Evaluation of high-throughput genotoxicity assays used in profiling the US EPA ToxCast™ chemicals

Knight, Andrew W.; Little, Stephen B.; Houck, Keith A.; Dix, David J.; Judson, Richard S.; Richard, Ann M.; McCarroll, Nancy; Akerman, Gregory; Yang, Chihae; Birrell, Louise; Walmsley, Richard M.

doi:10.1016/j.yrtph.2009.07.004

Cited by 112 publications

(72 citation statements)

References 45 publications

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“…93 As expected, only a small fraction of the tested compounds gave positive hits (10%); a full listing of the chemicals found to be genotoxic can be found at the EPA ToxCast Web site (epa.gov/ncct/toxcast/ accessed November 27, 2012). A caveat to this study is that this high-throughput screen lacked a metabolic activation system, which might have caused false-negative results to be reported, and positive hits were found at high concentrations of 12.5 lM or higher.…”

Section: Cell-based and Animal Studies To Establish Biomarkers Of Pesmentioning

confidence: 54%

Increased cancer burden among pesticide applicators and others due to pesticide exposure

Alavanja

Ross

Bonner

2013

CA A Cancer J Clinicians

294

213

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A growing number of well-designed epidemiological and molecular studies provide substantial evidence that the pesticides used in agricultural, commercial, and home and garden applications are associated with excess cancer risk. This risk is associated both with those applying the pesticide and, under some conditions, those who are simply bystanders to the application. In this article, the epidemiological, molecular biology, and toxicological evidence emerging from recent literature assessing the link between specific pesticides and several cancers including prostate cancer, non-Hodgkin lymphoma, leukemia, multiple myeloma, and breast cancer are integrated. Although the review is not exhaustive in its scope or depth, the literature does strongly suggest that the public health problem is real. If we are to avoid the introduction of harmful chemicals into the environment in the future, the integrated efforts of molecular biology, pesticide toxicology, and epidemiology are needed to help identify the human carcinogens and thereby improve our understanding of human carcinogenicity and reduce cancer risk. CA Cancer J Clin 2013;63:120-142.

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Section: Cell-based and Animal Studies To Establish Biomarkers Of Pesmentioning

confidence: 54%

Increased cancer burden among pesticide applicators and others due to pesticide exposure

Alavanja

Ross

Bonner

2013

CA A Cancer J Clinicians

294

213

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“…However, it is difficult to determine the possible genotoxicity of chemicals with a single assay. Therefore, to assess the genotoxicity of a compound accurately, it is necessary to use a battery of diverse assays (20). In this study, we developed a high-throughput ATAD5-luc assay that will be a valuable addition to this battery.…”

Section: Discussionmentioning

confidence: 99%

High-throughput genotoxicity assay identifies antioxidants as inducers of DNA damage response and cell death

Fox

Sakamuru

Huang

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

110

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Human ATAD5 is a biomarker for identifying genotoxic compounds because ATAD5 protein levels increase posttranscriptionally in response to DNA damage. We screened over 4,000 compounds with a cell-based quantitative high-throughput ATAD5-luciferase assay detecting genotoxic compounds. We identified 22 antioxidants, including resveratrol, genistein, and baicalein, that are currently used or investigated for the treatment of cardiovascular disease, type 2 diabetes, osteopenia, osteoporosis, and chronic hepatitis, as well as for antiaging. Treatment of dividing cells with these compounds induced DNA damage and resulted in cell death. Despite their genotoxic effects, resveratrol, genistein, and baicalein did not cause mutagenesis, which is a major side effect of conventional anticancer drugs. Furthermore, resveratrol and genistein killed multidrug-resistant cancer cells. We therefore propose that resveratrol, genistein, and baicalein are attractive candidates for improved chemotherapeutic agents.chemotherapy | high-throughput screening O ne distinctive characteristic of cancer cells is persistent cell division that requires DNA replication. This feature is often exploited to develop chemotherapeutic drugs because cancer cells are exquisitely sensitive to the inhibition of DNA replication by the introduction of DNA damage by radiation or genotoxic chemicals. DNA lesions resulting from exposure to genotoxic agents stall DNA replication, collapse replication forks, and produce DNA double-strand breaks (DSBs), resulting in cell death. If not repaired properly, many of these genomic insults can also induce gene mutations or chromosomal alterations that may make cells more resilient to cell-cycle checkpoints or apoptosis. Thus, cancer treatment may greatly benefit from the identification of genotoxic agents that kill rapidly dividing cells with minimal mutagenic side effects.ATAD5 is the homolog of yeast Enhanced Level of Genome Instability Gene 1 (ELG1), which makes a heteropentameric alternative replication factor C complex and suppresses genomic instability and tumorigenesis (1-3). ATAD5 plays a key role in the translesion synthesis (TLS) pathway where TLS polymerases are used to bypass DNA lesions that stall or collapse DNA replication forks (4, 5). In the TLS pathway, switching from replicative polymerases to TLS polymerases is promoted through the interaction between proliferating cell nuclear antigen (PCNA) monoubiquitylated at lysine 164 and an ubiquitin-binding motif in TLS polymerases, a mechanism that is conserved from yeast to humans (6). ATAD5 is stabilized and forms nuclear foci at the site of stalled replication forks in response to DNA damage (7) and appears to participate in the removal of ubiquitin from chromatinbound monoubiquitylated PCNA through its interaction with ubiquitin-specific peptidase 1 (5). The ATAD5-mediated deubiquitylation of PCNA allows lesion-bypassed TLS polymerases to switch back to replicative polymerases, and thereby prevents the low-fidelity TLS polymerases from causing harmful muta...

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“…Phase 1, focusing mainly on pesticides and off-the-shelf available pathway assays in HTS platforms, has delivered impressive first results supporting the concept of PoT for carcinogenicity and genotoxicity as well (Knight et al, 2009;Martin et al, 2009a). The current expansion to more substances and substance classes, as well as PoT assays, represents a prime opportunity to explore this approach.…”

Section: Pathways Of Toxicity (Pot) and Systems Toxicologymentioning

confidence: 99%

A roadmap for the development of alternative (non-animal) methods for systemic toxicity testing

Basketter

Clewell

Kimber

et al. 2012

ALTEX

203

165

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Evaluation of high-throughput genotoxicity assays used in profiling the US EPA ToxCast™ chemicals

Cited by 112 publications

References 45 publications

Increased cancer burden among pesticide applicators and others due to pesticide exposure

Increased cancer burden among pesticide applicators and others due to pesticide exposure

High-throughput genotoxicity assay identifies antioxidants as inducers of DNA damage response and cell death

A roadmap for the development of alternative (non-animal) methods for systemic toxicity testing

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