An Adverse Outcome Pathway Network for Chemically Induced Oxidative Stress Leading to (Non)genotoxic Carcinogenesis

Abstract

Nongenotoxic (NGTX) carcinogens induce cancer via other mechanisms than direct DNA damage. A recognized mode of action for NGTX carcinogens is induction of oxidative stress, a state in which the amount of oxidants in a cell exceeds its antioxidant capacity, leading to regenerative proliferation. Currently, carcinogenicity assessment of environmental chemicals primarily relies on genetic toxicity end points.Since NGTX carcinogens lack genotoxic potential, these chemicals may remain undetected in such evaluations. To enhance the predictivity of test strategies for carcinogenicity assessment, a shift toward mechanism-based approaches is required. Here, we present an adverse outcome pathway (AOP) network for chemically induced oxidative stress leading to (NGTX) carcinogenesis. To develop this AOP network, we first investigated the role of oxidative stress in the various cancer hallmarks. Next, possible mechanisms for chemical induction of oxidative stress and the biological effects of oxidative damage to macromolecules were considered. This resulted in an AOP network, of which associated uncertainties were explored. Ultimately, development of AOP networks relevant for carcinogenesis in humans will aid the transition to a mechanism-based, human relevant carcinogenicity assessment that involves a substantially lower number of laboratory animals.

A modular strategy for the testing and assessment of non-genotoxic carcinogens

“…A genotoxic carcinogen has the potential to induce cancer by interacting directly with DNA and/or the cellular apparatus involved in the preservation of the integrity of the genome. A non-genotoxic carcinogen has the potential to induce cancer without interacting directly with either DNA or the cellular apparatus involved in the preservation of the integrity of the genome Jacobs MN, Colacci A, Corvi R, et al (2020) '. and AOP pathways are further elucidated by (Veltman et al 2023), according to the OECD NGTxC IATA (Jacobs et al 2020). Additional intermediary core key events of inflammation, immune evasion and suppression, plus apoptotic mechanisms, are also proposed (Corsini et al, Vaccari et al, papers in prep).…”

Increased Cell Proliferation as a Key Event in Chemical Carcinogenesis: Application in an Integrated Approach for the Testing and Assessment of Non-Genotoxic Carcinogenesis

“…Another consideration is the understanding of the potential causal role of oxidative stress in non-genotoxic carcinogenesis, which is not completely understood and remains controversial. There is often an association between pre-carcinogenic lesions and oxidative stress [18], often in association with inflammation. However, direct oxidants (e.g., hydrogen peroxide, H 2 O 2 ) or redox cyclers (such as acetaminophen, due to its metabolite, or paraquat) are not carcinogenic.…”

New approach methodologies to facilitate and improve the hazard assessment of non-genotoxic carcinogens—a PARC project

“…In 2020, an OECD expert group developed an IATA for NGTxCs and published a consensus paper describing the overarching IATA, with the molecular initiating events (MIE) of cellular metabolism and receptor interactions, followed by the early key events (KEs) of inflammation and immune dysfunction, mitotic signaling, and cell injury, leading to (sustained) proliferation, morphological transformation and tumor formation ( Jacobs et al, 2020 ). Several assay evaluations and reviews have been conducted and published in relation to epigenetics ( Desaulniers et al, 2021 ), cell transformation ( Colacci et al, 2023 ), gap junction ( Sovadinova et al, 2021 ), gene signaling ( Oku et al, 2022 ), cell proliferation and oxidative stress ( Veltman et al, 2023 ). These publications provide details on the next steps needed to facilitate developments that will have regulatory relevance for the safety assessment of NGTxCs.…”

“…Oxidative stress, resulting from an imbalance between the generation of oxidants and their scavenging by antioxidants, may lead to sustained cytotoxicity and regenerative proliferation and is therefore a MoA relevant for carcinogenesis ( Hanahan and Weinberg, 2000 ; Hanahan and Weinberg, 2011 ; Leuthold et al, 2019 ; Hanahan, 2022 ). Oxidative stress can be induced through endogenous processes, but also upon exposure to chemical substances ( Heusinkveld et al, 2020b ; Veltman et al, 2023 ). This is known to promote carcinogenesis through DNA damage and impaired repair, as well as through indirect actions influencing homeostasis and signaling ( Klaunig, 2018 ).…”