Next Article in Journal
Dynamic In Vivo Profiling of DNA Damage and Repair after Radiotherapy Using Canine Patients as a Model
Next Article in Special Issue
Tumor Microenvironment and Metabolism
Previous Article in Journal
Low-Symmetry Mixed Fluorinated Subphthalocyanines as Fluorescence Imaging Probes in MDA-MB-231 Breast Tumor Cells
Previous Article in Special Issue
Nanomedicine Strategies to Target Tumor-Associated Macrophages
Article Menu
Issue 6 (June) cover image

Export Article

Open AccessReview
Int. J. Mol. Sci. 2017, 18(6), 1179; doi:10.3390/ijms18061179

A Tox21 Approach to Altered Epigenetic Landscapes: Assessing Epigenetic Toxicity Pathways Leading to Altered Gene Expression and Oncogenic Transformation In Vitro

1
Mechanistic Studies Division, Environmental Health Science and Research Bureau,HealthyEnvironments and Consumer Safety Branch, Health Canada, 50 Columbine Driveway,Tunney’s Pasture, Ottawa, ON K1A 0K9, Canada
2
Hazard Identification Division, Environmental Health Science and Research Bureau,HealthyEnvironments and Consumer Safety Branch, Health Canada, 50 Columbine Driveway,Tunney’s Pasture, Ottawa, ON K1A 0K9, Canada
*
Author to whom correspondence should be addressed.
Received: 12 January 2017 / Revised: 19 May 2017 / Accepted: 22 May 2017 / Published: 1 June 2017
(This article belongs to the Special Issue Tumor Microenvironment and Metabolism)
View Full-Text   |   Download PDF [4470 KB, uploaded 5 June 2017]   |  

Abstract

An emerging vision for toxicity testing in the 21st century foresees in vitro assays assuming the leading role in testing for chemical hazards, including testing for carcinogenicity. Toxicity will be determined by monitoring key steps in functionally validated molecular pathways, using tests designed to reveal chemically-induced perturbations that lead to adverse phenotypic endpoints in cultured human cells. Risk assessments would subsequently be derived from the causal in vitro endpoints and concentration vs. effect data extrapolated to human in vivo concentrations. Much direct experimental evidence now shows that disruption of epigenetic processes by chemicals is a carcinogenic mode of action that leads to altered gene functions playing causal roles in cancer initiation and progression. In assessing chemical safety, it would therefore be advantageous to consider an emerging class of carcinogens, the epigenotoxicants, with the ability to change chromatin and/or DNA marks by direct or indirect effects on the activities of enzymes (writers, erasers/editors, remodelers and readers) that convey the epigenetic information. Evidence is reviewed supporting a strategy for in vitro hazard identification of carcinogens that induce toxicity through disturbance of functional epigenetic pathways in human somatic cells, leading to inactivated tumour suppressor genes and carcinogenesis. In the context of human cell transformation models, these in vitro pathway measurements ensure high biological relevance to the apical endpoint of cancer. Four causal mechanisms participating in pathways to persistent epigenetic gene silencing were considered: covalent histone modification, nucleosome remodeling, non-coding RNA interaction and DNA methylation. Within these four interacting mechanisms, 25 epigenetic toxicity pathway components (SET1, MLL1, KDM5, G9A, SUV39H1, SETDB1, EZH2, JMJD3, CBX7, CBX8, BMI, SUZ12, HP1, MPP8, DNMT1, DNMT3A, DNMT3B, TET1, MeCP2, SETDB2, BAZ2A, UHRF1, CTCF, HOTAIR and ANRIL) were found to have experimental evidence showing that functional perturbations played “driver” roles in human cellular transformation. Measurement of epigenotoxicants presents challenges for short-term carcinogenicity testing, especially in the high-throughput modes emphasized in the Tox21 chemicals testing approach. There is need to develop and validate in vitro tests to detect both, locus-specific, and genome-wide, epigenetic alterations with causal links to oncogenic cellular phenotypes. Some recent examples of cell-based high throughput chemical screening assays are presented that have been applied or have shown potential for application to epigenetic endpoints. View Full-Text
Keywords: carcinogenesis; carcinogenicity tests; carcinogens; chemical safety; chromatin; DNA methylation; environmental exposure; epigenesis; epigenomics; gene silencing; tumour suppressor; histones; neoplasms; nucleosomes; risk assessment carcinogenesis; carcinogenicity tests; carcinogens; chemical safety; chromatin; DNA methylation; environmental exposure; epigenesis; epigenomics; gene silencing; tumour suppressor; histones; neoplasms; nucleosomes; risk assessment
Figures

This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

Supplementary material

Scifeed alert for new publications

Never miss any articles matching your research from any publisher
  • Get alerts for new papers matching your research
  • Find out the new papers from selected authors
  • Updated daily for 49'000+ journals and 6000+ publishers
  • Define your Scifeed now

SciFeed Share & Cite This Article

MDPI and ACS Style

Parfett, C.L.; Desaulniers, D. A Tox21 Approach to Altered Epigenetic Landscapes: Assessing Epigenetic Toxicity Pathways Leading to Altered Gene Expression and Oncogenic Transformation In Vitro. Int. J. Mol. Sci. 2017, 18, 1179.

Show more citation formats Show less citations formats

Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Related Articles

Article Metrics

Article Access Statistics

1

Comments

[Return to top]
Int. J. Mol. Sci. EISSN 1422-0067 Published by MDPI AG, Basel, Switzerland RSS E-Mail Table of Contents Alert
Back to Top