenitor cell population and overexpression of estrogen receptor-alpha (ERα) that was due to the overexpression and altered regulation of the ERα transcripts derived from exons O and OT in response to estradiol. These results suggest that in utero exposure to cadmium increases stem/progenitor cells, cell density, and expression of estrogen receptor-alpha that may contribute to the risk of developing breast cancer. Full article
(This article belongs to the Special Issue Advances in the Research of Endocrine Disrupting Chemicals)
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Open AccessArticle
Determination of Highly Sensitive Biological Cell Model Systems to Screen BPA-Related Health Hazards Using Pathway Studio
Int. J. Mol. Sci. 2017, 18(9), 1909; https://doi.org/10.3390/ijms18091909 - 06 Sep 2017
Cited by 2
Abstract
Bisphenol-A (BPA) is a ubiquitous endocrine-disrupting chemical. Recently, many issues have arisen surrounding the disease pathogenesis of BPA. Therefore, several studies have been conducted to investigate the proteomic biomarkers of BPA that are associated with disease processes. However, studies on identifying highly sensitive [...] Read more.
Bisphenol-A (BPA) is a ubiquitous endocrine-disrupting chemical. Recently, many issues have arisen surrounding the disease pathogenesis of BPA. Therefore, several studies have been conducted to investigate the proteomic biomarkers of BPA that are associated with disease processes. However, studies on identifying highly sensitive biological cell model systems in determining BPA health risk are lacking. Here, we determined suitable cell model systems and potential biomarkers for predicting BPA-mediated disease using the bioinformatics tool Pathway Studio. We compiled known BPA-mediated diseases in humans, which were categorized into five major types. Subsequently, we investigated the differentially expressed proteins following BPA exposure in several cell types, and analyzed the efficacy of altered proteins to investigate their associations with BPA-mediated diseases. Our results demonstrated that colon cancer cells (SW480), mammary gland, and Sertoli cells were highly sensitive biological model systems, because of the efficacy of predicting the majority of BPA-mediated diseases. We selected glucose-6-phosphate dehydrogenase (G6PD), cytochrome b-c1 complex subunit 1 (UQCRC1), and voltage-dependent anion-selective channel protein 2 (VDAC2) as highly sensitive biomarkers to predict BPA-mediated diseases. Furthermore, we summarized proteomic studies in spermatozoa following BPA exposure, which have recently been considered as another suitable cell type for predicting BPA-mediated diseases. Full article
(This article belongs to the Special Issue Advances in the Research of Endocrine Disrupting Chemicals)
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Review

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Open AccessReview
Current Knowledge on Endocrine Disrupting Chemicals (EDCs) from Animal Biology to Humans, from Pregnancy to Adulthood: Highlights from a National Italian Meeting
Int. J. Mol. Sci. 2018, 19(6), 1647; https://doi.org/10.3390/ijms19061647 - 02 Jun 2018
Cited by 12
Abstract
Wildlife has often presented and suggested the effects of endocrine disrupting chemicals (EDCs). Animal studies have given us an important opportunity to understand the mechanisms of action of many chemicals on the endocrine system and on neurodevelopment and behaviour, and to evaluate the [...] Read more.
Wildlife has often presented and suggested the effects of endocrine disrupting chemicals (EDCs). Animal studies have given us an important opportunity to understand the mechanisms of action of many chemicals on the endocrine system and on neurodevelopment and behaviour, and to evaluate the effects of doses, time and duration of exposure. Although results are sometimes conflicting because of confounding factors, epidemiological studies in humans suggest effects of EDCs on prenatal growth, thyroid function, glucose metabolism and obesity, puberty, fertility, and on carcinogenesis mainly through epigenetic mechanisms. This manuscript reviews the reports of a multidisciplinary national meeting on this topic. Full article
(This article belongs to the Special Issue Advances in the Research of Endocrine Disrupting Chemicals)
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Open AccessReview
Overview of Cadmium Thyroid Disrupting Effects and Mechanisms
Int. J. Mol. Sci. 2018, 19(5), 1501; https://doi.org/10.3390/ijms19051501 - 17 May 2018
Cited by 19
Abstract
Humans are exposed to a significant number of chemicals that are suspected to produce disturbances in hormone homeostasis. Hence, in recent decades, there has been a growing interest in endocrine disruptive chemicals. One of the alleged thyroid disrupting substances is cadmium (Cd), a [...] Read more.
Humans are exposed to a significant number of chemicals that are suspected to produce disturbances in hormone homeostasis. Hence, in recent decades, there has been a growing interest in endocrine disruptive chemicals. One of the alleged thyroid disrupting substances is cadmium (Cd), a ubiquitous toxic metal shown to act as a thyroid disruptor and carcinogen in both animals and humans. Multiple PubMed searches with core keywords were performed to identify and evaluate appropriate studies which revealed literature suggesting evidence for the link between exposure to Cd and histological and metabolic changes in the thyroid gland. Furthermore, Cd influence on thyroid homeostasis at the peripheral level has also been hypothesized. Both in vivo and in vitro studies revealed that a Cd exposure at environmentally relevant concentrations results in biphasic Cd dose-thyroid response relationships. Development of thyroid tumors following exposure to Cd has been studied mainly using in vitro methodologies. In the thyroid, Cd has been shown to activate or stimulate the activity of various factors, leading to increased cell proliferation and a reduction in normal apoptotic activity. Evidence establishing the association between Cd and thyroid disruption remains ambiguous, with further studies needed to elucidate the issue and improve our understanding of Cd-mediated effects on the thyroid gland. Full article
(This article belongs to the Special Issue Advances in the Research of Endocrine Disrupting Chemicals)
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Open AccessReview
A Novel Action of Endocrine-Disrupting Chemicals on Wildlife; DDT and Its Derivatives Have Remained in the Environment
Int. J. Mol. Sci. 2018, 19(5), 1377; https://doi.org/10.3390/ijms19051377 - 05 May 2018
Cited by 2
Abstract
Huge numbers of chemicals are released uncontrolled into the environment and some of these chemicals induce unwanted biological effects, both on wildlife and humans. One class of these chemicals are endocrine-disrupting chemicals (EDCs), which are released even though EDCs can affect not only [...] Read more.
Huge numbers of chemicals are released uncontrolled into the environment and some of these chemicals induce unwanted biological effects, both on wildlife and humans. One class of these chemicals are endocrine-disrupting chemicals (EDCs), which are released even though EDCs can affect not only the functions of steroid hormones but also of various signaling molecules, including any ligand-mediated signal transduction pathways. Dichlorodiphenyltrichloroethane (DDT), a pesticide that is already banned, is one of the best-publicized EDCs and its metabolites have been considered to cause adverse effects on wildlife, even though the exact molecular mechanisms of the abnormalities it causes still remain obscure. Recently, an industrial raw material, bisphenol A (BPA), has attracted worldwide attention as an EDC because it induces developmental abnormalities even at low-dose exposures. DDT and BPA derivatives have structural similarities in their chemical features. In this short review, unclear points on the molecular mechanisms of adverse effects of DDT found on alligators are summarized from data in the literature, and recent experimental and molecular research on BPA derivatives is investigated to introduce novel perspectives on BPA derivatives. Especially, a recently developed BPA derivative, bisphenol C (BPC), is structurally similar to a DDT derivative called dichlorodiphenyldichloroethylene (DDE). Full article
(This article belongs to the Special Issue Advances in the Research of Endocrine Disrupting Chemicals)
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Open AccessReview
Contributions of Bioactive Molecules in Stem Cell-Based Periodontal Regeneration
Int. J. Mol. Sci. 2018, 19(4), 1016; https://doi.org/10.3390/ijms19041016 - 28 Mar 2018
Cited by 2
Abstract
Periodontal disease is a widespread disease, which without proper treatment, may lead to tooth loss in adults. Because stem cells from the inflammatory microenvironment created by periodontal disease exhibit impaired regeneration potential even under favorable conditions, it is difficult to obtain satisfactory therapeutic [...] Read more.
Periodontal disease is a widespread disease, which without proper treatment, may lead to tooth loss in adults. Because stem cells from the inflammatory microenvironment created by periodontal disease exhibit impaired regeneration potential even under favorable conditions, it is difficult to obtain satisfactory therapeutic outcomes using traditional treatments, which only focus on the control of inflammation. Therefore, a new stem cell-based therapy known as cell aggregates/cell sheets technology has emerged. This approach provides sufficient numbers of stem cells with high viability for treating the defective site and offers new hope in the field of periodontal regeneration. However, it is not sufficient for regenerating periodontal tissues by delivering cell aggregates/cell sheets to the impaired microenvironment in order to suppress the function of resident cells. In the present review, we summarize some promising bioactive molecules that act as cellular signals, which recreate a favorable microenvironment for tissue regeneration, recruit endogenous cells into the defective site and enhance the viability of exogenous cells. Full article
(This article belongs to the Special Issue Advances in the Research of Endocrine Disrupting Chemicals)
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Open AccessReview
Thyroid Disrupting Chemicals
Int. J. Mol. Sci. 2017, 18(12), 2583; https://doi.org/10.3390/ijms18122583 - 01 Dec 2017
Cited by 7
Abstract
Endocrine disruptor compounds are exogenous agents able to interfere with a gland function, exerting their action across different functional passages, from the synthesis to the metabolism and binding to receptors of the hormone produced. Several issues, such as different levels and time of [...] Read more.
Endocrine disruptor compounds are exogenous agents able to interfere with a gland function, exerting their action across different functional passages, from the synthesis to the metabolism and binding to receptors of the hormone produced. Several issues, such as different levels and time of exposure and different action across different ages as well as gender, make the study of endocrine disruptors still a challenge. The thyroid is very sensitive to the action of disruptors, and considering the importance of a correct thyroid function for physical and cognitive functioning, addressing this topic should be considered a priority. In this review, we examined the most recent studies, many of them concentrating on maternal and child exposure, conducted to assess the impact of industrial chemicals which showed an influence on thyroid function. So far, the number of studies conducted on that topic is not sufficient to provide solid conclusions and lead to homogeneous guidelines. The lack of uniformity is certainly due to differences in areas and populations examined, the different conditions of exposures and the remarkable inter-subject variability. Nonetheless, the European Commission for Health and Food Safety is implementing recommendations to ensure that substances identified as endocrine disruptors will be withdrawn from the market. Full article
(This article belongs to the Special Issue Advances in the Research of Endocrine Disrupting Chemicals)
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