Funding period: 2019-2024
Lead: Francesco Marchetti and Matthew Meier
Total GRDI funding: $1,190,000
This program aims to produce genomic solutions to reduce costs and animal use, and increase the speed of regulatory toxicology testing of environmental chemicals. The goal is to develop and implement genomic methods in human cells in culture for hazard identification and risk assessment. To accomplish this, the research leverages the Adverse Outcome Pathway (AOP) framework, which catalogues and weighs the evidence linking cellular/tissue level perturbations to detrimental health outcomes following chemical exposures. It is being used to predict whether a chemical agent causes mutations, chromosome damage, and other genetic effects that lead to diseases such as cancer and developmental toxicity. Case studies applying these modern testing strategies are then applied in collaboration with Health Canada's regulatory community to evaluate effectiveness, feasibility and willingness to adopt the strategies for decision-making related to human health risk assessment.
Publications
- Buick JK, Williams A, Meier MJ, Swartz CD, Recio L, Gagné R, Ferguson SS, Engelward BP, Yauk CL. 2021. A modern genotoxicity testing paradigm: Integration of the high-throughput CometChip® and the TGx-DDI transcriptomic biomarker in human HepaRG™ cell cultures. Front Public Health. 2021. 9:694834. https://doi.org/10.3389/fpubh.2021.694834
- Buick JK, Rowan-Carroll A, Gagné R, Williams A, Chen R, Li H-H, Fornace AJ, Chao C, Engelward BP, Frötschl R, Ellinger-Ziegelbauer H, Pettit SD, Aubrecht J, Yauk CL. 2022. Integrated Genotoxicity Testing of three anti-infective drugs using the TGx-DDI transcriptomic biomarker and high-throughput CometChip® assay in TK6 cells. Front. Toxicol. 4:991590. https://doi.org/10.3389/ftox.2022.991590
- Buick JK, Williams A, Gagné R, Swartz CD, Recio L, Ferguson SS, Yauk CL. 2020. Flow cytometric micronucleus assay and TGx-DDI transcriptomic biomarker analysis of ten genotoxic and non-genotoxic chemicals in human HepaRG™ cells. Genes and Environ. 42(1):5. https://doi.org/10.1186/s41021-019-0139-2
- Chauhan V, Wilkins R, Beaton D, Sachana M, Delrue N, Yauk C, O'Brien J, Marchetti F, Halappanavar S, Boyd M, Villeneuve D, Barton-Maclaren TS, Meek B, Anghel C, Heghes C, Barber C, Perkins E, Leblanc J, Burtt J, Laakso H, Laurier D, Lazo T, Whelan M, Thomas R, Cool D. 2021. Bringing Together Scientific Disciplines for Collaborative Undertakings: A Vision for Advancing the Adverse Outcome Pathway Framework. Int J Radiat Biol. 4:1-30. https://doi.org/ 10.1080/09553002.2021.1884314
- Cho E, Allemang A, Audebert M, Chauhan V, Dertinger S, Hendriks G, Luijten M, Marchetti F, Minocherhomji S, Pfuhler S, Roberts DJ, Trenz K, Yauk CL. 2019. AOP 296: Oxidative DNA damage leading to chromosomal aberrations and mutations. Submitted to the External Advisory Group for Molecular Screening and Toxicogenomics of the OECD on the AOP-wiki (November 2019). https://aopwiki.org/aops/296
- Cho E, Allemang A, Audebert M, Chuahan V, Dertinger S, Hendriks G, Luijten M, Marchetti F, Minocherhomji S, Pfuhler S, Roberts D, Trenz K, Yauk CL. Development of an Adverse Outcome Pathway for oxidative DNA damage leading to mutations and chromosomal aberrations. Environ Mol Mutagen. 63:118-134. https://doi.org/10.1002/em.22479
- Cho E, Rowan-Carroll A, Williams A, Corton JC, Li H-H, Fornace AJ Jr, Hobbs CA, Yauk CL. 2021. Development and validation of the TGx-HDACi transcriptomic biomarker to detect histone deacetylase inhibitors in human TK6 cells. Arch. Toxicol. 95(5):1631-1645. https://doi.org/10.1007/s00204-021-03014-2
- Cho E, Schwatz CD, William A, Rivas M, Recio L, Witt KL, Schmidt EK, Yaplee F, Smith TH, Van P, Lo FY, Valentine CC, Salk JJ, Marchetti F, Smith-Roe SL, Yauk CL. 2023. Error-corrected duplex sequencing enables direct detection and quantification of mutations in human TK6 cells with strong inter-laboratory consistency. Mutation Research. Epub: May 20, 2023. https://doi.org/10.1016/j.mrgentox.2023.503649
- Cho E, Williams A, Yauk CL. 2021. A transcriptomic dataset used to derive biomarkers of chemically induced histone deacetylase inhibition (HDACi) in human TK6 cells. Data Brief. 36:e107097. https://doi.org/10.1016/j.dib.2021.107097
- Corton JC, Liu J, Williams A, Cho E, Yauk CL. 2022. A Gene Expression Biomarker Identifies Inhibitors of Two Classes of Epigenome Effectors in a Human Microarray Compendium. Chemico--Biological Interactions. 635:110032. https://doi.org/10.1016/j.cbi.2022.110032
- Corton JC, Witt KL, Yauk CL. 2019. Identification of p53 activators in a human microarray compendium. Chem. Res. Toxicol. 32(9):1748-1759. https://doi.org/10.1021/acs.chemrestox.9b00052
- Fortin AV, Long AS, Williams A, Meier MJ, Cox J, Pinsonnault C, Yauk CL, White PA. Application of a new approach methodology (NAM)-based strategy for genotoxicity assessment of data-poor compounds. Front Toxicol. 2023. 5:1098432. https://doi.org/10.3389/ftox.2023.1098432
- Gannon AM, Moreau M, Farmahin R, Thomas RS, Barton-Maclaren T, Nong A, Curran I, Yauk CL. 2019. Hexabromocyclododecane (HBCD): a case study applying tiered testing for human health risk assessment. Food Chem. Toxicol. 131:e110581. https://doi.org/10.1016/j.fct.2019.110581
- Harrill JA, Viant MR, Yauk CL, Sachana M, Gant TW, Auerbach SS, Beger RD, Bouhifd M, O'Brien J, Burgoon L, Caiment F, Carpi D, Chen T, Chorley BN, Colbourne J, Corvi R, Debrauwer L, O'Donovan C, Ebbels TMD, et al.2021. Progress towards an OECD reporting framework for transcriptomics and metabolomics in regulatory toxicology. Regulatory Toxicology and Pharmacology, 125, [105020]. https://doi.org/10.1016/j.yrtph.2021.105020
- Huliganga E, Marchetti F, O'Brien JM, Chauhan V, Carole LY. 2022. A case study on integrating a new key event into an existing Adverse Outcome Pathway on oxidative damage: challenges and approaches in a data rich area. Frontiers in Toxicology, 4:827328. https://doi.org/10.3389/ftox.2022.827328
- Krewski D, Andersen ME, Tyshenko MG, Krishnan K, Hartung T, Boekelheide K, Wambaugh JF, Jones D, Whelan M, Thomas R, Yauk C, Barton-Maclaren T, Cote I. 2019. Toxicity testing in the 21st century: progress in the past decade and future perspectives. Arch. Toxicol. 94:1-58. https://doi.org/10.1007/s00204-019-02613-4
- Kuo B, Beal MA, Wills J, White P, Marchetti F, Nong A, Barton-Maclaren, Houck K, Yauk CL. 2022. Comprehensive interpretation of in vitro micronucleus test results for 292 chemicals: from hazard identification to risk assessment application. Arch Toxicol. 96(7):2067-2085. https://doi.org/10.1021/es501955g
- Lawson TN, Leite SB, Leonards PEG, Luijten M, Martin A, Moussa L, Rudaz S, Schmitz O, Sobanski T, Strauss V, Vaccari M, Vijay V, Weber RJM, Williams AJ, Williams A, Thomas RS, Whelan M. 2021. Progress towards an OECD reporting framework for transcriptomics and metabolomics in regulatory toxicology. Regul Toxicol Pharmacol. 125:105020. https://doi.org/10.1016/j.yrtph.2021.105020
- Li H-H, Yauk CL, Chen R, Hyduke DR, Williams A, Frötschl R, Ellinger-Ziegelbauer H, Pettit S, Aubrecht J, Fornace AJ Jr. 2019. TGx-DDI, a transcriptomic biomarker for genotoxicity hazard assessment of pharmaceuticals and environmental chemicals. Front. Big Data. 2:e36. https://doi.org/10.3389/fdata.2019.00036
- Martus HJ, Fröetschl R, Gollapudi B, Honma M, Marchetti F, Pfuhler S, Schoeny R, Uno Y, Yauk C, Kirkland DJ. 2020. Summary of major conclusions from the 7th international workshop on genotoxicity testing (IWGT), Tokyo, Japan. Mutat. Res./Genet. Toxicol. Environ. Mutagen. 852:e503134. https://doi.org/10.1016/j.mrgentox.2020.503134
- Peshdary V, Hobbs CA, Maynor T, Shepard K, Gagné R, Williams A, Kuo B, Chepelev B, Recio L, Yauk C, Atlas E. 2021. Transcriptomics and Relative Potency Assessments using Bench Mark Dose of Bisphenol A, Bisphenol S, Bisphenol F, and 3,3',5,5'-Tetrabromobisphenol A in H9 human embryonic stem cells. Toxicol In Vitro. 72:105097. https://doi.org/10.1016/j.tiv.2021.105097
- Rowan-Carroll A, Reardon A, Leingartner K, Gagné R, Williams A, Meier MJ, ... & Yauk C. 2021. High-throughput transcriptomic analysis of human primary hepatocyte spheroids exposed to per-and polyfluoroalkyl substances as a platform for relative potency characterization. Toxicological Sciences, 181(2): 199-214. https://doi.org/10.1093/toxsci/kfab039
- Sasaki JC, Allemang A, Bryce SM, Custer L, Dearfield KL, Dietz Y, Elhajouji A, Escobar PA, Fornace AJ Jr, Fröetschl R, Galloway S, Hemmann U, Hendriks G, Li H-H, Luijten M, Ouedraogo G, Peel L, Pfuhler S, Roberts DJ, Thybaud V, van Benthem J, Yauk CL, Schuler M. 2020. Application of the adverse outcome pathway (AOP) framework to genotoxic modes of action (MOA). Environ. Mol. Mutagen. 61(1):114-134. https://doi.org/10.1002/em.22339
- Verheijen MC, Meier MJ, Asensio JO, Gant TW, Tong W, Yauk CL, Caiment F. 2022. R-ODAF: Omics data analysis framework for regulatory application. Regulatory Toxicology and Pharmacolog. 131:105143. https://doi.org/10.1016/j.yrtph.2022.105143
- Yauk CL, Harrill AH, Ellinger-Ziegelbauer H, van der Laan JW, Moggs J, Fröetschl R, Sistare F, Pettit S. 2020. A cross-sector call to improve carcinogenicity risk assessment through use of genomic methodologies. Regul. Toxicol. Pharmacol. 110:e104526. https://doi.org/10.1016/j.yrtph.2019.104526
- Yauk CL, Heflich RH, DeMarini DM. 2020. Celebrating 50 years of EMGS: a visionary idea continues. Environ. Mol. Mutagen. 61(1):5-6. https://doi.org/10.1002/em.22350
Contact us
For additional information, please contact:
Genomics R&D Initiative
Email: info@grdi-irdg.collaboration.gc.ca