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An Adverse Outcome Pathway Network for Chemically Induced Oxidative Stress Leading to (Non)genotoxic Carcinogenesis
Christina H J Veltman1,2, Jeroen L A Pennings1, Bob van de Water2
1Centre for Health Protection, National Institute for Public Health and the Environment (RIVM), 3720 BA Bilthoven, The Netherlands.
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.
Insights
Nongenotoxic carcinogens cause cancer through oxidative stress, not DNA damage. This study presents an adverse outcome pathway network to better detect these chemicals and improve cancer risk assessment.
Area of Science:
- Toxicology
- Carcinogenesis
- Environmental Health
Background:
- Nongenotoxic (NGTX) carcinogens induce cancer through mechanisms other than direct DNA damage, such as oxidative stress.
- Current carcinogenicity assessments focus on genetic toxicity, potentially missing NGTX chemicals.
- Oxidative stress occurs when oxidant levels overwhelm antioxidant capacity, leading to regenerative proliferation and potentially cancer.
Purpose of the Study:
- To develop an adverse outcome pathway (AOP) network for chemically induced oxidative stress leading to NGTX carcinogenesis.
- To investigate the role of oxidative stress in cancer hallmarks.
- To identify mechanisms of chemical induction of oxidative stress and its biological effects.
Main Methods:
- Literature review and pathway analysis to construct the AOP network.
- Investigation of oxidative stress in cancer development.
- Exploration of uncertainties within the AOP network.
Main Results:
- An AOP network detailing the pathway from chemical-induced oxidative stress to NGTX carcinogenesis was developed.
- The role of oxidative stress in cancer hallmarks and mechanisms of induction were elucidated.
- Associated uncertainties in the AOP network were identified.
Conclusions:
- The developed AOP network provides a mechanism-based approach for assessing NGTX carcinogens.
- This approach enhances the predictivity of carcinogenicity assessment strategies.
- Transitioning to mechanism-based, human-relevant assessments using AOPs can reduce animal testing.
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