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Advances in Mechanism Based Toxicity and Hazard Assessment of NGTxC 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 (31 May 2022) | Viewed by 19170

Special Issue Editors

Department of Toxicology, Centre for Radiation, Chemical and Environmental Hazards Public Health England, Chilton OX11 0RQ, UK
Interests: non-genotoxic carcinogens; endocrine disruption; chemical safety; public and environmental health
Special Issues, Collections and Topics in MDPI journals
Department of Environmental Health, Agency for Prevention, Environment and Energy, Emilia-Romagna, Viale Filopanti, I-40126 Bologna, Italy
Interests: non-genotoxic carcinogens; cancer research; endocrine disruptors; environmental health
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

There is a regulatory gap in addressing the hazard assessment of Non Genotoxic Carcinogenic Chemicals to better protect public health for many product and regulatory sectors, and alternative mechanistic based approaches are needed to address this gap.

This Special Issue focuses on recent advances in the hazard assessment of non genotoxic carcinogenic (NGTxC) chemicals and will include papers on:

  1. Assay developments and chemicals screened that plausibly address relevant mechanisms and modes of action, including: ADME; Immune response and inflammatory biomarkers, and specifically measurement of cytokine release; Cytoskeleton modification, to discriminate between adaptive to the adverse response; Cancer specific kinase activation;  3D models that can genuinely address the complexity at the tissue level that the individual cell based molecular based assays cannot address.
  2. Relevant quantitative and qualitative pathway based approaches for NGTxC.
  3. Applications of molecular targets from human clinical data for mechanistic understanding of key biomarkers in the carcinogenesis process.
  4. Discussion on human relevance of mechanisms and modes of action. For example rodent CAR/PXR and peroxisome proliferation/PPARs induction in liver tumours are generally dismissed as not being human relevant, but looking more holistically, is this really the case?
  5. Potentiation effects of viruses on chemical non genotoxic carcinogenicity.

We warmly welcome submissions, including original papers and reviews, on these topical needs.

Dr. Miriam N. Jacobs
Prof. Annamaria Colacci
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

  • Non genotoxic carcinogens
  • Carcinogenicity
  • Inflammation
  • Hazard assessment
  • Molecular targets

Related Special Issue

Published Papers (6 papers)

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Research

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29 pages, 2704 KiB  
Article
Mechanistic Interrogation of Cell Transformation In Vitro: The Transformics Assay as an Exemplar of Oncotransformation
by Gelsomina Pillo, Maria Grazia Mascolo, Cristina Zanzi, Francesca Rotondo, Stefania Serra, Francesco Bortone, Sandro Grilli, Monica Vaccari, Miriam N. Jacobs and Annamaria Colacci
Int. J. Mol. Sci. 2022, 23(14), 7603; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23147603 - 09 Jul 2022
Cited by 2 | Viewed by 1661
Abstract
The Transformics Assay is an in vitro test which combines the BALB/c 3T3 Cell Transformation Assay (CTA) with microarray transcriptomics. It has been shown to improve upon the mechanistic understanding of the CTA, helping to identify mechanisms of action leading to chemical-induced transformation [...] Read more.
The Transformics Assay is an in vitro test which combines the BALB/c 3T3 Cell Transformation Assay (CTA) with microarray transcriptomics. It has been shown to improve upon the mechanistic understanding of the CTA, helping to identify mechanisms of action leading to chemical-induced transformation thanks to RNA extractions in specific time points along the process of in vitro transformation. In this study, the lowest transforming concentration of the carcinogenic benzo(a)pyrene (B(a)P) has been tested in order to find molecular signatures of initial events relevant for oncotransformation. Application of Enrichment Analysis (Metacore) to the analyses of the results facilitated key biological interpretations. After 72 h of exposure, as a consequence of the molecular initiating event of aryl hydrocarbon receptor (AhR) activation, there is a cascade of cellular events and microenvironment modification, and the immune and inflammatory responses are the main processes involved in cell response. Furthermore, pathways and processes related to cell cycle regulation, cytoskeletal adhesion and remodeling processes, cell differentiation and transformation were observed. Full article
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29 pages, 7455 KiB  
Article
Gene Expression over Time during Cell Transformation Due to Non-Genotoxic Carcinogen Treatment of Bhas 42 Cells
by Kiyomi Ohmori, Asuka Kamei, Yuki Watanabe and Keiko Abe
Int. J. Mol. Sci. 2022, 23(6), 3216; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23063216 - 16 Mar 2022
Cited by 9 | Viewed by 2419
Abstract
The Bhas 42 cell transformation assay (Bhas 42 CTA) is the first Organization for Economic Cooperation and Development (OECD)-certificated method used as a specific tool for the detection of the cell-transformation potential of tumor-promoting compounds, including non-genotoxic carcinogens (NGTxCs), as separate from genotoxic [...] Read more.
The Bhas 42 cell transformation assay (Bhas 42 CTA) is the first Organization for Economic Cooperation and Development (OECD)-certificated method used as a specific tool for the detection of the cell-transformation potential of tumor-promoting compounds, including non-genotoxic carcinogens (NGTxCs), as separate from genotoxic carcinogens. This assay offers the great advantage of enabling the phenotypic detection of oncotransformation. A key benefit of using the Bhas 42 CTA in the study of the cell-transformation mechanisms of tumor-promoting compounds, including non-genotoxic carcinogens, is that the cell-transformation potential of the chemical can be detected directly without treatment with a tumor-initiating compound since Bhas 42 cell line was established by transfecting the v-Ha-ras gene into a mouse fibroblast cloned cell line. Here, we analyzed the gene expression over time, using DNA microarrays, in Bhas 42 cells treated with the tumor-promoting compound 12-O-tetradecanoylphorbol-13-acetate (TPA), and NGTxC, with a total of three repeat experiments. This is the first paper to report on gene expression over time during the process of cell transformation with only a tumor-promoting compound. Pathways that were activated or inactivated during the process of cell transformation in the Bhas 42 cells treated with TPA were related not only directly to RAS but also to various pathways in the hallmarks of cancer. Full article
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Review

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42 pages, 2582 KiB  
Review
The Cell Transformation Assay: A Historical Assessment of Current Knowledge of Applications in an Integrated Approach to Testing and Assessment for Non-Genotoxic Carcinogens
by Annamaria Colacci, Raffaella Corvi, Kyomi Ohmori, Martin Paparella, Stefania Serra, Iris Da Rocha Carrico, Paule Vasseur and Miriam Naomi Jacobs
Int. J. Mol. Sci. 2023, 24(6), 5659; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24065659 - 16 Mar 2023
Cited by 3 | Viewed by 2452
Abstract
The history of the development of the cell transformation assays (CTAs) is described, providing an overview of in vitro cell transformation from its origin to the new transcriptomic-based CTAs. Application of this knowledge is utilized to address how the different types of CTAs, [...] Read more.
The history of the development of the cell transformation assays (CTAs) is described, providing an overview of in vitro cell transformation from its origin to the new transcriptomic-based CTAs. Application of this knowledge is utilized to address how the different types of CTAs, variously addressing initiation and promotion, can be included on a mechanistic basis within the integrated approach to testing and assessment (IATA) for non-genotoxic carcinogens. Building upon assay assessments targeting the key events in the IATA, we identify how the different CTA models can appropriately fit, following preceding steps in the IATA. The preceding steps are the prescreening transcriptomic approaches, and assessment within the earlier key events of inflammation, immune disruption, mitotic signaling and cell injury. The CTA models address the later key events of (sustained) proliferation and change in morphology leading to tumor formation. The complementary key biomarkers with respect to the precursor key events and respective CTAs are mapped, providing a structured mechanistic approach to represent the complexity of the (non-genotoxic) carcinogenesis process, and specifically their capacity to identify non-genotoxic carcinogenic chemicals in a human relevant IATA. Full article
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27 pages, 1668 KiB  
Review
Analyses of Transcriptomics Cell Signalling for Pre-Screening Applications in the Integrated Approach for Testing and Assessment of Non-Genotoxic Carcinogens
by Yusuke Oku, Federica Madia, Pierre Lau, Martin Paparella, Timothy McGovern, Mirjam Luijten and Miriam N. Jacobs
Int. J. Mol. Sci. 2022, 23(21), 12718; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232112718 - 22 Oct 2022
Cited by 6 | Viewed by 2009
Abstract
With recent rapid advancement of methodological tools, mechanistic understanding of biological processes leading to carcinogenesis is expanding. New approach methodologies such as transcriptomics can inform on non-genotoxic mechanisms of chemical carcinogens and can be developed for regulatory applications. The Organisation for the Economic [...] Read more.
With recent rapid advancement of methodological tools, mechanistic understanding of biological processes leading to carcinogenesis is expanding. New approach methodologies such as transcriptomics can inform on non-genotoxic mechanisms of chemical carcinogens and can be developed for regulatory applications. The Organisation for the Economic Cooperation and Development (OECD) expert group developing an Integrated Approach to the Testing and Assessment (IATA) of Non-Genotoxic Carcinogens (NGTxC) is reviewing the possible assays to be integrated therein. In this context, we review the application of transcriptomics approaches suitable for pre-screening gene expression changes associated with phenotypic alterations that underlie the carcinogenic processes for subsequent prioritisation of downstream test methods appropriate to specific key events of non-genotoxic carcinogenesis. Using case studies, we evaluate the potential of gene expression analyses especially in relation to breast cancer, to identify the most relevant approaches that could be utilised as (pre-) screening tools, for example Gene Set Enrichment Analysis (GSEA). We also consider how to address the challenges to integrate gene panels and transcriptomic assays into the IATA, highlighting the pivotal omics markers identified for assay measurement in the IATA key events of inflammation, immune response, mitogenic signalling and cell injury. Full article
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95 pages, 7021 KiB  
Review
Integration of Epigenetic Mechanisms into Non-Genotoxic Carcinogenicity Hazard Assessment: Focus on DNA Methylation and Histone Modifications
by Daniel Desaulniers, Paule Vasseur, Abigail Jacobs, M. Cecilia Aguila, Norman Ertych and Miriam N. Jacobs
Int. J. Mol. Sci. 2021, 22(20), 10969; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222010969 - 11 Oct 2021
Cited by 16 | Viewed by 5912
Abstract
Epigenetics involves a series of mechanisms that entail histone and DNA covalent modifications and non-coding RNAs, and that collectively contribute to programing cell functions and differentiation. Epigenetic anomalies and DNA mutations are co-drivers of cellular dysfunctions, including carcinogenesis. Alterations of the epigenetic system [...] Read more.
Epigenetics involves a series of mechanisms that entail histone and DNA covalent modifications and non-coding RNAs, and that collectively contribute to programing cell functions and differentiation. Epigenetic anomalies and DNA mutations are co-drivers of cellular dysfunctions, including carcinogenesis. Alterations of the epigenetic system occur in cancers whether the initial carcinogenic events are from genotoxic (GTxC) or non-genotoxic (NGTxC) carcinogens. NGTxC are not inherently DNA reactive, they do not have a unifying mode of action and as yet there are no regulatory test guidelines addressing mechanisms of NGTxC. To fil this gap, the Test Guideline Programme of the Organisation for Economic Cooperation and Development is developing a framework for an integrated approach for the testing and assessment (IATA) of NGTxC and is considering assays that address key events of cancer hallmarks. Here, with the intent of better understanding the applicability of epigenetic assays in chemical carcinogenicity assessment, we focus on DNA methylation and histone modifications and review: (1) epigenetic mechanisms contributing to carcinogenesis, (2) epigenetic mechanisms altered following exposure to arsenic, nickel, or phenobarbital in order to identify common carcinogen-specific mechanisms, (3) characteristics of a series of epigenetic assay types, and (4) epigenetic assay validation needs in the context of chemical hazard assessment. As a key component of numerous NGTxC mechanisms of action, epigenetic assays included in IATA assay combinations can contribute to improved chemical carcinogen identification for the better protection of public health. Full article
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39 pages, 1301 KiB  
Review
Applicability of Scrape Loading-Dye Transfer Assay for Non-Genotoxic Carcinogen Testing
by Iva Sovadinová, Brad L. Upham, James E. Trosko and Pavel Babica
Int. J. Mol. Sci. 2021, 22(16), 8977; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22168977 - 20 Aug 2021
Cited by 11 | Viewed by 3179
Abstract
Dysregulation of gap junction intercellular communication (GJIC) is recognized as one of the key hallmarks for identifying non-genotoxic carcinogens (NGTxC). Currently, there is a demand for in vitro assays addressing the gap junction hallmark, which would have the potential to eventually become an [...] Read more.
Dysregulation of gap junction intercellular communication (GJIC) is recognized as one of the key hallmarks for identifying non-genotoxic carcinogens (NGTxC). Currently, there is a demand for in vitro assays addressing the gap junction hallmark, which would have the potential to eventually become an integral part of an integrated approach to the testing and assessment (IATA) of NGTxC. The scrape loading-dye transfer (SL-DT) technique is a simple assay for the functional evaluation of GJIC in various in vitro cultured mammalian cells and represents an interesting candidate assay. Out of the various techniques for evaluating GJIC, the SL-DT assay has been used frequently to assess the effects of various chemicals on GJIC in toxicological and tumor promotion research. In this review, we systematically searched the existing literature to gather papers assessing GJIC using the SL-DT assay in a rat liver epithelial cell line, WB-F344, after treating with chemicals, especially environmental and food toxicants, drugs, reproductive-, cardio- and neuro-toxicants and chemical tumor promoters. We discuss findings derived from the SL-DT assay with the known knowledge about the tumor-promoting activity and carcinogenicity of the assessed chemicals to evaluate the predictive capacity of the SL-DT assay in terms of its sensitivity, specificity and accuracy for identifying carcinogens. These data represent important information with respect to the applicability of the SL-DT assay for the testing of NGTxC within the IATA framework. Full article
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