Statistical analysis of lacZ mutant frequency data from Muta<sup>TM</sup>Mouse mutagenicity assays

Fung, Karen Y.; Douglas, George R.; Krewski, Daniel

doi:10.1093/mutage/13.3.249

Cited by 8 publications

(4 citation statements)

References 17 publications

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“…Dose-response study DMDBC was administered once by s.c. injection at doses ranging from 3 to 180 mg/kg and the liver was sampled 28 days later (Table I). Control MF values are within the range of our previously reported data (11) and are consistent with data reported by others (18,19). The mean MF was slightly increased at 3 and 10 mg/kg (1.2-and 2.0-fold, respectively), and markedly increased at 30, 90 and 180 mg/kg (24.0-, 48.5and 58.2-fold, respectively) suggesting a non-linear response.…”

Section: Resultssupporting

confidence: 92%

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Kinetics of induction of DNA adducts, cell proliferation and gene mutations in the liver of Muta™Mice treated with 5,9-dimethyldibenzo[c,g]carbazole

Tombolan¹,

Renault²,

Bron³

et al. 1999

Carcinogenesis

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5,9-Dimethyldibenzo[c,g]carbazole (DMDBC) is a synthetic derivative of the environmental pollutant 7H-dibenzo[c,g]carbazole. DMDBC is a potent genotoxic carcinogen specific for mouse liver. Using the MutaMouse lacZ transgenic mouse model and a positive selection assay, we measured lacZ mutant frequency (MF) in the liver 28 days after a single s.c. administration of DMDBC at 3, 10, 30, 90 or 180 mg/kg. MF remained low at 3 and 10 mg/kg, but increased markedly from 30 mg/kg onwards. To investigate the reason for this non-linear response, we examined mechanisms potentially involved in mutation induction in the liver. Genotoxic effects such as DNA adduct formation were detected in 32P-post-labelling studies. Liver sections were examined for microscopic changes and cell proliferation. These parameters, and MF, were studied 2, 4, 7, 14, 21 and 28 days after a single s.c. administration of 10 or 90 mg/kg DMDBC. At 10 mg/kg, a dose found to double the MF on day 28, DNA adducts reached a level of 200-600 adducts per 10(8) nucleotides from day 4 to day 28. No changes in histology or cell proliferation were detected at this low dose. At 90 mg/kg, MF increased gradually from day 7 to day 28 (maximum 44-fold). The DNA adduct level ranged from 400 to 4500 adducts per 10(8) nucleotides on day 2, then stabilized at approximately 400 adducts per 10(8) nucleotides on day 4. An early cytotoxic effect was detected microscopically in centrilobular hepatocytes, and was followed by liver cell proliferation. These data suggest that the marked increase in MF in MutaMouse liver after treatment in vivo with DMDBC at 90 mg/kg may be explained by the induction of replicative DNA synthesis due to a cytotoxic effect, allowing the fixation of persistent DNA adducts into mutations.

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Section: Resultssupporting

confidence: 92%

“…These results strongly suggest a non-linear response. Wide animal-to-animal variability has been reported in transgenic mouse mutation assays (18,20,21) and it is thus recommended to use at least five animals per group (14,22). However, the great overdispersion observed here warrants discussion.…”

Section: Discussionmentioning

confidence: 88%

Kinetics of induction of DNA adducts, cell proliferation and gene mutations in the liver of Muta™Mice treated with 5,9-dimethyldibenzo[c,g]carbazole

Tombolan¹,

Renault²,

Bron³

et al. 1999

Carcinogenesis

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“…3C ), consistent with previous studies [ 7 , 64 , 65 ]. (It is noteworthy that variation in mutation frequency among normal animals has similarly been shown in several other mouse models for mutation detection [ 66 – 69 ]). Unexpectedly, in animals that were subjected to three bouts of inflammation, we did not detect any increase in the frequency of recombination events (indicated by fluorescent foci; Fig.…”

Section: Resultsmentioning

confidence: 72%

Inflammation-Induced Cell Proliferation Potentiates DNA Damage-Induced Mutations In Vivo

et al. 2015

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Mutations are a critical driver of cancer initiation. While extensive studies have focused on exposure-induced mutations, few studies have explored the importance of tissue physiology as a modulator of mutation susceptibility in vivo. Of particular interest is inflammation, a known cancer risk factor relevant to chronic inflammatory diseases and pathogen-induced inflammation. Here, we used the fluorescent yellow direct repeat (FYDR) mice that harbor a reporter to detect misalignments during homologous recombination (HR), an important class of mutations. FYDR mice were exposed to cerulein, a potent inducer of pancreatic inflammation. We show that inflammation induces DSBs (γH2AX foci) and that several days later there is an increase in cell proliferation. While isolated bouts of inflammation did not induce HR, overlap between inflammation-induced DNA damage and inflammation-induced cell proliferation induced HR significantly. To study exogenously-induced DNA damage, animals were exposed to methylnitrosourea, a model alkylating agent that creates DNA lesions relevant to both environmental exposures and cancer chemotherapy. We found that exposure to alkylation damage induces HR, and importantly, that inflammation-induced cell proliferation and alkylation induce HR in a synergistic fashion. Taken together, these results show that, during an acute bout of inflammation, there is a kinetic barrier separating DNA damage from cell proliferation that protects against mutations, and that inflammation-induced cell proliferation greatly potentiates exposure-induced mutations. These studies demonstrate a fundamental mechanism by which inflammation can act synergistically with DNA damage to induce mutations that drive cancer and cancer recurrence.

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“…As can be seen in Figure 2A, HR frequencies are not normally distributed and display considerable variation. High animal-to-animal variability is well documented in gene-specific mouse mutation assays (25)(26)(27)(28), including the FYDR mouse (18). Notably, the inter-animal distribution of DNA base lesion frequencies is surprisingly similar to the distribution of mutation and HR frequencies (29), which points to a potential source of variability.…”

Section: The Aag Glycosylase Is a Major Driver Of Spontaneous Hr In Vivomentioning

confidence: 96%

DNA glycosylase activity and cell proliferation are key factors in modulating homologous recombination in vivo

Király¹,

Gong²,

Roytman³

et al. 2014

Carcinogenesis

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Cancer susceptibility varies between people, affected by genotoxic exposures, genetic makeup and physiological state. Yet, how these factors interact among each other to define cancer risk is largely unknown. Here, we uncover the interactive effects of genetical, environmental and physiological factors on genome rearrangements driven by homologous recombination (HR). Using FYDR mice to quantify HR-driven rearrangements in pancreas tissue, we show that DNA methylation damage (induced by methylnitrosourea) and cell proliferation (induced by thyroid hormone) each induce HR and together act synergistically to induce HR-driven rearrangements in vivo. These results imply that developmental or regenerative proliferation as well as mitogenic exposures may sensitize tissues to DNA damaging exposures. We exploited mice genetically deficient in alkyl-adenine DNA glycosylase (Aag) to analyse the relative contributions of unrepaired DNA base lesions versus intermediates formed during base excision repair (BER). Remarkably, results show that, in the pancreas, Aag is a major driver of spontaneous HR, indicating that BER intermediates (including abasic sites and single strand breaks) are more recombinogenic than the spontaneous base lesions removed by Aag. Given that mammals have about a dozen DNA glycosylases, these results point to BER as a major source of pressure on the HR pathway in vivo. Taken together, methylation damage, cell proliferation and Aag interact to define the risk of HR-driven sequence rearrangements in vivo. These data identify important sources of sequence changes in a cancer-relevant organ, and advance the effort to identify populations at high-risk for cancer.

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Statistical analysis of lacZ mutant frequency data from Muta^TMMouse mutagenicity assays

Cited by 8 publications

References 17 publications

Kinetics of induction of DNA adducts, cell proliferation and gene mutations in the liver of Muta™Mice treated with 5,9-dimethyldibenzo[c,g]carbazole

Kinetics of induction of DNA adducts, cell proliferation and gene mutations in the liver of Muta™Mice treated with 5,9-dimethyldibenzo[c,g]carbazole

Inflammation-Induced Cell Proliferation Potentiates DNA Damage-Induced Mutations In Vivo

DNA glycosylase activity and cell proliferation are key factors in modulating homologous recombination in vivo

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Statistical analysis of lacZ mutant frequency data from MutaTMMouse mutagenicity assays

Cited by 8 publications

References 17 publications

Kinetics of induction of DNA adducts, cell proliferation and gene mutations in the liver of Muta™Mice treated with 5,9-dimethyldibenzo[c,g]carbazole

Kinetics of induction of DNA adducts, cell proliferation and gene mutations in the liver of Muta™Mice treated with 5,9-dimethyldibenzo[c,g]carbazole

Inflammation-Induced Cell Proliferation Potentiates DNA Damage-Induced Mutations In Vivo

DNA glycosylase activity and cell proliferation are key factors in modulating homologous recombination in vivo

Contact Info

Product

Resources

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Statistical analysis of lacZ mutant frequency data from Muta^TMMouse mutagenicity assays