Application of the adverse outcome pathway framework to genotoxic modes of action

Sasaki, Jennifer C.; Allemang, Ashley; Bryce, Steven M.; Custer, Laura; Dearfield, Kerry L.; Dietz, Yasmin; Elhajouji, Azeddine; Escobar, Patricia; Fornace, Albert J.; Frötschl, Roland; Galloway, Sheila M.; Hemmann, Ulrike; Hendriks, Giel; Li, Heng‐Hong; Luijten, Mirjam; Ouédraogo, Gladys; Peel, Lauren; Pfuhler, Stefan; Roberts, Daniel J.; Thybaud, Véronique; Benthem, Jan van; Yauk, Carole L.; Schuler, Maik

doi:10.1002/em.22339

Cited by 46 publications

(52 citation statements)

References 147 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Further work in our laboratory will explore the repair mechanisms involved in mammalian cells following exposure to hydrazine. We recognize that although hazard identification approaches have been used in the past to support genotoxicity assessment, discussions regarding the formalization of adverse outcome pathways (AOPs) to describe the sequence and molecular events contributing to a genotoxic/carcinogenic endpoint may provide further perspective on risk characterization (Sasaki et al ., 2020).…”

Section: Discussionmentioning

confidence: 99%

In vitro and in vivo mammalian mutation assays support a nonmutagenic mechanism of carcinogenicity for hydrazine

Nicolette

Murray

Sonders

et al. 2020

Environ and Mol Mutagen

View full text Add to dashboard Cite

Hydrazine has been described as a mutagenic, probable human carcinogen. It is mutagenic in in vitro systems such as bacterial reverse mutation (Ames) tests and some yeast systems, as well as in in vivo systems with drosophila. It was shown to cause chromosome damage both in vitro and in vivo but was negative in some wellvalidated mammalian mutation systems such as CHO HPRT assays. Importantly, there is only one in vivo gene mutation test reported, which was negative. Our objective was to determine if hydrazine is mutagenic in mammalian test systems. Thus, we conducted an in vitro gene mutation test in Muta™Mouse lung epithelial cells (FE1 cell assay) and a regulatory-compliant in vivo Big Blue ® mouse test. Consistent with previous reports, an additional six-well Ames assay showed that hydrazine was mutagenic to bacteria. The FE1 cell assay was negative in conditions with and without metabolic activation when tested to cytotoxicity limits. In the Big Blue ® mouse study, female mice received dosages of hydrazine up to 10.9 mg/kg via drinking water for 28 days. This dose is comparable to a dose used in a carcinogenicity study where female mice had significant increases in hepatocellular adenoma at 11.5 mg/kg. There were no increases in mutant frequency in liver and lung, two tissues sensitive to the carcinogenic effects of hydrazine in mice. Our research shows that hydrazine is not mutagenic in mammalian cells either in vitro or in vivo, indicating mutagenicity may not play a role in the carcinogenicity of hydrazine.

show abstract

Section: Discussionmentioning

confidence: 99%

In vitro and in vivo mammalian mutation assays support a nonmutagenic mechanism of carcinogenicity for hydrazine

Nicolette

Murray

Sonders

et al. 2020

Environ and Mol Mutagen

View full text Add to dashboard Cite

show abstract

“…Since the MultiFlow responses were generated with Topo II poisons, we focused on the AOP development for such class of Topo II poison compounds (as opposed to Topo II catalytic inhibitors) with MultiFlow endpoints being the identifiable and measurable KEs. The Mode of Action Workgroup of HESI GTTC has proposed an AOP outlined as “Binding to the DNA‐Topo II Cleavage Complex (Topo II Inhibition) Leading to Increases in Chromosome Breaks and Rearrangements and/or Gene Mutations” (Sasaki et al, ). The workgroup indicates the MIE as “Binding to the DNA‐Topo II Complex,” KE1 as “Stabilization of the cleavage complex (cleaved DNA),” KE2 as “DNA Double Strand Breaks,” KE3 as “Disrupted replication forks,” KE4 as “Inadequate repair,” AO1 as “Increases in gene mutations,” and AO2 as “Chromosome breaks and rearrangements.” Figure shows how MultiFlow endpoints can be utilized in the AOP for Topo II poisons.…”

Section: Resultsmentioning

confidence: 99%

Benchmark Dose Analysis of DNA Damage Biomarker Responses Provides Compound Potency and Adverse Outcome Pathway Information for the Topoisomerase II Inhibitor Class of Compounds

Wheeldon

Bernacki

Dertinger

et al. 2020

Environ and Mol Mutagen

Self Cite

View full text Add to dashboard Cite

Genetic toxicology data have traditionally been utilized for hazard identification to provide a binary call for a compound's risk. Recent advances in the scientific field, especially with the development of high-throughput methods to quantify DNA damage, have influenced a change of approach in genotoxicity assessment. The in vitro MultiFlow ® DNA Damage Assay is one such method which multiplexes γH2AX, p53, phospho-histone H3 biomarkers into a single-flow cytometric analysis : Environ Mol Mutagen 57:546-558). This assay was used to study human TK6 cells exposed to each of eight topoisomerase II poisons for 4 and 24 hr. Using PROAST v65.5, the Benchmark Dose approach was applied to the resulting flow cytometric datasets. With "compound" serving as covariate, all eight compounds were combined into a single analysis, per time point and endpoint. The resulting 90% confidence intervals, plotted in Log scale, were considered as the potency rank for the eight compounds. The in vitro MultiFlow data showed a maximum confidence interval span of 1Log, which indicates data of good quality. Patterns observed in the compound potency rank were scrutinized by using the expert rule-based software program Derek Nexus, developed by Lhasa Limited. Compound sub-classification and structural alerts were considered contributory to the potencies observed for the topoisomerase II poisons studied herein. The Topo II poison Adverse Outcome Pathway was evaluated with MultiFlow endpoints serving as Key Events. The step-wise approach described herein can be considered as a foundation for risk assessment of compounds within a specific mode of action of interest. Environ. Mol. Mutagen. 61:396-407, 2020.

show abstract

“…During the past 10 years, the concept has attracted a large amount of attention, as documented by an increasing number of competent review articles [also see Leist et al ( 2017 ), Villeneuve et al ( 2014 ), Becker et al ( 2015 ), Burden et al ( 2015 ), Perkins et al ( 2015 ), Edwards et al ( 2016 ), OECD ( 2014 ) Vinken et al ( 2017 ), Spinu et al ( 2020 ) and Sasaki et al ( 2020 )]. A few important aspects are described in the following section.…”

Section: The Adverse Outcome Pathway (Aop) Conceptmentioning

confidence: 99%

Role of Damage-Associated Molecular Patterns in Light of Modern Environmental Research: A Tautological Approach

Land

2020

Int J Environ Res

View full text Add to dashboard Cite

Two prominent models emerged as a result of intense interdisciplinary discussions on the environmental health paradigm, called the "exposome" concept and the "adverse outcome pathway" (AOP) concept that links a molecular initiating event to the adverse outcome via key events. Here, evidence is discussed, suggesting that environmental stress/injury-induced damageassociated molecular patterns (DAMPs) may operate as an essential integrating element of both environmental health research paradigms. DAMP-promoted controlled/uncontrolled innate/adaptive immune responses reflect the key events of the AOP concept. The whole process starting from exposure to a distinct environmental stress/injury-associated with the presence/ emission of DAMPs-up to the manifestation of a disease may be regarded as an exposome. Clinical examples of such a scenario are briefly sketched, in particular, a model in relation to the emerging COVID-19 pandemic, where the interaction of noninfectious environmental factors (e.g., particulate matter) and infectious factors (SARS CoV-2) may promote SARS case fatality via superimposition of both exogenous and endogenous DAMPs. Article Highlights • This review is devoted to the first scientific attempt to integrate DAMP-controlled innate immune inflammatory and adaptive immune defense responses as well as DAMP-uncontrolled dysregulated pathological responses (acute and chronic human diseases) in the environmental health paradigm, called the "exposome" concept and the "adverse outcome pathway" (AOP) concept. • Evidence is discussed that DAMP-promoted controlled/uncontrolled innate immune/adaptive immune responses reflect the key events of the AOP concept. • The whole process starting from exposure to a distinct environmental stress/injury-associated with the presence/ emission of DAMPs-up to the manifestation of a disease may be regarded as an exposome. • Some exemplifying models of such a scenario are briefly sketched, including respiratory infections, autoimmune/ allergic diseases, organ fibrosis, and cancer. • In particular, a model in relation to the emerging COVID-19 pandemic is presented, where the interaction of noninfectious environmental factors (e.g., particulate matter) and infectious factors (SARS CoV-2) may promote SARS case fatality via superimposition of both exogenous and endogenous DAMPs.

show abstract

Application of the adverse outcome pathway framework to genotoxic modes of action

Cited by 46 publications

References 147 publications

In vitro and in vivo mammalian mutation assays support a nonmutagenic mechanism of carcinogenicity for hydrazine

In vitro and in vivo mammalian mutation assays support a nonmutagenic mechanism of carcinogenicity for hydrazine

Benchmark Dose Analysis of DNA Damage Biomarker Responses Provides Compound Potency and Adverse Outcome Pathway Information for the Topoisomerase II Inhibitor Class of Compounds

Role of Damage-Associated Molecular Patterns in Light of Modern Environmental Research: A Tautological Approach

Contact Info

Product

Resources

About