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Metabolism Disrupting Chemicals: Screening, Testing and Molecular Pathway Identification

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

Deadline for manuscript submissions: closed (31 December 2022) | Viewed by 20305

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Special Issue Editors

Dr. Paloma Alonso-Magdalena

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Guest Editor

1. Instituto de Investigación, Desarrollo e Innovación en Biotecnología Sanitaria de Elche (IDiBE), Universidad Miguel Hernández, 03202 Elche, Spain
2. Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid, Spain
Interests: endocrine disrupting chemicals; type 2 diabetes; pancreatic cells; gestational diabetes

Dr. Karine Audouze

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Guest Editor

Université de Paris, Inserm UMR S-1124, 75006 Paris, France
Interests: systems toxicology; network biology; multi-omics; adverse outcome pathways

Prof. Dr. Juliette Legler

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Guest Editor

Institute for Risk Assessment Sciences, Department of Population Health Sciences, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands
Interests: endocrine disrupting chemicals; obesity; adipogenesis; test development and validation
Special Issues, Collections and Topics in MDPI journals

Dr. Jorke Kamstra

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Guest Editor

Institute for Risk Assessment Sciences, Department of Population Health Sciences, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands
Interests: endocrine disrupting chemicals; adipogenesis; Zebrafish; environmental epigenetics; transcriptomics

Prof. Dr. Anna-Liisa Levonen

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Guest Editor

A.I. Virtanen Institute for Molecular Sciences, Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland
Interests: molecular toxicology; gene regulation; non-alcoholic fatty liver disease; metabolic syndrome

Dr. Jenni Küblbeck

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Guest Editor

A.I. Virtanen Institute for Molecular Sciences, Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland
Interests: endocrine disrupting chemicals; nuclear receptors; in vitro assays; metabolic disease

Special Issue Information

Dear Colleagues,

Anthropogenic chemicals in our environment have become part of our everyday life. Some of them can interfere with the normal function of the endocrine system, causing adverse health effects. This subset of chemicals is collectively known as endocrine disrupting chemicals (EDCs). EDCs are used in a variety of applications such as plastics additives, flame retardants, personal care products, pesticides, and food packaging, among others. They are ubiquitous, resulting in exposure to virtually all individuals, mainly through the intake of water and food but also via inhalation and dermal contact.

EDCs have been associated with several health disorders, including developmental and reproductive abnormalities, increased prevalence of hormone-sensitive cancers, or neurodevelopmental disorders. Furthermore, an expanding body of scientific evidence has demonstrated an association between exposure to EDCs and metabolic disorders including diabetes, obesity or hepatic steatosis. Despite this, there is a lack of test methods to screen these metabolism disrupting chemicals (MDCs). This is extremely relevant as metabolic diseases have become one of the most pressing health problems of our time, affecting hundreds of millions of individuals.

New and improved approaches for screening and testing these chemicals will help predict EDC-related metabolic impact. In addition, these approaches will contribute to the identification of molecular mechanisms underlying EDC action, which represents a major challenge in the field.

This Special Issue will focus on reviews and original data manuscripts that concern: (1) studies on screening and testing strategies to identify MDCs; (2) molecular mechanisms of MDC action leading to adverse metabolic outcomes; (3) in silico, in vitro, in vivo, and epidemiological studies on the exposure and effects of MDCs.

Dr. Paloma Alonso-Magdalena
Dr. Karine Audouze
Prof. Dr. Juliette Legler
Dr. Jorke Kamstra
Prof. Dr. Anna-Liisa Levonen
Dr. Jenni Küblbeck
Guest Editors

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 submissions that pass pre-check are 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

endocrine disrupting chemicals
metabolic disorders
testing
molecular pathway

Published Papers (8 papers)

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Research

Jump to: Review

15 pages, 1357 KiB

Open AccessArticle

Prenatal Exposure to Metabolism-Disrupting Chemicals, Cord Blood Transcriptome Perturbations, and Birth Weight in a Belgian Birth Cohort

by Anran Cai, Lützen Portengen, Gökhan Ertaylan, Juliette Legler, Roel Vermeulen, Virissa Lenters and Sylvie Remy

Int. J. Mol. Sci. 2023, 24(8), 7607; https://doi.org/10.3390/ijms24087607 - 20 Apr 2023

Cited by 2 | Viewed by 1275

Abstract

Prenatal exposure to metabolism-disrupting chemicals (MDCs) has been linked to birth weight, but the molecular mechanisms remain largely unknown. In this study, we investigated gene expressions and biological pathways underlying the associations between MDCs and birth weight, using microarray transcriptomics, in a Belgian birth cohort. Whole cord blood measurements of dichlorodiphenyldichloroethylene (p,p’-DDE), polychlorinated biphenyls 153 (PCB-153), perfluorooctanoic acid (PFOA), perfluorooctane sulfonic acid (PFOS), and transcriptome profiling were conducted in 192 mother–child pairs. A workflow including a transcriptome-wide association study, pathway enrichment analysis with a meet-in-the-middle approach, and mediation analysis was performed to characterize the biological pathways and intermediate gene expressions of the MDC–birth weight relationship. Among 26,170 transcriptomic features, we successfully annotated five overlapping metabolism-related gene expressions associated with both an MDC and birth weight, comprising BCAT2, IVD, SLC25a16, HAS3, and MBOAT2. We found 11 overlapping pathways, and they are mostly related to genetic information processing. We found no evidence of any significant mediating effect. In conclusion, this exploratory study provides insights into transcriptome perturbations that may be involved in MDC-induced altered birth weight. Full article

(This article belongs to the Special Issue Metabolism Disrupting Chemicals: Screening, Testing and Molecular Pathway Identification)

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26 pages, 10358 KiB

Open AccessArticle

A New In Vivo Zebrafish Bioassay Evaluating Liver Steatosis Identifies DDE as a Steatogenic Endocrine Disruptor, Partly through SCD1 Regulation

by Hélène Le Mentec, Emmanuelle Monniez, Antoine Legrand, Céline Monvoisin, Dominique Lagadic-Gossmann and Normand Podechard

Int. J. Mol. Sci. 2023, 24(4), 3942; https://doi.org/10.3390/ijms24043942 - 15 Feb 2023

Cited by 5 | Viewed by 2186

Abstract

Non-alcoholic fatty liver disease (NAFLD), which starts with liver steatosis, is a growing worldwide epidemic responsible for chronic liver diseases. Among its risk factors, exposure to environmental contaminants, such as endocrine disrupting compounds (EDC), has been recently emphasized. Given this important public health concern, regulation agencies need novel simple and fast biological tests to evaluate chemical risks. In this context, we developed a new in vivo bioassay called StAZ (Steatogenic Assay on Zebrafish) using an alternative model to animal experimentation, the zebrafish larva, to screen EDCs for their steatogenic properties. Taking advantage of the transparency of zebrafish larvae, we established a method based on fluorescent staining with Nile red to estimate liver lipid content. Following testing of known steatogenic molecules, 10 EDCs suspected to induce metabolic disorders were screened and DDE, the main metabolite of the insecticide DDT, was identified as a potent inducer of steatosis. To confirm this and optimize the assay, we used it in a transgenic zebrafish line expressing a blue fluorescent liver protein reporter. To obtain insight into DDE’s effect, the expression of several genes related to steatosis was analyzed; an up-regulation of scd1 expression, probably relying on PXR activation, was found, partly responsible for both membrane remodeling and steatosis. Full article

(This article belongs to the Special Issue Metabolism Disrupting Chemicals: Screening, Testing and Molecular Pathway Identification)

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23 pages, 5227 KiB

Open AccessArticle

Modulation of Unfolded Protein Response Restores Survival and Function of β-Cells Exposed to the Endocrine Disruptor Bisphenol A

by Laura Maria Daian, Gabriela Tanko, Andrei Mircea Vacaru, Luiza Ghila, Simona Chera and Ana-Maria Vacaru

Int. J. Mol. Sci. 2023, 24(3), 2023; https://doi.org/10.3390/ijms24032023 - 19 Jan 2023

Cited by 4 | Viewed by 1710

Abstract

Diabetes is a metabolic disease that currently affects nearly half a billion people worldwide. β-cells dysfunction is one of the main causes of diabetes. Exposure to endocrine-disrupting chemicals is correlated with increased diabetes incidence. We hypothesized that treatment with bisphenol A (BPA) induces endoplasmic reticulum (ER) stress that activates the unfolded protein response (UPR), leading to impaired function of the β-cells, which over time, can cause diabetes. In this study, we aimed to evaluate UPR pathways activation under BPA treatment in β-cells and possible recovery of ER homeostasis. MIN6 cells (mouse insulinoma cell line) and isolated pancreatic islets from NOR (non-obese diabetes resistant) mice were treated with BPA. We analyzed the impact of BPA on β-cell viability, the architecture of the early secretory pathway, the synthesis and processing of insulin and the activation of UPR sensors and effectors. We found that the addition of the chemical chaperone TUDCA rescues the deleterious effects of BPA, resulting in improved viability, morphology and function of the β-cells. In conclusion, we propose that modulators of UPR can be used as therapeutic interventions targeted towards regaining β-cells homeostasis. Full article

(This article belongs to the Special Issue Metabolism Disrupting Chemicals: Screening, Testing and Molecular Pathway Identification)

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19 pages, 4292 KiB

Open AccessArticle

Exploring the Effects of Metabolism-Disrupting Chemicals on Pancreatic α-Cell Viability, Gene Expression and Function: A Screening Testing Approach

by Ruba Al-Abdulla, Hilda Ferrero, Talía Boronat-Belda, Sergi Soriano, Iván Quesada and Paloma Alonso-Magdalena

Int. J. Mol. Sci. 2023, 24(2), 1044; https://doi.org/10.3390/ijms24021044 - 5 Jan 2023

Cited by 4 | Viewed by 1903

Abstract

Humans are constantly exposed to many environmental pollutants, some of which have been largely acknowledged as key factors in the development of metabolic disorders such as diabetes and obesity. These chemicals have been classified as endocrine-disrupting chemicals (EDCs) and, more recently, since they can interfere with metabolic functions, they have been renamed as metabolism-disrupting chemicals (MDCs). MDCs are present in many consumer products, including food packaging, personal care products, plastic bottles and containers, and detergents. The scientific literature has ever-increasingly focused on insulin-releasing pancreatic β-cells as one of the main targets for MDCs. Evidence highlights that these substances may disrupt glucose homeostasis by altering pancreatic β-cell physiology. However, their potential impact on glucagon-secreting pancreatic α-cells remains poorly known despite the essential role that this cellular type plays in controlling glucose metabolism. In the present study, we have selected seven paradigmatic MDCs representing major toxic classes, including bisphenols, phthalates, perfluorinated compounds, metals, and pesticides. By using an in vitro cell-based model, the pancreatic α-cell line αTC1-9, we have explored the effects of these compounds on pancreatic α-cell viability, gene expression, and secretion. We found that cell viability was moderately affected after bisphenol-A (BPA), bisphenol-F (BPF), and perfluorooctanesulfonic acid (PFOS) exposure, although cytotoxicity was relatively low. In addition, all bisphenols, as well as di(2-ethylhexyl) phthalate (DEHP) and cadmium chloride (CdCl₂), promoted a marked decreased on glucagon secretion, together with changes in the expression of glucagon and/or transcription factors involved in cell function and identity, such as Foxo1 and Arx. Overall, our results indicated that most of the selected chemicals studied caused functional alterations in pancreatic α-cells. Moreover, we revealed, for the first time, their direct effects on key molecular aspects of pancreatic α-cell biology. Full article

(This article belongs to the Special Issue Metabolism Disrupting Chemicals: Screening, Testing and Molecular Pathway Identification)

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14 pages, 3222 KiB

Open AccessArticle

Screening of Metabolism-Disrupting Chemicals on Pancreatic α-Cells Using In Vitro Methods

by Reinaldo Sousa Dos Santos, Ignacio Babiloni-Chust, Laura Marroqui and Angel Nadal

Int. J. Mol. Sci. 2023, 24(1), 231; https://doi.org/10.3390/ijms24010231 - 23 Dec 2022

Cited by 2 | Viewed by 1758

Abstract

Metabolism-disrupting chemicals (MDCs) are endocrine disruptors with obesogenic and/or diabetogenic action. There is mounting evidence linking exposure to MDCs to increased susceptibility to diabetes. Despite the important role of glucagon in glucose homeostasis, there is little information on the effects of MDCs on α-cells. Furthermore, there are no methods to identify and test MDCs with the potential to alter α-cell viability and function. Here, we used the mouse α-cell line αTC1-9 to evaluate the effects of MDCs on cell viability and glucagon secretion. We tested six chemicals at concentrations within human exposure (from 0.1 pM to 1 µM): bisphenol-A (BPA), tributyltin (TBT), perfluorooctanoic acid (PFOA), triphenylphosphate (TPP), triclosan (TCS), and dichlorodiphenyldichloroethylene (DDE). Using two different approaches, MTT assay and DNA-binding dyes, we observed that BPA and TBT decreased α-cell viability via a mechanism that depends on the activation of estrogen receptors and PPARγ, respectively. These two chemicals induced ROS production, but barely altered the expression of endoplasmic reticulum (ER) stress markers. Although PFOA, TPP, TCS, and DDE did not alter cell viability nor induced ROS generation or ER stress, all four compounds negatively affected glucagon secretion. Our findings suggest that αTC1-9 cells seem to be an appropriate model to test chemicals with metabolism-disrupting activity and that the improvement of the test methods proposed herein could be incorporated into protocols for the screening of diabetogenic MDCs. Full article

(This article belongs to the Special Issue Metabolism Disrupting Chemicals: Screening, Testing and Molecular Pathway Identification)

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19 pages, 5222 KiB

Open AccessArticle

In Vitro Assays to Identify Metabolism-Disrupting Chemicals with Diabetogenic Activity in a Human Pancreatic β-Cell Model

by Reinaldo Sousa Dos Santos, Regla María Medina-Gali, Ignacio Babiloni-Chust, Laura Marroqui and Angel Nadal

Int. J. Mol. Sci. 2022, 23(9), 5040; https://doi.org/10.3390/ijms23095040 - 1 May 2022

Cited by 10 | Viewed by 3109

Abstract

There is a need to develop identification tests for Metabolism Disrupting Chemicals (MDCs) with diabetogenic activity. Here we used the human EndoC-βH1 β-cell line, the rat β-cell line INS-1E and dispersed mouse islet cells to assess the effects of endocrine disruptors on cell viability and glucose-stimulated insulin secretion (GSIS). We tested six chemicals at concentrations within human exposure (from 0.1 pM to 1 µM). Bisphenol-A (BPA) and tributyltin (TBT) were used as controls while four other chemicals, namely perfluorooctanoic acid (PFOA), triphenylphosphate (TPP), triclosan (TCS) and dichlorodiphenyldichloroethylene (DDE), were used as “unknowns”. Regarding cell viability, BPA and TBT increased cell death as previously observed. Their mode of action involved the activation of estrogen receptors and PPARγ, respectively. ROS production was a consistent key event in BPA-and TBT-treated cells. None of the other MDCs tested modified viability or ROS production. Concerning GSIS, TBT increased insulin secretion while BPA produced no effects. PFOA decreased GSIS, suggesting that this chemical could be a “new” diabetogenic agent. Our results indicate that the EndoC-βH1 cell line is a suitable human β-cell model for testing diabetogenic MDCs. Optimization of the test methods proposed here could be incorporated into a set of protocols for the identification of MDCs. Full article

(This article belongs to the Special Issue Metabolism Disrupting Chemicals: Screening, Testing and Molecular Pathway Identification)

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Graphical abstract

29 pages, 46263 KiB

Open AccessArticle

Screening of Relevant Metabolism-Disrupting Chemicals on Pancreatic β-Cells: Evaluation of Murine and Human In Vitro Models

by Ruba Al-Abdulla, Hilda Ferrero, Sergi Soriano, Talía Boronat-Belda and Paloma Alonso-Magdalena

Int. J. Mol. Sci. 2022, 23(8), 4182; https://doi.org/10.3390/ijms23084182 - 10 Apr 2022

Cited by 11 | Viewed by 3032

Abstract

Endocrine-disrupting chemicals (EDCs) are chemical substances that can interfere with the normal function of the endocrine system. EDCs are ubiquitous and can be found in a variety of consumer products such as food packaging materials, personal care and household products, plastic additives, and flame retardants. Over the last decade, the impact of EDCs on human health has been widely acknowledged as they have been associated with different endocrine diseases. Among them, a subset called metabolism-disrupting chemicals (MDCs) is able to promote metabolic changes that can lead to the development of metabolic disorders such as diabetes, obesity, hepatic steatosis, and metabolic syndrome, among others. Despite this, today, there are still no definitive and standardized in vitro tools to support the metabolic risk assessment of existing and emerging MDCs for regulatory purposes. Here, we evaluated the following two different pancreatic cell-based in vitro systems: the murine pancreatic β-cell line MIN6 as well as the human pancreatic β-cell line EndoC-βH1. Both were challenged with the following range of relevant concentrations of seven well-known EDCs: (bisphenol-A (BPA), bisphenol-S (BPS), bisphenol-F (BPF), perfluorooctanesulfonic acid (PFOS), di(2-ethylhexyl) phthalate (DEHP), cadmium chloride (CdCl₂), and dichlorodiphenyldichloroethylene (DDE)). The screening revealed that most of the tested chemicals have detectable, deleterious effects on glucose-stimulated insulin release, insulin content, electrical activity, gene expression, and/or viability. Our data provide new molecular information on the direct effects of the selected chemicals on key aspects of pancreatic β-cell function, such as the stimulus-secretion coupling and ion channel activity. In addition, we found that, in general, the sensitivity and responses were comparable to those from other in vivo studies reported in the literature. Overall, our results suggest that both systems can serve as effective tools for the rapid screening of potential MDC effects on pancreatic β-cell physiology as well as for deciphering and better understanding the molecular mechanisms that underlie their action. Full article

(This article belongs to the Special Issue Metabolism Disrupting Chemicals: Screening, Testing and Molecular Pathway Identification)

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Review

Jump to: Research

23 pages, 760 KiB

Open AccessReview

Metabolism-Disrupting Chemicals Affecting the Liver: Screening, Testing, and Molecular Pathway Identification

by Kristin Fritsche, Andrea Ziková-Kloas, Philip Marx-Stoelting and Albert Braeuning

Int. J. Mol. Sci. 2023, 24(3), 2686; https://doi.org/10.3390/ijms24032686 - 31 Jan 2023

Viewed by 4087

Abstract

The liver is the central metabolic organ of the body. The plethora of anabolic and catabolic pathways in the liver is tightly regulated by physiological signaling but may become imbalanced as a consequence of malnutrition or exposure to certain chemicals, so-called metabolic endocrine disrupters, or metabolism-disrupting chemicals (MDCs). Among different metabolism-related diseases, obesity and non-alcoholic fatty liver disease (NAFLD) constitute a growing health problem, which has been associated with a western lifestyle combining excessive caloric intake and reduced physical activity. In the past years, awareness of chemical exposure as an underlying cause of metabolic endocrine effects has continuously increased. Within this review, we have collected and summarized evidence that certain environmental MDCs are capable of contributing to metabolic diseases such as liver steatosis and cholestasis by different molecular mechanisms, thereby contributing to the metabolic syndrome. Despite the high relevance of metabolism-related diseases, standardized mechanistic assays for the identification and characterization of MDCs are missing. Therefore, the current state of candidate test systems to identify MDCs is presented, and their possible implementation into a testing strategy for MDCs is discussed. Full article

(This article belongs to the Special Issue Metabolism Disrupting Chemicals: Screening, Testing and Molecular Pathway Identification)

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