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Special Issue "Endocrine Disrupting Chemicals: Effects on the Health of Humans and Wildlife 2.0"

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: 15 January 2022.

Special Issue Editor

Prof. Dr. J. Thomas Sanderson
E-Mail Website
Guest Editor
INRS - Centre Armand-Frappier Santé Biotechnologie, Laval, QC H7V 1B7, Canada
Interests: toxicology; endocrine disruptors; aromatase (CYP19); steroidogenesis; pesticides; natural compounds; cytochrome P450;physiologically relevant cell bioassays
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Endocrine disrupting chemicals are generally defined as substances in our environment, food and consumer products that can disrupt hormonal balance in humans and wildlife and result in adverse health effects, or in their offspring.

In this Special Issue we will address the state-of-the -art knowledge of the mechanisms and consequences of endocrine disrupting chemicals for the health of humans and wildlife, and their offspring. Hormonal systems are often considered the targets of endocrine disrupting chemicals, but every organ in the body is a receptor of these hormonal signals to perform appropriately. It is here where things can go wrong.

Prof. Dr. J. Thomas Sanderson
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.

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Published Papers (8 papers)

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Research

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Article
Bisphenol A Modulates Autophagy and Exacerbates Chronic Kidney Damage in Mice
Int. J. Mol. Sci. 2021, 22(13), 7189; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22137189 - 03 Jul 2021
Cited by 1 | Viewed by 919
Abstract
BACKGROUND: Bisphenol A (BPA) is a ubiquitous environmental toxin that accumulates in chronic kidney disease (CKD). Our aim was to explore the effect of chronic exposition of BPA in healthy and injured kidney investigating potential mechanisms involved. METHODS: In C57Bl/6 mice, administration of [...] Read more.
BACKGROUND: Bisphenol A (BPA) is a ubiquitous environmental toxin that accumulates in chronic kidney disease (CKD). Our aim was to explore the effect of chronic exposition of BPA in healthy and injured kidney investigating potential mechanisms involved. METHODS: In C57Bl/6 mice, administration of BPA (120 mg/kg/day, i.p for 5 days/week) was done for 2 and 5 weeks. To study BPA effect on CKD, a model of subtotal nephrectomy (SNX) combined with BPA administration for 5 weeks was employed. In vitro studies were done in human proximal tubular epithelial cells (HK-2 line). RESULTS: Chronic BPA administration to healthy mice induces inflammatory infiltration in the kidney, tubular injury and renal fibrosis (assessed by increased collagen deposition). Moreover, in SNX mice BPA exposure exacerbates renal lesions, including overexpression of the tubular damage biomarker Hepatitis A virus cellular receptor 1 (Havcr-1/KIM-1). BPA upregulated several proinflammatory genes and increased the antioxidant response [Nuclear factor erythroid 2-related factor 2 (Nrf2), Heme Oxygenase-1 (Ho-1) and NAD(P)H dehydrogenase quinone 1 (Nqo-1)] both in healthy and SNX mice. The autophagy process was modulated by BPA, through elevated autophagy-related gene 5 (Atg5), autophagy-related gene 7 (Atg7), Microtubule-associated proteins 1A/1B light chain 3B (Map1lc3b/Lc3b) and Beclin-1 gene levels and blockaded the autophagosome maturation and flux (p62 levels). This autophagy deregulation was confirmed in vitro. CONCLUSIONS: BPA deregulates autophagy flux and redox protective mechanisms, suggesting a potential mechanism of BPA deleterious effects in the kidney. Full article
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Article
BPA, BPAF and TMBPF Alter Adipogenesis and Fat Accumulation in Human Mesenchymal Stem Cells, with Implications for Obesity
Int. J. Mol. Sci. 2021, 22(10), 5363; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22105363 - 19 May 2021
Cited by 4 | Viewed by 928
Abstract
Bisphenol A (BPA) is an endocrine-disrupting chemical used in the production of plastics, and is linked to developmental, reproductive, and metabolic disorders including obesity. Manufacturers have begun using ‘BPA-free’ alternatives instead of BPA in many consumer products. However, these alternatives have had much [...] Read more.
Bisphenol A (BPA) is an endocrine-disrupting chemical used in the production of plastics, and is linked to developmental, reproductive, and metabolic disorders including obesity. Manufacturers have begun using ‘BPA-free’ alternatives instead of BPA in many consumer products. However, these alternatives have had much less testing and oversight, yet they are already being mass-produced and used across industries from plastics to food-contact coatings. Here, we used human female adipose-derived stem cells (hASCs), a type of adult mesenchymal stem cell, to compare the effects of BPA and BPA alternatives on adipogenesis or fat cell development in vitro. We focused on two commonly used BPA replacements, bisphenol AF (BPAF) and tetramethyl bisphenol F (TMBPF; monomer of the new valPure V70 food-contact coating). Human ASCs were differentiated into adipocytes using chemically defined media in the presence of control differentiation media with and without 17β-estradiol (E2; 10 μM), or with increasing doses of BPA (0, 0.1 and 1 μM), BPAF (0, 0.1, 1 and 10 nM), or TMBPF (0, 0.01 and 0.1 μM). After differentiation, the cells were stained and imaged to visualize and quantify the accumulation of lipid vacuoles and number of developing fat cells. Treated cells were also examined for cell viability and apoptosis (programmed cell death) using the respective cellular assays. Similar to E2, BPA at 0.1 μM and BPAF at 0.1 nM, significantly increased adipogenesis and lipid production by 20% compared to control differentiated cells (based on total lipid vacuole number to cell number ratios), whereas higher levels of BPA and BPAF significantly decreased adipogenesis (p < 0.005). All tested doses of TMBPF significantly reduced adipogenesis and lipid production by 30–40%, likely at least partially through toxic effects on stem cells, as viable cell numbers decreased and apoptosis levels increased throughout differentiation. These findings indicate that low, environmentally-relevant doses of BPA, BPAF, and TMBPF have significant effects on fat cell development and lipid accumulation, with TMBPF having non-estrogenic, anti-adipogenic effects. These and other recent results may provide a potential cellular mechanism between exposure to bisphenols and human obesity, and underscore the likely impact of these chemicals on fat development in vivo. Full article
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Article
Plasma Metabolomics Analysis of Polyvinyl Chloride Workers Identifies Altered Processes and Candidate Biomarkers for Hepatic Hemangiosarcoma and Its Development
Int. J. Mol. Sci. 2021, 22(10), 5093; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22105093 - 11 May 2021
Viewed by 696
Abstract
Background: High-level occupational vinyl chloride (VC) exposures have been associated with hepatic hemangiosarcoma, which typically develops following a long latency period. Although VC is genotoxic, a more comprehensive mode of action has not been determined and diagnostic biomarkers have not been established. The [...] Read more.
Background: High-level occupational vinyl chloride (VC) exposures have been associated with hepatic hemangiosarcoma, which typically develops following a long latency period. Although VC is genotoxic, a more comprehensive mode of action has not been determined and diagnostic biomarkers have not been established. The purpose of this study is to address these knowledge gaps through plasma metabolomics. Methods: Plasma samples from polyvinyl chloride polymerization workers who developed hemangiosarcoma (cases, n = 15) and VC exposure-matched controls (n = 17) underwent metabolomic analysis. Random forest and bioinformatic analyses were performed. Results: Cases and controls had similar demographics and routine liver biochemistries. Mass spectroscopy identified 606 known metabolites. Random forest analysis had an 82% predictive accuracy for group classification. 60 metabolites were significantly increased and 44 were decreased vs. controls. Taurocholate, bradykinin and fibrin degradation product 2 were up-regulated by greater than 80-fold. The naturally occurring anti-angiogenic phenol, 4-hydroxybenzyl alcohol, was down-regulated 5-fold. Top affected ontologies involved: (i) metabolism of bile acids, taurine, cholesterol, fatty acids and amino acids; (ii) inflammation and oxidative stress; and (iii) nicotinic cholinergic signaling. Conclusions: The plasma metabolome was differentially regulated in polyvinyl chloride workers who developed hepatic hemangiosarcoma. Ontologies potentially involved in hemangiosarcoma pathogenesis and candidate biomarkers were identified. Full article
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Article
Human Erythrocytes Exposed to Phthalates and Their Metabolites Alter Antioxidant Enzyme Activity and Hemoglobin Oxidation
Int. J. Mol. Sci. 2020, 21(12), 4480; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21124480 - 24 Jun 2020
Cited by 5 | Viewed by 916
Abstract
Phthalates used as plasticizers have become a part of human life because of their important role in various industries. Human exposure to these compounds is unavoidable, and therefore their mechanisms of toxicity should be investigated. Due to their structure and function, human erythrocytes [...] Read more.
Phthalates used as plasticizers have become a part of human life because of their important role in various industries. Human exposure to these compounds is unavoidable, and therefore their mechanisms of toxicity should be investigated. Due to their structure and function, human erythrocytes are increasingly used as a cell model for testing the in vitro toxicity of various xenobiotics. Therefore, the purpose of our study was to assess the effect of selected phthalates on methemoglobin (metHb), reactive oxygen species (ROS) including hydroxyl radical levels, as well as the activity of antioxidative enzymes, such as superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px), in human erythrocytes. Erythrocytes were incubated with di-n-butyl phthalate (DBP), butylbenzyl phthalate (BBP), and their metabolites, i.e., mono-n-butyl phthalate (MBP) and monobenzyl phthalate (MBzP), at concentrations ranging from 0.5 to 100 µg/mL for 6 or 24 h. This study shows that the analyzed phthalates disturbed the redox balance in human erythrocytes. DBP and BBP, at much lower concentrations than their metabolites, caused a statistically significant increase of metHb and ROS, including hydroxyl radical levels, and changed the activity of antioxidant enzymes. The studied phthalates disturbed the redox balance in human erythrocytes, which may contribute to the accelerated removal of these cells from the circulation. Full article
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Article
Evaluation of the Effect of Selected Brominated Flame Retardants on Human Serum Albumin and Human Erythrocyte Membrane Proteins
Int. J. Mol. Sci. 2020, 21(11), 3926; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21113926 - 30 May 2020
Cited by 3 | Viewed by 976
Abstract
Brominated flame retardants (BFRs) have been using to reduce the flammability of plastics contained in many products, such as household articles, furniture, mattresses, textiles or insulation. Considering the fact that these compounds may be released into the environment leading to the exposure of [...] Read more.
Brominated flame retardants (BFRs) have been using to reduce the flammability of plastics contained in many products, such as household articles, furniture, mattresses, textiles or insulation. Considering the fact that these compounds may be released into the environment leading to the exposure of living organisms, it is necessary to study their possible effects and mechanisms of action. Proteins play a crucial role in all biological processes. For this reason, a simple model of human serum albumin (HSA) was chosen to study the mechanism of BFRs’ effect on proteins. The study determined interactions between selected BFRs, i.e., tetrabromobisphenol A (TBBPA), tetrabromobisphenol S (TBBPS), 2,4-dibromophenol (2,4-DBP), 2,4,6-tribromophenol (2,4,6-TBP) and pentabromophenol (PBP), and HSA by measurement of fluorescence of intrinsic tryptophan and absorbance of circular dichroism (CD). In addition, in order to understand the possible effect of these compounds in their native environment, the effect of BFRs on membrane proteins of human erythrocytes (red blood cells, RBCs) was also assessed. Among bromophenols, PBP had the strongest oxidative effect on RBC membrane, and 2,4-DBP demonstrated the weakest fluorescence-quenching effect of both membrane tryptophan and HSA. By contrast to PBP, 2,4-DBP and 2,4,6-TBP caused spatial changes of HSA. We have observed that among all analyzed BFRs, TBBPA caused the strongest oxidation of RBC membrane proteins and the model HSA protein, causing reduction of fluorescence of tryptophan contained in them. TBBPA also changed albumin conformation properties, leading to impairment of the α-helix structure. However, TBBPS had the weakest oxidative effect on proteins among studied BFRs and did not affect the secondary structure of HSA. Full article
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Article
Oncogenic Potential of Bisphenol A and Common Environmental Contaminants in Human Mammary Epithelial Cells
Int. J. Mol. Sci. 2020, 21(10), 3735; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21103735 - 25 May 2020
Cited by 6 | Viewed by 1501
Abstract
There is an ample epidemiological evidence to support the role of environmental contaminants such as bisphenol A (BPA) in breast cancer development but the molecular mechanisms of their action are still not fully understood. Therefore, we sought to analyze the effects of three [...] Read more.
There is an ample epidemiological evidence to support the role of environmental contaminants such as bisphenol A (BPA) in breast cancer development but the molecular mechanisms of their action are still not fully understood. Therefore, we sought to analyze the effects of three common contaminants (BPA; 4-tert-octylphenol, OP; hexabromocyclododecane, HBCD) on mammary epithelial cell (HME1) and MCF7 breast cancer cell line. We also supplied some data on methoxychlor, MXC; 4-nonylphenol, NP; and 2-amino-1-methyl-6-phenylimidazo [4–b] pyridine, PhIP. We focused on testing the prolonged (two months) exposure to low nano-molar concentrations (0.0015–0.0048 nM) presumed to be oncogenic and found that they induced DNA damage (evidenced by upregulation of pH2A.X, pCHK1, pCHK2, p-P53) and disrupted the cell cycle. Some agents induced epigenetic (methylation) changes of tumor suppressor genes TIMP3, CHFR, ESR1, IGSF4, CDH13, and GSTP1. Obviously, the accumulation of these molecular alterations is an essential base for cancer development. Consistent with this, we observed that these agents increased cellular invasiveness through collagen. Cellular abilities to form colonies in soft agar were increased for MCF7. Toxic agents induced phosphorylation of protein kinase such as EGFR, CREB, STAT6, c-Jun, STAT3, HSP6, HSP27, AMPKα1, FAK, p53, GSK-3α/β, and P70S6 in HME1. Most of these proteins are involved in potential oncogenic pathways. Overall, these data clarify the molecular alterations that can be induced by some common environmental contaminants in mammary epithelial cells which could be a foundation to understand environmental carcinogenesis. Full article
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Review

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Review
Endocrine Disruptor Potential of Short- and Long-Chain Perfluoroalkyl Substances (PFASs)—A Synthesis of Current Knowledge with Proposal of Molecular Mechanism
Int. J. Mol. Sci. 2021, 22(4), 2148; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22042148 - 21 Feb 2021
Viewed by 1013
Abstract
Endocrine disruptors are a group of chemical compounds that, even in low concentrations, cause a hormonal imbalance in the body, contributing to the development of various harmful health disorders. Many industry compounds, due to their important commercial value and numerous applications, are produced [...] Read more.
Endocrine disruptors are a group of chemical compounds that, even in low concentrations, cause a hormonal imbalance in the body, contributing to the development of various harmful health disorders. Many industry compounds, due to their important commercial value and numerous applications, are produced on a global scale, while the mechanism of their endocrine action has not been fully understood. In recent years, per- and polyfluoroalkyl substances (PFASs) have gained the interest of major international health organizations, and thus more and more studies have been aimed to explain the toxicity of these compounds. PFASs were firstly synthesized in the 1950s and broadly used in the industry in the production of firefighting agents, cosmetics and herbicides. The numerous industrial applications of PFASs, combined with the exceptionally long half-life of these substances in the human body and extreme environmental persistence, result in a common and chronic exposure of the general population to their action. Available data have suggested that human exposure to PFASs can occur during different stages of development and may cause short- or/and long-term health effects. This paper synthetizes the current literature reports on the presence, bioaccumulation and, particularly, endocrine toxicity of selected long- and short-chain PFASs, with a special emphasis on the mechanisms underlying their endocrine actions. Full article
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Review
Potential Mechanisms of Bisphenol A (BPA) Contributing to Human Disease
Int. J. Mol. Sci. 2020, 21(16), 5761; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21165761 - 11 Aug 2020
Cited by 31 | Viewed by 2378
Abstract
Bisphenol A (BPA) is an organic synthetic compound serving as a monomer to produce polycarbonate plastic, widely used in the packaging for food and drinks, medical devices, thermal paper, and dental materials. BPA can contaminate food, beverage, air, and soil. It accumulates in [...] Read more.
Bisphenol A (BPA) is an organic synthetic compound serving as a monomer to produce polycarbonate plastic, widely used in the packaging for food and drinks, medical devices, thermal paper, and dental materials. BPA can contaminate food, beverage, air, and soil. It accumulates in several human tissues and organs and is potentially harmful to human health through different molecular mechanisms. Due to its hormone-like properties, BPA may bind to estrogen receptors, thereby affecting both body weight and tumorigenesis. BPA may also affect metabolism and cancer progression, by interacting with GPR30, and may impair male reproductive function, by binding to androgen receptors. Several transcription factors, including PPARγ, C/EBP, Nrf2, HOX, and HAND2, are involved in BPA action on fat and liver homeostasis, the cardiovascular system, and cancer. Finally, epigenetic changes, such as DNA methylation, histones modification, and changes in microRNAs expression contribute to BPA pathological effects. This review aims to provide an extensive and comprehensive analysis of the most recent evidence about the potential mechanisms by which BPA affects human health. Full article
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