Stress response pathways, toxicity pathways and adverse outcome pathways

Abstract

The aim of this editorial is to address ambiguities and misconceptions regarding the terms stress response pathways, toxicity pathways and adverse outcome pathways. A large number of tightly regulated stress response pathways have evolved to allow cells to cope with and manage different types of cell stress. The purpose of these pathways is to maintain or reinstate homoeostasis in the face of perturbations of particular cellular processes. Here, I give a few well-characterised examples [for an in-depth review of these and other stress response pathways see (Jennings et al. 2012)]. The granddaddy of stress response pathways is the p53 pathway. It is considered a gatekeeper of DNA integrity, preventing cells with compromised DNA from proliferating further and thus can be considered a DNA damage stress response. Its activation induces the transcription of genes which, depending on the context lead to cell cycle arrest, senescence or apoptosis. Failure of the p53 pathway to engage correctly allows the propagation of cells with unstable DNA and is one of the major initiators of cancer development. The Nrf2 pathway is the main oxidative stress response and thus also of high importance to the field of toxicology. The activation of this pathway induces the transcription of genes involved in glutathione synthesis, glutathione recycling and detoxification. The lack of appropriate Nrf2 activation would result in a rapid depletion of glutathione leading to cell death at ordinarily tolerable concentrations of oxidant. This is illustrated in Nrf2 knockout mice, which are far more sensitive to acetaminophen than wild type mice (Enomoto et al. 2001). Harnessing the Nrf2 pathway also has therapeutic potential. Indeed, activation of Nrf2 via modification of its inhibitor KEAP-1 with bardoxolone methyl is in late clinical trials for the treatment of chronic renal disease progression (Crunkhorn 2012). The unfolded protein response (UPR) is activated by perturbations in the endoplasmic reticulum (ER) environment or due to protein overloading, collectively termed ER stress. The pathway temporarily shuts down protein translation and activates three transcriptional master regulators, ATF4, ATF6 and XBP1. These transcription factors have specific roles in the restoration of translation, increasing molecular chaperones and induction of both amino acid utilisation and aminoacyl tRNA synthetases. Several other stress response pathways have been identified, including the hypoxic stress response (regulated by hypoxia inducible factor) and the heavy metal stress response (regulated by metal responsive transcription factor). In the context of toxicology, it is important to remember that these stress response pathways are not the perturbation but the response to the perturbation. A toxicity pathway was defined in the National Research Council’s (NRC), Toxicity testing in the 21st century: a vision and a strategy, as ‘‘cellular response pathways that, when sufficiently perturbed in an intact animal, are expected to result in adverse health effects’’ (NRC 2007). This would by definition exclude stress response pathways as (1) their activation is a normal biological response to a specific stimulus not a perturbation and (2) they function to protect the cell or the tissue. However, I am certain the authors did not mean to exclude stress response pathways, especially since in a follow-up review the Nrf2 pathway was used to illustrate the toxicity pathway concept (Krewski et al. 2010). Adverse outcome pathways (AOPs) were first described in the field of ecotoxicology as ‘‘a P. Jennings (&) Division of Physiology, Department of Physiology and Medical Physics, Innsbruck Medical University, Fritz-Pregl Strasse 3/1, 6020 Innsbruck, Austria e-mail: paul.jennings@i-med.ac.at; paul.other@gmail.com URL: http://physiologie.i-med.ac.at/jennings