title: A predictive toxicogenomics signature to classify genotoxic versus non-genotoxic chemicals in human TK6 cells.
abstract: Genotoxicity testing is a critical component of chemical assessment. The use of integrated approaches in genetic toxicology, including the incorporation of gene expression data to determine the DNA damage response pathways involved in response, is becoming more common. In companion papers previously published in Environmental and Molecular Mutagenesis, Li et al. (2015) [6] developed a dose optimization protocol that was based on evaluating expression changes in several well-characterized stress-response genes using quantitative real-time PCR in human lymphoblastoid TK6 cells in culture. This optimization approach was applied to the analysis of TK6 cells exposed to one of 14 genotoxic or 14 non-genotoxic agents, with sampling 4 h post-exposure. Microarray-based transcriptomic analyses were then used to develop a classifier for genotoxicity using the nearest shrunken centroids method. A panel of 65 genes was identified that could accurately classify toxicants as genotoxic or non-genotoxic. In Buick et al. (2015) [1], the utility of the biomarker for chemicals that require metabolic activation was evaluated. In this study, TK6 cells were exposed to increasing doses of four chemicals (two genotoxic that require metabolic activation and two non-genotoxic chemicals) in the presence of rat liver S9 to demonstrate that S9 does not impair the ability to classify genotoxicity using this genomic biomarker in TK6cells.
authors.affiliation: Environmental Health Science and Research Bureau, Health Canada, Ottawa, Ontario, Canada K1A 0K9.
authors.forename: Andrew
authors.initials: A
authors.lastname: Williams
authors.affiliation: Environmental Health Science and Research Bureau, Health Canada, Ottawa, Ontario, Canada K1A 0K9.
authors.forename: Julie K
authors.initials: JK
authors.lastname: Buick
authors.affiliation: Environmental Health Science and Research Bureau, Health Canada, Ottawa, Ontario, Canada K1A 0K9 ; Water and Air Quality Bureau, Health Canada, Ottawa, Ontario, Canada K1A 0K9.
authors.forename: Ivy
authors.initials: I
authors.lastname: Moffat
authors.affiliation: Integrated Laboratory Systems Inc., Research Triangle Park, NC 27709, USA.
authors.forename: Carol D
authors.initials: CD
authors.lastname: Swartz
authors.affiliation: Integrated Laboratory Systems Inc., Research Triangle Park, NC 27709, USA.
authors.forename: Leslie
authors.initials: L
authors.lastname: Recio
authors.affiliation: Biological Engineering Department, Utah State University, Logan, UT 84322, USA ; Department of Biochemistry and Molecular and Cellular Biology, and Department of Oncology, Georgetown University Medical Center, Washington, District of Columbia 20057, USA.
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Hyduke
authors.affiliation: Department of Biochemistry and Molecular and Cellular Biology, and Department of Oncology, Georgetown University Medical Center, Washington, District of Columbia 20057, USA.
authors.forename: Heng-Hong
authors.initials: HH
authors.lastname: Li
authors.affiliation: Department of Biochemistry and Molecular and Cellular Biology, and Department of Oncology, Georgetown University Medical Center, Washington, District of Columbia 20057, USA.
authors.forename: Albert J
authors.initials: AJ
authors.lastname: Fornace
authors.affiliation: Drug Safety Research and Development, Pfizer Inc., Groton, CT 06340, USA.
authors.forename: Jiri
authors.initials: J
authors.lastname: Aubrecht
authors.affiliation: Environmental Health Science and Research Bureau, Health Canada, Ottawa, Ontario, Canada K1A 0K9.
authors.forename: Carole L
authors.initials: CL
authors.lastname: Yauk