Abstract
Insights into the modes of action (MoAs) of xenobiotics are of utmost importance for the definition of adverse outcome pathways (AOPs), which are essential for a mechanism-based risk assessment. A well-established strategy to reveal MoAs of xenobiotics is the use of omics. However, often an even more comprehensive approach is needed, which can be achieved using multi-omics. Since the immune system plays a central role in the defense against foreign substances and pathogens, with the innate immune system building a first barrier, we systematically reviewed multi-omics studies investigating the effects of xenobiotics on macrophages. Surprisingly, only nine publications were identified, combining proteomics with transcriptomics or metabolomics. We summarized pathways and single proteins, transcripts, or metabolites, which were described to be affected upon treatment with xenobiotics in the reviewed studies, thus revealing a broad range of effects. In summary, we show that macrophages are a relevant model system to investigate the toxicological effects induced by xenobiotics. Furthermore, the multi-omics approaches led to a more comprehensive overview compared to only one omics layer with slight advantages for combinations that complement each other directly, e.g., proteome and metabolome.
Highlights
One step towards a facilitated risk assessment of xenobiotics is to identify approaches, which allow to decipher modes of action (MoAs)
Thereby, the statins acted via the pregnane X receptor (PXR), which is related to the detoxification of xenobiotics and has been shown to affect the induction of the NLR family pyrin domain containing 3 (NLRP3) inflammasome in endothelial cells [41] and macrophages [42]
Based on the here presented publications, the combination of proteome and metabolome seems to be preferable even though both combinations might be generally beneficial to decipher xenobiotics MoAs
Summary
One step towards a facilitated risk assessment of xenobiotics is to identify approaches, which allow to decipher modes of action (MoAs). Xenobiotics can be a molecular initiating event (MIE), followed by causally related intermediate events, called key events (KEs), resulting in an adverse outcome (AO), which is referred to as adverse outcome pathway (AOP) [1]. Unravelling AOPs is relevant for risk assessment and the regulation of xenobiotics since it allows to understand undesirable effects better [1,2]
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