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A Pathway Analysis, Connectivity Mapping and Transcriptional Benchmark Dosing Based Exploration of Oxidative Stress Mediated Genetic Toxicology Modes of Actions

ABSTRACT: While current genetic toxicology practices can detect downstream genotoxicity effects, such as gene mutation and double strand breaks, they are unable to detect the underlying Mode of Action (MoA) of a chemical or differentiate between direct and indirect acting genotoxicants without additional modification. The Adverse Outcome Pathway (AOP) framework is a useful tool to critically identify and evaluate MOAs and can enable subsequent quantitative dose response assessments of genotoxicity endpoints. The recently developed AOP, “Oxidative DNA damage leading to chromosomal aberrations and mutations” ( https://aopwiki.org/aops/296), pertains to one common genetic toxicology relevant MOA: oxidative stress. ROS are key to regulating many biological processes, however, when disrupted, an excess of ROS can eventually lead to DNA damage and double-strand breaks. Here, we look at 18 compounds with a complete or mixed oxidative stress MOA and use a combination of genomic tools such as Pathway analysis, Connectivity mapping and Transcriptional benchmark dose modeling to investigate the diversity of mechanisms that contribute to genotoxicity. TK6 cells were treated with the 18 compounds for 4 hours and the resulting genomic data was analyzed in correlation to the downstream genotoxic endpoint, micronucleus formation. We provide both a qualitative and quantitative analysis of the contribution of oxidative stress MoAs towards the overall genotoxicity outcome of each chemical. These methods have the potential to evolve into Next Generation Risk Assessment (NGRA) tools that can be used for determining the contribution of the oxidative stress MoA in a predictive toxicology setting.

ORGANISM(S): Homo sapiens

PROVIDER: GSE287194 | GEO | 2025/04/01

REPOSITORIES: GEO

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Project description:Adverse outcome pathways (AOP) contain summarizing sequences of key events (KE) relating toxicant exposures to specific adverse outcomes (AO) observed in exposed populations. Quantitative AOPs (qAOP) provide frameworks to assess AO risks based on KE quantification and the modeling of their relationships. This work aimed to develop the quantitative component of AOP 411 <Oxidative stress leading to decreased lung function>. To examine the pertinence of the resulting qAOP-based risk assessment approach, we applied it to predict the medium-term lung function evolution after switching from combustible cigarettes (CC) to heated tobacco products (HTP). We used publicly available data for oxidative stress (in vitro), ciliary beating frequency (in vitro), mucociliary clearance (human), and lung function (human). Following the course of smoking-related lung function decline (Fletcher and Peto, 1977, PMID 871704), we assumed a non-monotonic time evolution where the risk of the AO <decreased lung function> begins to decline after quitting smoking CC or switching to HTP use. Consequently, we designed our qAOP to evaluate the relative reduction (RR) of AO risk for HTP switching compared to the two scenarios of continuing or quitting CC consumption. We developed both data- and physiology-based KE relationship (KER) models. Despite sparse data with respect to dose- and time-response relationships, we successfully connected the measured KEs through in silico KER models. We then used the resulting qAOP to evaluate the exposure effects of switching from CC smoking to HTP use along AOP 411. This approach enabled in silico prediction of the AO RR for which in vivo data were not yet available. In summary, our qAOP provides a multiscale mechanistic approach to evaluate medium-term lung function evolution for the use case of switching from CC smoking to HTP use. The presented approach demonstrates how 21st Century Toxicology principles such as in vitro testing and in silico predictions can be integrated to achieve a meaningful risk assessment approach. It also represents a starting point for integrating additional AOP into an extended AOP network that includes other mechanisms leading to decreased lung function.

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A Pathway Analysis, Connectivity Mapping and Transcriptional Benchmark Dosing Based Exploration of Oxidative Stress Mediated Genetic Toxicology Modes of Actions

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