Unravelling species differences in stress responses to inform the selection, and reduce the use, of animals in preclinical drug safety testing

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Preclinical toxicology studies are a vital component of the drug development process to ensure that new drug candidates are safe for use in humans. As such, the selection of preclinical model species (e.g., mouse, rat, and monkey) should be informed by our understanding of the physiological, anatomical and genetic similarities and differences between these species and humans. One important, though relatively unexplored, aspect is the ability of a given species to sense, adapt to, and tolerate chemical insult via activation of various protective pathways that have evolved to protect cells against stresses such as oxidative stress, DNA damage and protein misfolding. Therefore, this project aims to investigate potential inter-species differences in the sensitivity and activity of various stress response pathways that may influence the translatability of preclinical drug toxicity studies to humans. This project will focus, in particular, on hepatic stress responses to chemical insult as the liver is the site of most drug detoxification and is one of the most common targets of drug toxicity. We will use publicly-available and experimental transcriptomic data to establish inter-species differences in the basal expression of stress response-associated genes, focussing on species that are commonly used during preclinical toxicology studies on new medicines, along with human tissues. Primary hepatocytes from each species will be used to investigate and quantify inter-species differences in the inducible levels of the stress responses. It is hoped that this research will help inform the selection of appropriate species to improve the human translatability of preclinical toxicity studies. Further, this project will contribute to the 3R's by supporting the refinement, and ultimate reduction, of animal use in the drug development process.