Addressing systematic inconsistencies between in vitro and in vivo transcriptomic mode of action signatures

Toxicology in Vitro : an International Journal Published in Association with BIBRA
Patrick D McMullenRebecca A Clewell

Abstract

Because of their broad biological coverage and increasing affordability transcriptomic technologies have increased our ability to evaluate cellular response to chemical stressors, providing a potential means of evaluating chemical response while decreasing dependence on apical endpoints derived from traditional long-term animal studies. It has recently been suggested that dose-response modeling of transcriptomic data may be incorporated into risk assessment frameworks as a means of approximating chemical hazard. However, identification of mode of action from transcriptomics lacks a similar systematic framework. To this end, we developed a web-based interactive browser-MoAviz-that allows visualization of perturbed pathways. We populated this browser with expression data from a large public toxicogenomic database (TG-GATEs). We evaluated the extent to which gene expression changes from in-life exposures could be associated with mode of action by developing a novel similarity index-the Modified Jaccard Index (MJI)-that provides a quantitative description of genomic pathway similarity (rather than gene level comparison). While typical compound-compound similarity is low (median MJI = 0.026), clustering of the TG-GATES compounds ide...Continue Reading

Citations

May 19, 2020·Nucleic Acids Research·Sisira Kadambat NairBenjamin Haibe-Kains
Oct 20, 2019·Toxicology in Vitro : an International Journal Published in Association with BIBRA·Patrick D McMullenMelvin E Andersen
Dec 28, 2019·Toxicology and Applied Pharmacology·Rance NaultVenkataraman Bringi
Dec 31, 2020·Chemical Research in Toxicology·Mirjam LuijtenHarm J Heusinkveld

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