Persistence of alkylated DNA bases in the Mongolian gerbil (<i>Meriones unguiculatus</i>) following a single dose of methylnitrosourea

Kleihues, Paul; Bamborschke, S; Doerjer, Gerhard

doi:10.1093/carcin/1.1.111

Cited by 30 publications

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“…XP-A patients have the most severe and earliest forms of the neurological disorder with premature aging features of peripheral neuropathy, progressive sensorineural hearing and neurodegeneration (Rizza et al, 2021). The lack of predominant neuronal cell death in the face of elevated alkyl DNA damage in the brain of MAM-treated mice is consistent with their persistence and inefficient removal by rodent brain DNA-repair processes (Margison and Kleihues, 1975;Buecheler and Kleihues, 1977;Kleihues and Bucheler, 1977;Kleihues et al, 1980). Moreover, the 60 genes that were anchored to the MAM-induced DNA lesions (p53, NFk-B, MAPK) reported by play an important role in DNA damage-induced senescence in neurons (Dong et al, 2014).…”

Section: Somatic Mutationsmentioning

confidence: 89%

Genotoxic Damage During Brain Development Presages Prototypical Neurodegenerative Disease

Kisby

Spencer

2021

Front. Neurosci.

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Western Pacific Amyotrophic Lateral Sclerosis and Parkinsonism-Dementia Complex (ALS/PDC) is a disappearing prototypical neurodegenerative disorder (tau-dominated polyproteinopathy) linked with prior exposure to phytogenotoxins in cycad seed used for medicine and/or food. The principal cycad genotoxin, methylazoxymethanol (MAM), forms reactive carbon-centered ions that alkylate nucleic acids in fetal rodent brain and, depending on the timing of systemic administration, induces persistent developmental abnormalities of the cortex, hippocampus, cerebellum, and retina. Whereas administration of MAM prenatally or postnatally can produce animal models of epilepsy, schizophrenia or ataxia, administration to adult animals produces little effect on brain structure or function. The neurotoxic effects of MAM administered to rats during cortical brain development (specifically, gestation day 17) are used to model the histological, neurophysiological and behavioral deficits of human schizophrenia, a condition that may precede or follow clinical onset of motor neuron disease in subjects with sporadic ALS and ALS/PDC. While studies of migrants to and from communities impacted by ALS/PDC indicate the degenerative brain disorder may be acquired in juvenile and adult life, a proportion of indigenous cases shows neurodevelopmental aberrations in the cerebellum and retina consistent with MAM exposure in utero. MAM induces specific patterns of DNA damage and repair that associate with increased tau expression in primary rat neuronal cultures and with brain transcriptional changes that parallel those associated with human ALS and Alzheimer’s disease. We examine MAM in relation to neurodevelopment, epigenetic modification, DNA damage/replicative stress, genomic instability, somatic mutation, cell-cycle reentry and cellular senescence. Since the majority of neurodegenerative disease lacks a solely inherited genetic basis, research is needed to explore the hypothesis that early-life exposure to genotoxic agents may trigger or promote molecular events that culminate in neurodegeneration.

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Section: Somatic Mutationsmentioning

confidence: 89%

Genotoxic Damage During Brain Development Presages Prototypical Neurodegenerative Disease

Kisby

Spencer

2021

Front. Neurosci.

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“…McCalla (1968) and Nagao et al (1969) reported that the formation and persistence of O 6alkylguanine appears to parallel carcinogenicity. However, Kleihues et al (1980) reported that the persistence of O 6 -methylguanine in cerebral DNA of Mongolian gerbils is similar to that in rat brain, though Mongolian gerbils differ markedly from rats in their susceptibility to the neuro-oncogenic effect of alkylnitrosoureas. Kleihues et al (1980) suggested that the tissue-specific carcinogenicity of these compounds does not depend solely on the formation and persistence of O 6 -alkylguanine in the DNA, thus supporting our conclusion.…”

Section: Discussionmentioning

confidence: 98%

“…However, Kleihues et al (1980) reported that the persistence of O 6 -methylguanine in cerebral DNA of Mongolian gerbils is similar to that in rat brain, though Mongolian gerbils differ markedly from rats in their susceptibility to the neuro-oncogenic effect of alkylnitrosoureas. Kleihues et al (1980) suggested that the tissue-specific carcinogenicity of these compounds does not depend solely on the formation and persistence of O 6 -alkylguanine in the DNA, thus supporting our conclusion. Yamada and Kato (1989) suggested that since the lamina muscularis mucosa is significantly thinner and the glands are packed more firmly in the fundic mucosa than in the antral mucosa, lateral growth of cancer cells might be blocked in the fundic mucosa.…”

Section: Discussionmentioning

confidence: 98%

“…Gastric cancers develop in rats at a high rate within 1 year after oral administration of N-methyl-NЈ-nitro-N-nitrosoguanidine (MNNG) (Sugimura and Fujimura, 1967). Some investigators have suggested that methylation of nucleic acids or proteins by MNNG may be responsible for carcinogenesis (McCalla, 1968;Nagao et al, 1969), but this does not completely explain the carcinogenic mechanism (Kleihues et al, 1980). We previously found that an anti-oxidant reagent, butylated hydroxytoluene, inhibits the development of MNNG-induced gastric cancer (Tatsuta et al, 1983) and that hydroxyl free radical (·OH) is produced by the reaction between MNNG and H 2 O 2 (Mikuni et al, 1985(Mikuni et al, , 1992 or by MNNG degradation (Mikuni and Tatsuta, 1994).…”

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confidence: 99%

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Slow rate of free radical scavenging in the gastric antral mucosa of male Wistar rats: A possible mechanism of gastric carcinogenesis induced byN-methyl-N′-nitro-N-nitrosoguanidine

Mikuni

Tatsuta

1998

Int. J. Cancer

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We previously suggested that hydroxyl free radical (·OH) production may play a role in carcinogenesis induced by N‐methyl‐N′‐nitro‐N‐nitrosoguanidine (MNNG). MNNG‐induced gastric cancer in rats and human gastric carcinoma occur most often in the antral mucosa and rarely in the normal fundic mucosa. We hypothesized that regional differences in anti‐oxidant activity may be responsible. In the present study, we examined anti‐oxidant activity by comparing the relative rates of reduction of a nitroxide free radical, 4‐hydroxy‐2,2,6,6‐tetramethyl‐1‐piperidinyloxy (Tempol), in the antral and fundic mucosa of male Wistar rats using ESR. The relative rate of Tempol reduction was significantly slower in the antral portion of the wall than in the fundic portion when Tempol (4 × 10−6 mole/mg wet weight of gastric wall) in HEPES buffer (pH 7.4) was spread over the mucosal surface of a section of the gastric wall. Addition of a sulfhydryl group modulator, N‐ethylmaleimide, to the mucosal surface before treatment with Tempol removed the significant difference observed in the rates of reduction in the antral and fundic portions of the gastric wall. No signals were detected in the muscle layer. Our results indicate that the relative rate of free radical reduction by sulfhydryl groups was significantly slower in the antral mucosa than in the fundic mucosa. We therefore conclude that a regional difference in the rates of reduction of free radicals by sulfhydryl groups may result in the site susceptible to development of MNNG‐induced gastric cancer. Int. J. Cancer 76:228–231, 1998.© 1998 Wiley‐Liss, Inc.

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“…DNA-repair mechanisms in cycling and postmitotic cells have been reviewed by Iyama and Wilson . Brain tissue is inefficient in the repair of DNA lesions ( O 6 -mdG and N7-dG adducts), and they persist in the brain of rodents for up to one year following a single injection of the alkylating agent methylnitrosourea. , …”

Section: Molecular Actions Of Hydrazine-related Compoundsmentioning

confidence: 99%

Role of Hydrazine-Related Chemicals in Cancer and Neurodegenerative Disease

Spencer

Kisby

2021

Chem. Res. Toxicol.

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Hydrazine-related chemicals (HRCs) with carcinogenic and neurotoxic potential are found in certain mushrooms and plants used for food and in products employed in various industries, including aerospace. Their propensity to induce DNA damage (mostly O 6-, N7- and 8-oxo-guanine lesions) resulting in multiple downstream effects is linked with both cancer and neurological disease. For cycling cells, unrepaired DNA damage leads to mutation and uncontrolled mitosis. By contrast, postmitotic neurons attempt to re-enter the cell cycle but undergo apoptosis or nonapoptotic cell death. Biomarkers of exposure to HRCs can be used to explore whether these substances are risk factors for sporadic amyotrophic laterals sclerosis and other noninherited neurodegenerative diseases, which is the focus of this paper.

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Persistence of alkylated DNA bases in the Mongolian gerbil (Meriones unguiculatus) following a single dose of methylnitrosourea

Cited by 30 publications

References 0 publications

Genotoxic Damage During Brain Development Presages Prototypical Neurodegenerative Disease

Genotoxic Damage During Brain Development Presages Prototypical Neurodegenerative Disease

Slow rate of free radical scavenging in the gastric antral mucosa of male Wistar rats: A possible mechanism of gastric carcinogenesis induced byN-methyl-N′-nitro-N-nitrosoguanidine

Role of Hydrazine-Related Chemicals in Cancer and Neurodegenerative Disease

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