AOP report: Development of an adverse outcome pathway for oxidative DNA damage leading to mutations and chromosomal aberrations

Abstract

The Genetic Toxicology Technical Committee (GTTC) of the Health and Environmental Sciences Institute (HESI) is developing adverse outcome pathways (AOPs) that describe modes of action leading to potentially heritable genomic damage. The goal was to enhance the use of mechanistic information in genotoxicity assessment by building empirical support for the relationships between relevant molecular initiating events (MIEs) and regulatory endpoints in genetic toxicology.Herein, we present an AOP network that links oxidative DNA damage to two adverse outcomes (AOs): mutations and chromosomal aberrations. We collected empirical evidence from the literature to evaluate the key event relationships between the MIE and the AOs, and assessed the weight of evidence using the modified Bradford-Hill criteria for causality. Oxidative DNA damage is constantly induced and repaired in

A Case Study on Integrating a New Key Event Into an Existing Adverse Outcome Pathway on Oxidative DNA Damage: Challenges and Approaches in a Data-Rich Area

“… Flow diagram of the adverse outcome pathway “Oxidative damage leading to mutations and chromosomal aberrations” ( Cho et al, 2022 ) with the inclusion of an upstream KE “increase in cellular ROS”, which represents the eventual consensus ROS KE, occurring after the multiple MIEs by which ROS are produced after toxicant exposure, and the resulting new KERs. …”

“…Initial work within the GTTC developed AOP #296: ‘Oxidative DNA damage leading to chromosomal aberrations and mutations’ ( Cho et al, 2022 ) ( Figure 2 ). This pathway was first suggested during a GTTC workshop in 2017, where the pathway was used to demonstrate how AOPs could be harnessed to advance mode of action analysis in genetic toxicology ( Sasaki et al, 2020 ).…”

“…It can lead to an increase in mutations (AO1), arising from replication of damaged template DNA, and/or to an increase in DNA strand breaks (KE2), occurring from the DNA repair process removing oxidative lesions. An increase in DNA strand breaks (KE2) can overwhelm the repair capacity and cause inadequate repair (KE1), leading to an increase in chromosomal aberrations (AO2) ( Cho et al, 2022 ).…”

“… Flow diagram of the adverse outcome pathway ‘Oxidative damage leading to mutations and chromosomal aberrations’ ( Cho et al, 2022 ). …”

Introducing AOP Reports: Collaborative review and publication of adverse outcome pathways

“…Instructions for authors that wish to contribute such articles will be made available on EMM's website. As part of this launch, we also are very pleased to introduce the very first AOP Report article (Cho et al, 2022). This article describes an AOP for oxidative DNA damage leading to mutations and chromosomal aberrations.…”