Progress towards an OECD reporting framework for transcriptomics and metabolomics in regulatory toxicology

Harrill, Joshua; Viant, Mark R.; Yauk, Carole; Sachana, Magdalini; Gant, Timothy W.; Auerbach, Scott S.; Beger, Richard D.; Bouhifd, Mounir; O’Brien, Jason M.; Burgoon, Lyle D.; Caiment, Florian; Carpi, Donatella; Chen, Tao; Chorley, Brian N.; Colbourne, John K.; Corvi, Raffaella; Debrauwer, Laurent; O′Donovan, Claire; Ebbels, Timothy M. D.; Ekman, Drew R.; Faulhammer, Frank; Gribaldo, Laura; Hilton, Gina M.; Jones, Stephanie P.; Kende, Anikó; Lawson, Thomas N.; Leite, Sofia B.; Leonards, P.E.G.; Luijten, Mirjam; Martin, Alberto J. M.; Moussa, Laura; Rudaz, Serge; Schmitz, Oliver; Sobański, Tomasz; Strauss, Volker; Vaccari, Monica; Vijay, Vikrant; Weber, Ralf; Williams, Antony; Williams, Andrew; Thomas, Russell S.; Whelan, Maurice

doi:10.1016/j.yrtph.2021.105020

Cited by 52 publications

(39 citation statements)

References 39 publications

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“…With the increasing understanding of cell culture conditions that may affect the epigenetic system and where biases may occur in the interpretation of effects induced by chemicals [100], there is a need for consistent and transparent reporting formats [221], as being developed for omics reporting at the OECD. Mass spectrometry analyses demonstrate that HPTM alterations occur with the transitions from the original tissues to primary cell cultures, and then to (immortalised, transformed and transfected) cell lines, with losses of acetylation marks being the earliest changes.…”

Section: Extrapolation From In Vitro Culture Systemsmentioning

confidence: 99%

Integration of Epigenetic Mechanisms into Non-Genotoxic Carcinogenicity Hazard Assessment: Focus on DNA Methylation and Histone Modifications

Desaulniers

Vasseur

Jacobs

et al. 2021

IJMS

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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.

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Section: Extrapolation From In Vitro Culture Systemsmentioning

confidence: 99%

Integration of Epigenetic Mechanisms into Non-Genotoxic Carcinogenicity Hazard Assessment: Focus on DNA Methylation and Histone Modifications

Desaulniers

Vasseur

Jacobs

et al. 2021

IJMS

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“…Reference standards can serve 2 purposes: first, they are required to achieve the highest level of confidence in metabolite identification, so-called MSI level 1 ( Sumner et al , 2007 ); and they are required if the absolute quantification of metabolites is sought. The levels of analytical confidence in both the identification and quantification of each metabolite measured in metabolomics or targeted metabolite assay will need to be reported according to the OECD Metabolomics Reporting Framework ( Harrill et al , 2021 ). Assay types were sourced from BASF, Bowes-44, Tox21, CTD, and multiple publications.…”

Section: Resultsmentioning

confidence: 99%

“…Although this problem can be alleviated using translation tools ( van Iersel et al , 2010 ; Wohlgemuth et al , 2010 ), sometimes these tools do not recognize metabolite names/identifiers leading to manual translation of the identifiers. For metabolomics to grow as a tool for assessing chemical hazards, it will be important that study authors define metabolite names and identifiers, as recently proposed in the OECD Metabolomics Reporting Framework ( Harrill et al , 2021 ). A further difficulty encountered was incomplete metabolic names, mainly for lipids, making it impossible to identify some potential biomarkers.…”

Section: Discussionmentioning

confidence: 99%

Knowledge-Driven Approaches to Create the MTox700+ Metabolite Panel for Predicting Toxicity

Sostare

Lawson

Saunders

et al. 2022

Toxicological Sciences

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Endogenous metabolite levels describe the molecular phenotype that is most downstream from chemical exposure. Consequently, quantitative changes in metabolite levels have the potential to predict mode-of-action and adversity, with regulatory toxicology predicated on the latter. However, toxicity-related metabolic biomarker resources remain highly fragmented and incomplete. While development of the S1500+ gene biomarker panel has accelerated the application of transcriptomics to toxicology, a similar initiative for metabolic biomarkers is lacking. Our aim was to define a publicly-available metabolic biomarker panel, equivalent to S1500+, capable of predicting pathway perturbations and/or adverse outcomes. We conducted a systematic review of multiple toxicological resources, yielding 189 proposed metabolic biomarkers from existing assays (BASF, Bowes-44 and Tox21), 342 biomarkers from databases (Adverse Outcome Pathway Wiki, Comparative Toxicogenomics Database, QIAGEN Ingenuity Pathway Analysis, and Toxin and Toxin-Target Database), and 435 biomarkers from the literature. Evidence mapping across all eight resources generated a panel of 722 metabolic biomarkers for toxicology (MTox700+), of which 462 (64%) are associated with molecular pathways and 575 (80%) with adverse outcomes. Comparing MTox700+ and S1500+ revealed that 418 (58%) metabolic biomarkers associate with pathways shared across both panels, with further metabolites mapping to unique pathways. Metabolite reference standards are commercially available for 646 (90%) of the panel metabolites, and assays exist for 578 (80%) of these biomarkers. This study has generated a publicly-available metabolic biomarker panel for toxicology, which through its future laboratory deployment, is intended to help build foundational knowledge to support the generation of molecular mechanistic data for chemical hazard assessment.

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“…In the era of NAM, a WoE approach that integrates multiple data streams is increasingly adopted in the Next Generation Risk Assessement. Transcriptomics has gained tremendous traction as an emerging high-coverage omics platform 76 and its importance to mechanistically-based safety assessment should be better appreciated and interpreted.…”

Section: Discussionmentioning

confidence: 99%

The phosphoproteome is a first responder in tiered cellular adaptation to chemical stress followed by proteomics and transcriptomics alteration

Chen

et al. 2022

Preprint

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Next-generation risk assessment for environmental chemicals and ingredients in consumer products involves a weight of evidence (WoE) framework integrating a suite of new approach methodologies (NAMs) based on points of departure (PoD) obtained from in vitro assays. Omics techniques provide broad coverages of the molecular toxicity pathway space. Transcriptomics assays especially play a leading role by providing relatively conservative PoDs in comparison with apical endpoints. However, it is unclear whether and how parameters measured using other omics technicquesparticipate in the cellular response to chemical perturbations, especially at exposure levels below the transcriptomically defined PoD. Multi-omics coverage may provide additional sensitive or confirmative biomarkers to complement and reduce the uncertainty in safety decisions made using targeted and transcriptomics assays. In the present study, we compared changes in transcriptomics, proteomics and phosphoproteomics with two prototype compounds, coumarin, as a main study and doxorubicin, as a complementary study to understand the sensitivity of the three omics techniques in response to chemically-induced changes in HepG2 and AC16 cells. With measurements obtained for multiple chemical concentrations and time points, we demonstrated that, compared with proteomics and transcriptomics, phosphoproteomics alterations occur not only earlier in time as expected, but also at much lower chemical concentrations and hence are proximal to the very early effects induced by chemical exposure. The phosphoproteomics changes appear to approach maximum when the transcriptomics alterations begin to be initiated. The results are consistent with a tiered framework of cellular response to chemical insults, where posttranslational modification of preexisting proteins is first seen before transcriptomics induction is engaged to launch a more energy-expensive defense that defines a useful PoD. We conclude that as the cost becomes more affordable, proteomics covering posttranslational modifications can be utilized to provide a more complete coverage of chemical-induced cellular alteration and supplement transcriptomics-based health safety decision making.

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Progress towards an OECD reporting framework for transcriptomics and metabolomics in regulatory toxicology

Cited by 52 publications

References 39 publications

Integration of Epigenetic Mechanisms into Non-Genotoxic Carcinogenicity Hazard Assessment: Focus on DNA Methylation and Histone Modifications

Integration of Epigenetic Mechanisms into Non-Genotoxic Carcinogenicity Hazard Assessment: Focus on DNA Methylation and Histone Modifications

Knowledge-Driven Approaches to Create the MTox700+ Metabolite Panel for Predicting Toxicity

The phosphoproteome is a first responder in tiered cellular adaptation to chemical stress followed by proteomics and transcriptomics alteration

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