Abstract
A criterion frequently used to group chemicals in risk assessment is “mode of toxic action” (MoA). Routinely, structure-based approaches are used for the MoA categorization of chemicals, but they can produce conflicting results or fail to classify compounds. Biological activity-based approaches such as toxicogenomics which provide an unbiased overview of the transcriptomic changes after exposure to a compound may complement structure-based approaches in MoA assignment. Here, we investigate whether toxicogenomic profiles as generated after in vitro exposure of an established cell line (C3A hepatoma cells) are able to group together chemicals with an uncoupling MoA, and to distinguish the uncouplers from chemicals with other MoAs. In a first step, we examined whether chemicals sharing the same uncoupling of oxidative phosphorylation (OXPHOS) MoA produce similar toxicogenomic profiles and can be grouped together. In a next step, we tested whether the toxicogenomic profiles discriminate between OXPHOS and chemicals displaying a (polar) narcotic MoA. Experimentally, cells were exposed in vitro to equipotent concentrations of the test compounds and gene expression profiles were measured. The resulting toxicogenomic profiles assigned OXPHOS to one cluster and discriminated between the OXPHOS and the (polar) narcotics. In addition, the toxicogenomics data revealed that one and the same chemical can display multiple MoAs, which may help to explain conflicting results of MoA classification from structure-based approaches. The results strongly suggest the feasibility of MoA grouping of chemicals by using in vitro cell assay-based toxicogenomic profiles.
Highlights
Chemical risk assessment has to deal with a large and ever growing number of chemical substances
MoA is a loosely defined term used in both human toxicology and ecotoxicology, In this article, MoA is referred to as key toxic processes (Escher and Hermens, 2002; Vonk et al, 2009; Carmichael et al, 2011; Kienzler et al, 2017)
As recently reviewed by Kienzler et al (2017), various structure-based classification schemes have been developed to group chemicals according to their MoAs, including the Verhaar scheme which classifies chemicals on the basis of correlations between apical toxic endpoints such as lethality and chemical descriptors like octanol-water partition coefficient (Verhaar et al, 1992), or the ASTER scheme of the US EPA which utilizes, among others, fish behavioral responses for MoA classification (Barron et al, 2015)
Summary
Chemical risk assessment has to deal with a large and ever growing number of chemical substances. One possibility is to assign MoA based on molecular interactions between the chemical and the biological system which initiate specific toxicity pathways like binding to the estrogen receptors, or measuring specific cellular reactions that are indicative for specific effects such as chlorophyll interference in tests with algae (Hamadeh et al, 2002; Escher et al, 2005; Nendza and Wenzel, 2006; Woods et al, 2007; Pereira-Fernandes et al, 2014) Another approach is the grouping of chemicals on the basis of structural rules (Schüürmann, 1998; Verhaar et al, 2000; Enoch et al, 2008; Blackburn et al, 2011). It has been suggested to extend the structure-based approaches to biological descriptors (Richard, 2006)
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