Developing metabolomics approaches for chemical risk assessment

Gruszczynska, Hanna (2023). Developing metabolomics approaches for chemical risk assessment. University of Birmingham. Ph.D.

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Abstract

Chemical use is highly dynamic and the chemical industry is projected to grow four-fold over the next four decades, according to the Organisation for Economic Co-operation and Development (OECD)1. However, complete toxicity data are often lacking for many chemicals and their potential harmful impacts on human and environmental health remain poorly characterised. It is widely recognised that traditional toxicity testing methods are no longer fit for purpose to address the huge backlog of untested substances worldwide. Therefore, there is a rapid demand for novel mechanistic approaches to fill information gaps for more robust chemical safety assessment. Among all omics, metabolomics is particularly well placed to address this knowledge gap as it captures the dynamics of molecular perturbations in a biological system, in response to xenobiotic exposure.

The overarching aim of this thesis was to develop and implement untargeted metabolomics approaches suited for safety assessment of chemicals in regulatory toxicology, exploring both toxicodynamics (TD; i.e. endogenous biochemistry) and toxicokinetics (TK; primarily xenobiotic metabolism). Specifically, two applications of toxicometabolomics were explored: 1) a regulatory scenario of chemical grouping for subsequent read-across (G/RAx), and 2) characterisation of xenobiotic metabolism through untargeted metabolomics. Firstly, a novel G/RAx workflow was developed to conduct biology-based grouping of seven data-poor azo dyes, whereby mechanistic multi-omics data (i.e. metabolic, lipid and transcriptional responses in Daphnia magna) were considered along conventional in silico structure-based approaches. These proof-of-principle investigations demonstrated the potential of metabolomics for more robust chemical grouping to facilitate future toxicity prediction (i.e. read-across), simultaneously addressing the relative lack of similar regulatory-relevant case studies.

Additionally, untargeted (specifically, nESI-DIMS and UHPLC-MS/MS) metabolomics, principally designed to probe the endogenous toxicity responses, unravelled promising insights into the metabolism of xenobiotics, thus demonstrating the ‘added value’ of this approach. Specifically, the TK/ADME (absorption, distribution, metabolism, elimination) information was successfully extracted from untargeted MS\(^1\) nESI-DIMS metabolomics datasets for the seven azo dyes from the multi-omics grouping study. Building upon this work, untargeted UHPLC-MS/MS metabolomics was applied to characterise ADME/TK properties of five industrial chemicals in rat plasma, revealing rich biotransformation patterns for these xenobiotics.

Although further research is warranted to address the existing knowledge gaps (e.g. annotation and identification of xenobiotic biotransformation products), this power to simultaneously characterise TK and TD properties (all within a single toxicometabolomics assay) holds a promising potential for deeper characterisation of chemical toxicity (i.e. via discovery of mode(s) of action, MoAs), ultimately empowering future chemical safety assessment.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):