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17 pages, 1707 KiB

Open AccessArticle

Comparative Analysis of Zearalenone Effects on Thyroid Receptor Alpha (TRα) and Beta (TRβ) Expression in Rat Primary Cerebellar Cell Cultures

by David Sandor Kiss, Eniko Ioja, Istvan Toth, Zoltan Barany, Gergely Jocsak, Tibor Bartha, Tamas L. Horvath and Attila Zsarnovszky

Int. J. Mol. Sci. 2018, 19(5), 1440; https://doi.org/10.3390/ijms19051440 - 11 May 2018

Cited by 8 | Viewed by 4236

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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14 pages, 28997 KiB

Open AccessArticle

Allosteric Activation of GDP-Bound Ras Isoforms by Bisphenol Derivative Plasticisers

by Miriam Schöpel, Oleksandr Shkura, Jana Seidel, Klaus Kock, Xueyin Zhong, Stefanie Löffek, Iris Helfrich, Hagen S. Bachmann, Jürgen Scherkenbeck, Christian Herrmann and Raphael Stoll

Int. J. Mol. Sci. 2018, 19(4), 1133; https://doi.org/10.3390/ijms19041133 - 10 Apr 2018

Cited by 11 | Viewed by 6841

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-, SOS^cat-, 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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19 pages, 4357 KiB

Open AccessArticle

The Influence of High and Low Doses of Bisphenol A (BPA) on the Enteric Nervous System of the Porcine Ileum

by Kamila Szymanska, Krystyna Makowska and Slawomir Gonkowski

Int. J. Mol. Sci. 2018, 19(3), 917; https://doi.org/10.3390/ijms19030917 - 20 Mar 2018

Cited by 49 | Viewed by 6003

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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2269 KiB

Open AccessArticle

Roles of Aryl Hydrocarbon Receptor in Aromatase-Dependent Cell Proliferation in Human Osteoblasts

by Yasuhiro Miki, Shuko Hata, Katsuhiko Ono, Takashi Suzuki, Kiyoshi Ito, Hiroyuki Kumamoto and Hironobu Sasano

Int. J. Mol. Sci. 2017, 18(10), 2159; https://doi.org/10.3390/ijms18102159 - 17 Oct 2017

Cited by 18 | Viewed by 4918

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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3602 KiB

Open AccessArticle

Interference of Paraben Compounds with Estrogen Metabolism by Inhibition of 17β-Hydroxysteroid Dehydrogenases

by Roger T. Engeli, Simona R. Rohrer, Anna Vuorinen, Sonja Herdlinger, Teresa Kaserer, Susanne Leugger, Daniela Schuster and Alex Odermatt

Int. J. Mol. Sci. 2017, 18(9), 2007; https://doi.org/10.3390/ijms18092007 - 19 Sep 2017

Cited by 50 | Viewed by 12986

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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4424 KiB

Open AccessArticle

Alteration of Mammary Gland Development and Gene Expression by In Utero Exposure to Cadmium

by Daniela A. Parodi, Morgan Greenfield, Claire Evans, Anna Chichura, Alexandra Alpaugh, James Williams, Kedra C. Cyrus and Mary Beth Martin

Int. J. Mol. Sci. 2017, 18(9), 1939; https://doi.org/10.3390/ijms18091939 - 9 Sep 2017

Cited by 15 | Viewed by 5367

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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4217 KiB

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Determination of Highly Sensitive Biological Cell Model Systems to Screen BPA-Related Health Hazards Using Pathway Studio

by Do-Yeal Ryu, Md Saidur Rahman and Myung-Geol Pang

Int. J. Mol. Sci. 2017, 18(9), 1909; https://doi.org/10.3390/ijms18091909 - 6 Sep 2017

Cited by 11 | Viewed by 7096

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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44 pages, 3779 KiB

Open AccessReview

Current Knowledge on Endocrine Disrupting Chemicals (EDCs) from Animal Biology to Humans, from Pregnancy to Adulthood: Highlights from a National Italian Meeting

by Maria Elisabeth Street, Sabrina Angelini, Sergio Bernasconi, Ernesto Burgio, Alessandra Cassio, Cecilia Catellani, Francesca Cirillo, Annalisa Deodati, Enrica Fabbrizi, Vassilios Fanos, Giancarlo Gargano, Enzo Grossi, Lorenzo Iughetti, Pietro Lazzeroni, Alberto Mantovani, Lucia Migliore, Paola Palanza, Giancarlo Panzica, Anna Maria Papini, Stefano Parmigiani, Barbara Predieri, Chiara Sartori, Gabriele Tridenti and Sergio Amarri Show full author list Hide full author list

Int. J. Mol. Sci. 2018, 19(6), 1647; https://doi.org/10.3390/ijms19061647 - 2 Jun 2018

Cited by 188 | Viewed by 22373

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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19 pages, 497 KiB

Open AccessReview

Overview of Cadmium Thyroid Disrupting Effects and Mechanisms

by Aleksandra Buha, Vesna Matovic, Biljana Antonijevic, Zorica Bulat, Marijana Curcic, Elisavet A. Renieri, Aristidis M. Tsatsakis, Amie Schweitzer and David Wallace

Int. J. Mol. Sci. 2018, 19(5), 1501; https://doi.org/10.3390/ijms19051501 - 17 May 2018

Cited by 157 | Viewed by 8878

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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14 pages, 1079 KiB

Open AccessReview

A Novel Action of Endocrine-Disrupting Chemicals on Wildlife; DDT and Its Derivatives Have Remained in the Environment

by Ayami Matsushima

Int. J. Mol. Sci. 2018, 19(5), 1377; https://doi.org/10.3390/ijms19051377 - 5 May 2018

Cited by 23 | Viewed by 7742

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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15 pages, 2896 KiB

Open AccessReview

Contributions of Bioactive Molecules in Stem Cell-Based Periodontal Regeneration

by An-Qi Liu, Cheng-Hu Hu, Fang Jin, Li-Shu Zhang and Kun Xuan

Int. J. Mol. Sci. 2018, 19(4), 1016; https://doi.org/10.3390/ijms19041016 - 28 Mar 2018

Cited by 17 | Viewed by 7173

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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257 KiB

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Thyroid Disrupting Chemicals

by Valeria Calsolaro, Giuseppe Pasqualetti, Filippo Niccolai, Nadia Caraccio and Fabio Monzani

Int. J. Mol. Sci. 2017, 18(12), 2583; https://doi.org/10.3390/ijms18122583 - 1 Dec 2017

Cited by 112 | Viewed by 8378

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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