Molecular dosimetry of chemical mutagens. Relationship between DNA adduct formation and genetic changes analyzed at the molecular level

Zeeland, A.A. van

doi:10.1016/0027-5107(95)00245-6

Cited by 16 publications

(6 citation statements)

References 75 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…All O 6 ‐alkylG adducts (including both O 6 ‐HEG and O 6 ‐HPG) were highly mutagenic (mutant fraction >80%), implying that correct insertion of a C across the O 6 ‐alkylG adducts is a minor event (<20%). As expected from reports on O 6 ‐MG mutagenesis, sequencing of the mutants obtained with the different adducts under investigation demonstrated that they resulted from mis‐insertion of T across from O 6 ‐alkylG, leading to G → A transition mutations (Bartsch, , van Zeeland, , De Bont and van Larebeke, , Rundle, ). In the repair proficient wild‐type (WT) strain, O 6 ‐MG‐induced mutagenesis is lost due to efficient ATase‐mediated repair.…”

Section: Defining a Research Strategy To Support Understanding The Apsupporting

confidence: 68%

“…As expected from reports on O 6 -MG mutagenesis, sequencing of the mutants obtained with the different adducts under investigation demonstrated that they resulted from mis-insertion of T across from O 6 -alkylG, leading to G ! A transition mutations (Bartsch, 1996, van Zeeland, 1996, De Bont and van Larebeke, 2004, Rundle, 2006. In the repair proficient wild-type (WT) strain, O 6 -MG-induced mutagenesis is lost due to efficient ATase-mediated repair.…”

Section: Lack Of N7-alkylg Adduct-induced Mutagenesismentioning

confidence: 99%

See 1 more Smart Citation

Understanding the importance of low‐molecular weight (ethylene oxide‐ and propylene oxide‐induced) DNA adducts and mutations in risk assessment: Insights from 15 years of research and collaborative discussions

Pottenger

Boysen

Brown

et al. 2018

Environ and Mol Mutagen

View full text Add to dashboard Cite

The interpretation and significance of DNA adduct data, their causal relationship to mutations, and their role in risk assessment have been debated for many years. An extended effort to identify key questions and collect relevant data to address them was focused on the ubiquitous low MW N 7‐alkyl/hydroxyalkylguanine adducts. Several academic, governmental, and industrial laboratories collaborated to gather new data aimed at better understanding the role and potential impact of these adducts in quantifiable genotoxic events (gene mutations/micronucleus). This review summarizes and evaluates the status of dose–response data for DNA adducts and mutations from recent experimental work with standard mutagenic agents and ethylene oxide and propylene oxide, and the importance for risk assessment. This body of evidence demonstrates that small N 7‐alkyl/hydroxyalkylguanine adducts are not pro‐mutagenic and, therefore, adduct formation alone is not adequate evidence to support a mutagenic mode of action. Quantitative methods for dose–response analysis and derivation of thresholds, benchmark dose (BMD), or other points‐of‐departure (POD) for genotoxic events are now available. Integration of such analyses of genetox data is necessary to properly assess any role for DNA adducts in risk assessment. Regulatory acceptance and application of these insights remain key challenges that only the regulatory community can address by applying the many learnings from recent research. The necessary tools, such as BMDs and PODs, and the example datasets, are now available and sufficiently mature for use by the regulatory community. Environ. Mol. Mutagen. 60: 100–121, 2019. © 2018 The Authors. Environmental and Molecular Mutagenesis published by Wiley Periodicals, Inc. on behalf of Environmental Mutagen Society.

show abstract

Section: Defining a Research Strategy To Support Understanding The Apsupporting

confidence: 68%

Section: Lack Of N7-alkylg Adduct-induced Mutagenesismentioning

confidence: 99%

Understanding the importance of low‐molecular weight (ethylene oxide‐ and propylene oxide‐induced) DNA adducts and mutations in risk assessment: Insights from 15 years of research and collaborative discussions

Pottenger

Boysen

Brown

et al. 2018

Environ and Mol Mutagen

View full text Add to dashboard Cite

show abstract

“…A large number of chemicals are known to have mutagenic potential and many cancer studies have used this characteristic to controllably induce cancer (72). Below we will discuss the most commonly used chemical inducers of colorectal cancer in rodents.…”

Section: Animal Models Of Human Colorectal Cancermentioning

confidence: 99%

Animal models of colorectal cancer

Johnson

Fleet

2012

Cancer Metastasis Rev

102

View full text Add to dashboard Cite

Colorectal cancer is a heterogeneous disease that afflicts a large number of people in the United States. The use of animal models has the potential to increase our understanding of carcinogenesis, tumor biology, and the impact of specific molecular events on colon biology. In addition, animal models with features of specific human colorectal cancers can be used to test strategies for cancer prevention and treatment. In this review we provide an overview of the mechanisms driving human cancer, we discuss the approaches one can take to model colon cancer in animals, and we describe a number of specific animal models that have been developed for the study of colon cancer. We believe that there are many valuable animal models to study various aspects of human colorectal cancer. However, opportunities for improving upon these models exist.

show abstract

“…In addition to mono adducts, compounds with multiple reactive groups were shown to have the ability to form protein-protein, DNA-DNA or protein-DNA cross-links [20]. The decades following have produced a better understanding of the relationship between carcinogen exposures, DNA adduct formation, mutagenesis, and carcinogenesis [4-7, 10, 12, 27]. Various technologies have been applied to animal and human exposure studies for routine analysis of N 7-guanine adducts and other DNA adducts.…”

Section: Introductionmentioning

confidence: 99%

The formation and biological significance of N7-guanine adducts

Boysen

Pachkowski

Nakamura

et al. 2009

Mutation Research/Genetic Toxicology and Environmental Mutagene

188

182

View full text Add to dashboard Cite

DNA alkylation or adduct formation occurs at nucleophilic sites in DNA, mainly the N7-position of guanine. Ever since identification of the first N7-guanine adduct, several hundred studies on DNA adducts have been reported. Major issues addressed include the relationships between N7-guanine adducts and exposure, mutagenesis, and other biological endpoints. It became quickly apparent that N7-guanine adducts are frequently formed, but may have minimal biological relevance, since they are chemically unstable and do not participate in Watson Crick base pairing. However, N7-guanine adducts have been shown to be excellent biomarkers for internal exposure to direct acting and metabolically activated carcinogens. Questions arise, however, regarding the biological significance for N7-guanine adducts that are readily formed, do not persist, and are not likely to be mutagenic. Thus, we set out to review the current literature to evaluate their formation and the mechanistic evidence for the involvement of N7-guanine adducts in mutagenesis or other biological processes. It was concluded that there is insufficient evidence that N7-guanine adducts can be used beyond confirmation of exposure to the target tissue and demonstration of the molecular dose. There is little to no evidence that N7-guanine adducts or their depurination product, apurinic sites, are the cause of mutations in cells and tissues, since increases in AP sites have not been shown unless toxicity is extant. However, more research is needed to define the extent of chemical depurination versus removal by DNA repair proteins. Interestingly, N7-guanine adducts are clearly present as endogenous background adducts and the endogenous background amounts appear to increase with age. Furthermore, the N7-guanine adducts have been shown to convert to ring opened lesions (FAPy), which are much more persistent and have higher mutagenic potency. Studies in humans are limited in sample size and differences between controls and study groups are small. Future investigations should involve human studies with larger numbers of individuals and analysis should include the corresponding ring opened FAPy derivatives.

show abstract

Molecular dosimetry of chemical mutagens. Relationship between DNA adduct formation and genetic changes analyzed at the molecular level

Cited by 16 publications

References 75 publications

Understanding the importance of low‐molecular weight (ethylene oxide‐ and propylene oxide‐induced) DNA adducts and mutations in risk assessment: Insights from 15 years of research and collaborative discussions

Understanding the importance of low‐molecular weight (ethylene oxide‐ and propylene oxide‐induced) DNA adducts and mutations in risk assessment: Insights from 15 years of research and collaborative discussions

Animal models of colorectal cancer

The formation and biological significance of N7-guanine adducts

Contact Info

Product

Resources

About