Formation and persistence of the miscoding DNA alkylation product O6-ethylguanine in male germ cells of the hamster

Seiler, Frank; Kamino, Kenji; Emura, M.; Möhr, U.; Thomale, Jürgen

doi:10.1016/s0921-8777(97)00043-8

Cited by 9 publications

(13 citation statements)

References 16 publications

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“…Fluorescence signals from immunostained O6-EtGua residues in DNA are visualized by fluorescence microscopy and quantitated using an image analysis system. Methods are described in (Seiler et al, 1997). An immunoslot blot assay for detection of O6-EtGua has been described previously in (Mientjes et al, 1996).…”

Section: Measurement Of Alkylation In Male Germ Cellsmentioning

confidence: 99%

“…Seiler, F., K. Kamino, M. Emura, U. Mohr and J. Thomale (1997), "Formation and persistence of the miscoding DNA alkylation product O6-ethylguanine in male germ cells of the hamster", Mutat. Res., 385: 205-211. van Zeeland, A.A., A. de Groot and A. Neuhäuser-Klaus (1990), "DNA adduct formation in mouse testis by ethylating agents: a comparison with germ-cell mutagenesis", Mutat.…”

Section: Measurement Of Alkylation In Male Germ Cellsmentioning

confidence: 99%

“…This indicates that repair has not effectively removed the adducts. For example, DNA adducts have been measured in hamster and rat spermatogonia several days following exposure to alkylating agents, indicating lack of repair (Seiler et al, 1997;Scherer et al, 1987).…”

Section: Indirect Measurementmentioning

confidence: 99%

“…Studies in both hamsters and rats show persistence of alkylated nucleotides several days postexposure, indicating lack of DNA repair of some adducts (Scherer et al, 1987;Seiler et al, 1997). For example, 101xC3H mouse hybrid testes exhibited DNA adducts within 1 hour of exposure to ENU (10 or 100 mg/kg by i.p.…”

Section: Empirical Support For Linkagementioning

confidence: 99%

See 3 more Smart Citations

Adverse Outcome Pathway on Alkylation of DNA in Male Pre-Meiotic Germ Cells Leading to Heritable Mutations

Yauk

Lambert

Marchetti

et al. 2016

OECD Series on Adverse Outcome Pathways

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Section: Measurement Of Alkylation In Male Germ Cellsmentioning

confidence: 99%

Section: Measurement Of Alkylation In Male Germ Cellsmentioning

confidence: 99%

Section: Indirect Measurementmentioning

confidence: 99%

Section: Empirical Support For Linkagementioning

confidence: 99%

See 2 more Smart Citations

Adverse Outcome Pathway on Alkylation of DNA in Male Pre-Meiotic Germ Cells Leading to Heritable Mutations

Yauk

Lambert

Marchetti

et al. 2016

OECD Series on Adverse Outcome Pathways

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“…All 48 slots were rinsed with 200 μl 1 M ammonium acetate and the membranes were baked for 2 hours at 80°C. After single-stranded DNA was immobilized onto the nitrocellular membranes, the membranes were blocked with 5% milk −1×TBS −0.05% Tween 20 and then hybridized with the (O 6 -EtGua)-specific mouse monoclonal antibody EM-2-3 (1:5000 diluted, kindly provided by Dr. Menfred F. Rajewsky's laboratory in University of Essen, Germany) for 150 min at room temperature with shaking [14]. The membrane was then hybridized with the secondary antibody goat anti-mouse horseradish peroxidase-labeled IgG (1:1000 diluted) (Chemicon, Temecula, CA) by shaking for 1 hour at room temperature.…”

Section: Immunoslot Blots Standard Curves and Dose Responsementioning

confidence: 99%

Polymorphisms of phase II xenobiotic-metabolizing and DNA repair genes and in vitro N-ethyl-N-nitrosourea-induced O6-ethylguanine levels in human lymphocytes

Jiao

Chang

Firozi

et al. 2007

Mutation Research/Genetic Toxicology and Environmental Mutagene

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This study tested the hypothesis that genetic variants of phase II detoxification enzymes and DNA repair proteins affect individual response to DNA damage from alkylating agents. In 171 healthy individuals, an immunoslot blot assay was used to measure O 6 -ethylguanosine (O 6 -EtGua) adduct levels in peripheral blood lymphocytes treated with N-ethyl-N-nitrosourea (ENU) in vitro. The genotypes of GSTM1, GSTT1, GSTP1 I 105 V and A 114 V, MGMT L 84 F and I 143 V, XPD D 312 N and K 751 Q, and XRCC3 T 241 M were determined. Demographic and exposure information was collected by in-person interview. Student's t test, analysis of (co)variance, and multiple linear regression models were used in statistical analyses. The mean and median (range) O 6 -EtGua levels were 94.6 and 84.8 (3.2-508.1) fmol/g DNA, respectively. The adduct level was significantly lower in people who smoked ≥ 25 years than that in never-smokers (square-root transformed mean values 8.20 versus 9.37, P = 0.03). Multiple linear regression models revealed that GSTT1 (β = −2.36, P = 0.009) polymorphism was a significant predictor of the level of adducts in 82 never-smokers, whereas the number of years smoked (β = −0.08, P = 0.005) and XRCC3 T 241 M (β = 2.22, P = 0.007) in 89 eversmokers. The association between GSTP1 I 105 V, MGMT I 143 V, and XPD D 312 N with the level of adducts was not conclusive. Each polymorphism could explain 2% to 10% of the variation of the adduct level. These observations suggest that GSTT1 null and XRCC3 T 241 M polymorphism may have some functional significance in modulating the level of ENU-induced DNA damage and these effects are smoking-dependent. Results from this exploratory study need to be confirmed in other experimental systems.

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Development of the adverse outcome pathway “alkylation of DNA in male premeiotic germ cells leading to heritable mutations” using the OECD's users' handbook supplement

Yauk

Lambert

Meek

et al. 2015

Environ and Mol Mutagen

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The Organisation for Economic Cooperation and Development's (OECD) Adverse Outcome Pathway (AOP) programme aims to develop a knowledgebase of all known pathways of toxicity that lead to adverse effects in humans and ecosystems. A Users' Handbook was recently released to provide supplementary guidance on AOP development. This article describes one AOP-alkylation of DNA in male premeiotic germ cells leading to heritable mutations. This outcome is an important regulatory endpoint. The AOP describes the biological plausibility and empirical evidence supporting that compounds capable of alkylating DNA cause germ cell mutations and subsequent mutations in the offspring of exposed males. Alkyl adducts are subject to DNA repair; however, at high doses the repair machinery becomes saturated. Lack of repair leads to replication of alkylated DNA and ensuing mutations in male premeiotic germ cells. Mutations that do not impair spermatogenesis persist and eventually are present in mature sperm. Thus, the mutations are transmitted to the offspring. Although there are some gaps in empirical support and evidence for essentiality of the key events for certain aspects of this AOP, the overall AOP is generally accepted as dogma and applies broadly to any species that produces sperm. The AOP was developed and used in an iterative process to test and refine the Users' Handbook, and is one of the first publicly available AOPs. It is our hope that this AOP will be leveraged to develop other AOPs in this field to advance method development, computational models to predict germ cell effects, and integrated testing strategies.

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Formation and persistence of the miscoding DNA alkylation product O6-ethylguanine in male germ cells of the hamster

Cited by 9 publications

References 16 publications

Adverse Outcome Pathway on Alkylation of DNA in Male Pre-Meiotic Germ Cells Leading to Heritable Mutations

Adverse Outcome Pathway on Alkylation of DNA in Male Pre-Meiotic Germ Cells Leading to Heritable Mutations

Polymorphisms of phase II xenobiotic-metabolizing and DNA repair genes and in vitro N-ethyl-N-nitrosourea-induced O6-ethylguanine levels in human lymphocytes

Development of the adverse outcome pathway “alkylation of DNA in male premeiotic germ cells leading to heritable mutations” using the OECD's users' handbook supplement

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