Advancing the use of noncoding RNA in regulatory toxicology: Report of an ECETOC workshop

Aigner, Achim; Buesen, Roland; Gant, Timothy W.; Gooderham, Nigel J.; Greim, Helmut; Hackermüller, Jörg; Hubesch, Bruno; Laffont, Madeleine; Marczylo, Emma L.; Meister, Gunter; Petrick, Jay S.; Rasoulpour, Reza J.; Sauer, Ursula G.; Schmidt, Kerstin; Seitz, Hervé; Slack, Frank J.; Sukata, Tokuo; Vies, Saskia M. van der; Verhaert, Jan; Witwer, Kenneth W.; Poole, Alan

doi:10.1016/j.yrtph.2016.09.018

Cited by 8 publications

(11 citation statements)

References 108 publications

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“…Most widely used application of TGx approaches is to understand the molecular mechanisms of different toxicological endpoints ( Ellinger-Ziegelbauer et al, 2008 ; Blomme et al, 2009 ; Rodrigues et al, 2016 ; Hendrickx et al, 2017 ; Rueda-Zárate et al, 2017 ). More recently, in addition to gene expression profiling, the study of microRNAs ( Wang et al, 2009 ; Yang et al, 2012 ; Ward et al, 2014 ; Liu et al, 2016 ) and long non-coding RNAs (lncRNAs) ( Aigner et al, 2016 ; Dempsey and Cui, 2017 ) are emerging as new technologies to be integrated into this field powered by next-generation sequencing technologies ( Yu et al, 2014 ).…”

Section: Introductionmentioning

confidence: 99%

Transcriptional Responses Reveal Similarities Between Preclinical Rat Liver Testing Systems

et al. 2018

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Toxicogenomics (TGx) is an important tool to gain an enhanced understanding of toxicity at the molecular level. Previously, we developed a pair ranking (PRank) method to assess in vitro to in vivo extrapolation (IVIVE) using toxicogenomic datasets from the Open Toxicogenomics Project-Genomics Assisted Toxicity Evaluation System (TG-GATEs) database. With this method, we investiagted three important questions that were not addressed in our previous study: (1) is a 1-day in vivo short-term assay able to replace the 28-day standard and expensive toxicological assay? (2) are some biological processes more conservative across different preclinical testing systems than others? and (3) do these preclinical testing systems have the similar resolution in differentiating drugs by their therapeutic uses? For question 1, a high similarity was noted (PRank score = 0.90), indicating the potential utility of shorter term in vivo studies to predict outcome in longer term and more expensive in vivo model systems. There was a moderate similarity between rat primary hepatocytes and in vivo repeat-dose studies (PRank score = 0.71) but a low similarity (PRank score = 0.56) between rat primary hepatocytes and in vivo single dose studies. To address question 2, we limited the analysis to gene sets relevant to specific toxicogenomic pathways and we found that pathways such as lipid metabolism were consistently over-represented in all three assay systems. For question 3, all three preclinical assay systems could distinguish compounds from different therapeutic categories. This suggests that any noted differences in assay systems was biological process-dependent and furthermore that all three systems have utility in assessing drug responses within a certain drug class. In conclusion, this comparison of three commonly used rat TGx systems provides useful information in utility and application of TGx assays.

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Section: Introductionmentioning

confidence: 99%

Transcriptional Responses Reveal Similarities Between Preclinical Rat Liver Testing Systems

et al. 2018

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“…The weight of evidence approach is a systematic method for decision-making that “involves consideration of known lines of evidence (LoEs) where a ‘weight’ is assigned to each LoE, according to its relevance and reliability.” 31 (p9) Epigenetic data may help corroborate other lines of evidence when only incomplete evidence exists. 32 - 35 In such a holistic approach, demonstration that an epigenetic modification is adverse may not be a precondition. Departure from a normal-range epigenome may become indicative of toxicity in the context of other genomic or physiological evidence.…”

Section: The Promise and Current Status Of Toxicoepigenetics For Risk...mentioning

confidence: 99%

Toxicoepigenetics for Risk Assessment: Bridging the Gap Between Basic and Regulatory Science

et al. 2022

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Toxicoepigenetics examines the health effects of environmental exposure associated with, or mediated by, changes in the epigenome. Despite high expectations, toxicoepigenomic data and methods have yet to become significantly utilized in chemical risk assessment. This article draws on a social science framework to highlight hitherto overlooked structural barriers to the incorporation of toxicoepigenetics in risk assessment and to propose ways forward. The present barriers stem not only from the lack of maturity of the field but also from differences in constraints and standards between the data produced by toxicoepigenetics and the regulatory science data that risk assessment processes require. Criteria and strategies that frame the validation of knowledge used for regulatory purposes limit the application of basic research in toxicoepigenetics toward risk assessment. First, the need in regulatory toxicology for standardized methods that form a consensus between regulatory agencies, basic research, and the industry conflicts with the wealth of heterogeneous data in toxicoepigenetics. Second, molecular epigenetic data do not readily translate into typical toxicological endpoints. Third, toxicoepigenetics investigates new forms of toxicity, in particular low-dose and long-term effects, that do not align well with the traditional framework of regulatory toxicology. We propose that increasing the usefulness of epigenetic data for risk assessment will require deliberate efforts on the part of the toxicoepigenetics community in 4 areas: fostering the understanding of epigenetics among risk assessors, developing knowledge infrastructure to demonstrate applicability, facilitating the normalization and exchange of data, and opening the field to other stakeholders.

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“…LncRNAs play critical roles in these processes (Dempsey & Cui, 2017;Karlsson & Baccarelli, 2016). The roles of lncRNAs in the toxicology of ECs receive great attention and are being investigated (Aigner et al, 2016). Table 1 presented various types of interactions between lncRNAs and ECs.…”

Section: Roles Of Long Non-coding Rna In the Health Impact Of Envirmentioning

confidence: 99%

Emerging roles of long non‐coding RNAs in the toxicology of environmental chemicals

Huang

Liu

Dong

2018

J of Applied Toxicology

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Environmental chemicals (ECs) are drawing great attention to their effects on health and their toxicological mechanisms are being investigated. Long non-coding RNA (lncRNA) is a class of RNA with more than 200 nucleotides and does not have protein coding potential. Recently, it is emerging as a star molecule that participates in a wide range of physiological and pathological processes. It has been reported to be abnormally expressed in diseases. As an epigenetic factor, lncRNAs play an important role in the response of organisms to environmental stress. Their roles in the toxicity of ECs are being identified. Altered expression profiles of lncRNAs have been explored after exposure to ECs. Various kinds of ECs are reported to disturb the expression of lncRNAs in vitro and in vivo. Then, dysregulated lncRNAs can affect the expression of target genes directly or indirectly via regulating the level of microRNAs. The network among lncRNAs, microRNAs and mRNAs can initiate or impede specific signaling pathway and lead to adverse outcome upon exposure to ECs. Recovery of the lncRNAs level by overexpression or knockdown technology diminished the effect induced by ECs. In the review, biological roles of lncRNAs are depicted. The lncRNAs involved in the toxicology are summarized. Types of ECs that have been reported to affect the expression of lncRNAs are categorized. The interaction between various types of ECs and lncRNAs is discussed.

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Advancing the use of noncoding RNA in regulatory toxicology: Report of an ECETOC workshop

Cited by 8 publications

References 108 publications

Transcriptional Responses Reveal Similarities Between Preclinical Rat Liver Testing Systems

Transcriptional Responses Reveal Similarities Between Preclinical Rat Liver Testing Systems

Toxicoepigenetics for Risk Assessment: Bridging the Gap Between Basic and Regulatory Science

Emerging roles of long non‐coding RNAs in the toxicology of environmental chemicals

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