The induction of chromosomal damage in rat hepatocytes and lymphocytes II. Alkylation damage and repair of rat-liver DNA after diethylnitrosamine, dimethylnitrosamine and ethyl methanesulphonate in relation to clastogenic effects

Engelse, L. Den; Floot, Ben; Brij, R.-J. De; Tates, A.D.

doi:10.1016/0027-5107(83)90085-4

Cited by 13 publications

(2 citation statements)

References 28 publications

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“…The most predominant oxygen moiety induced by ENU is O 6 eG, and although it is a well-known promutagen (Chang et al, 1980;Walker et al, 1996), it is also associated with SCEs and chromosome aberrations, as a secondary genotoxic lesion occurring after DNA replication (Kaina, 2004). In addition, phosphotriester backbone breaks have also been implicated as a contributor of chromosome aberrations in cells exposed to nitrosoureas (den Engelse et al, 1983;Singh et al, 1997). Such lesions, which are not repaired by MPG, may account for the observed linear dose-response attributable to an alternate repair process whose kinetics are such that little latitude is offered regarding genotoxic tolerance.…”

Section: Discussionmentioning

confidence: 99%

N-Methylpurine DNA Glycosylase Plays a Pivotal Role in the Threshold Response of Ethyl Methanesulfonate–Induced Chromosome Damage

Zaïr

Jenkins

Doak

et al. 2010

Toxicological Sciences

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Genotoxic tolerance to low-level exposure of monofunctional alkylating agents is compound specific, with the mechanism pertaining to alkyl-induced genotoxic threshold response as yet unknown. N-methylpurine DNA glycosylase (MPG), an initiator glycosylase of the base excision repair (BER) pathway, typically repairs alkyl-induced DNA adducts, many of which are associated with genomic instability and tumorigenic risk. Here we demonstrate the involvement of MPG in modulating the genotoxic threshold response induced by the Sn2 alkylating agent ethyl methanesulfonate (EMS) and not the Sn1 alkylating agent N-ethyl-N-nitrosourea (ENU) in human lymphoblastoid cells and suggest the lack of N7-ethylguanine adduct repair as a key factor attributable to an observed increase in EMS-induced chromosome damage. Moreover, an increase in MPG messenger RNA expression levels in response to EMS and not ENU doses administered below the low-observed effect level substantiates the proposed specific involvement of MPG in relation to EMS-induced genotoxicity. We further report an unexpected dose-dependent decrease in the mutation frequency of the MPG-deficient cell line M09B when challenged with ENU, a response deemed consequential to a pronounced dose-dependent increase in the number of apoptotic cells relative to wild type. Collectively, these findings implicate the differential involvement of MPG-directed BER as a primary mechanism of action for the chromosome damage threshold response and cytotoxicity induced by alkane sulfonates and N-nitrosourea compounds, respectively.

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Section: Discussionmentioning

confidence: 99%

N-Methylpurine DNA Glycosylase Plays a Pivotal Role in the Threshold Response of Ethyl Methanesulfonate–Induced Chromosome Damage

Zaïr

Jenkins

Doak

et al. 2010

Toxicological Sciences

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“…30 Thus, hydrogen bonds between bases can be cleaved or whole bases can be eliminated, leading to DNA instability due to apurinic and apyrimidinic sites, 31,32 and, eventually, an increased risk of singlestrand breaks. 33 Methyl-methanesulfonate (MMS; 99%; CAS-Nr. 66273) acts as a directly acting genotoxic substance.…”

Section: Experimental Model Genotoxicantsmentioning

confidence: 99%

Gene-TEQ—a standardized comparative assessment of effects in the comet assay using genotoxicity equivalents

2012

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Existing methods for the comparison of genotoxic effects in the comet assay bear considerable disadvantages such as the problem to link information about concentration dependence and severity of effects. Moreover, given the lack of standardized protocols and the use of various standards, it may be extremely difficult to compare different studies. In order to provide a method for standardized comparative assessment of genotoxic effects, the concept of genotoxicity equivalents (Gene-TEQ) was developed. As potential reference compounds for genotoxic effects, three directly acting (N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), methyl-methanesulfonate, and N-methyl-N-nitrosourea) and three indirectly acting (cyclophosphamide, dimethylnitrosamine, and 4-nitroquinoline-oxide) genotoxic substances were compared with respect to their cytotoxic (neutral red) and genotoxic (comet assay) concentration-response profiles in the permanent fish cell line RTL-W1. For further comparison, two sediment extracts from the upper Danube River were investigated as environmental samples. Based on the results of cytotoxicity and genotoxicity testing, MNNG was selected as the reference compound. At several exposure levels and durations, genotoxic effects of both the other pure substances and the environmental samples were calculated as percentages of the maximum MNNG effect and related to the absolute MNNG effect (EC values). Thus, genotoxicity equivalent factors (Gene-TEQs) relative to MNNG could be calculated. Gene-TEQs can easily be applied to pure substances, mixtures and field samples to provide information about their toxicity relative to the reference compound. Furthermore, the Gene-TEQ concept allows a direct comparison of environmental samples from different laboratories.

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The induction of chromosomal damage in rat hepatocytes and lymphocytes I. Time-dependent changes of the clastogenic effects of diethylnitrosamine, dimethylnitrosamine and ethyl methanesulfonate

Tates

Neuteboom

Vogel

et al. 1983

Mutation Research/Fundamental and Molecular Mechanisms of Mutag

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The induction of chromosomal damage in rat hepatocytes and lymphocytes II. Alkylation damage and repair of rat-liver DNA after diethylnitrosamine, dimethylnitrosamine and ethyl methanesulphonate in relation to clastogenic effects

Cited by 13 publications

References 28 publications

N-Methylpurine DNA Glycosylase Plays a Pivotal Role in the Threshold Response of Ethyl Methanesulfonate–Induced Chromosome Damage

N-Methylpurine DNA Glycosylase Plays a Pivotal Role in the Threshold Response of Ethyl Methanesulfonate–Induced Chromosome Damage

Gene-TEQ—a standardized comparative assessment of effects in the comet assay using genotoxicity equivalents

The induction of chromosomal damage in rat hepatocytes and lymphocytes I. Time-dependent changes of the clastogenic effects of diethylnitrosamine, dimethylnitrosamine and ethyl methanesulfonate

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