Oxidative-stress-driven mutagenesis in the small intestine of the gpt delta mouse induced by oral administration of potassium bromate

Aoki, Yosuke; Taniguchi, Yoshihiro; Matsumoto, Michi; Ohno, Mizuki; Masumura, Kenichi; Sasaki, Shigeki; Tsuzuki, Teruhisa; Yamamoto, Masayuki; Nohmi, Takehiko

doi:10.1016/j.mrgentox.2020.503136

Cited by 10 publications

(14 citation statements)

References 67 publications

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“…Interestingly, recent in vivo mutation studies with potassium bromate (KBrO 3 ) have provided evidence that oxidative stress can result in increased MF in gpt delta mice (Aoki et al 2020). KBrO 3 induces tumors in the proximal SI (and other organs), and Aoki et al (2020) have shown that KBrO 3 increased oxidative DNA damage and G to T transversions in a threshold manner consistent with an observed threshold in MF in the duodenum. These findings not only provide insight into the MOA for bromate-induced SI cancer in mice but also demonstrate that the gpt delta TGR model might have detected increases in MF for Cr(VI) if increased oxidative stress were a driver in the MOAs.…”

Section: Alternative Modes Of Actionmentioning

confidence: 82%

“…Although there is some transcriptomic evidence for this idea, such as induction of genes involved in GSH synthesis , oxidative DNA damage has not been observed in the mouse duodenum following Cr(VI) exposure in drinking water at up to 180 ppm for up to 9 months (De Flora et al 2008;. Interestingly, recent in vivo mutation studies with potassium bromate (KBrO 3 ) have provided evidence that oxidative stress can result in increased MF in gpt delta mice (Aoki et al 2020). KBrO 3 induces tumors in the proximal SI (and other organs), and Aoki et al (2020) have shown that KBrO 3 increased oxidative DNA damage and G to T transversions in a threshold manner consistent with an observed threshold in MF in the duodenum.…”

Section: Alternative Modes Of Actionmentioning

confidence: 99%

“…These findings not only provide insight into the MOA for bromate-induced SI cancer in mice but also demonstrate that the gpt delta TGR model might have detected increases in MF for Cr(VI) if increased oxidative stress were a driver in the MOAs. Even with an increase in MF, Aoki et al (2020) proposed a threshold no-observed-genotoxic-effect-level level for KBrO 3 protective of SI cancer.…”

Section: Alternative Modes Of Actionmentioning

confidence: 99%

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An adverse outcome pathway for small intestinal tumors in mice involving chronic cytotoxicity and regenerative hyperplasia: a case study with hexavalent chromium, captan, and folpet

Bhat

Cohen

Gordon³

et al. 2020

Critical Reviews in Toxicology

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Small intestinal (SI) tumors are relatively uncommon outcomes in rodent cancer bioassays, and limited information regarding chemical-induced SI tumorigenesis has been reported in the published literature. Herein, we propose a cytotoxicity-mediated adverse outcome pathway (AOP) for SI tumors by leveraging extensive target species-and site-specific molecular, cellular, and histological mode of action (MOA) research for three reference chemicals, the fungicides captan and folpet and the transition metal hexavalent chromium (Cr(VI)). The gut barrier functions through highly efficient homeostatic regulation of SI epithelial cell sloughing, regenerative proliferation, and repair, which involves the replacement of up to 10 11 cells per day. This dynamic turnover in the SI provides a unique local environment for a cytotoxicity mediated AOP/ MOA. Upon entering the duodenum, cytotoxicity to the villous epithelium is the molecular initiating event, as indicated by crypt elongation, villous atrophy/blunting, and other morphologic changes. Over time, the regenerative capacity of the gut epithelium to compensate declines as epithelial loss accelerates, especially at higher exposures. The first key event (KE), sustained regenerative crypt proliferation/hyperplasia, requires sufficient durations, likely exceeding 6 or 12 months, due to extensive repair capacity, to create more opportunities for the second KE, spontaneous mutation/transformation, ultimately leading to proximal SI tumors. Per OECD guidance, biological plausibility, essentiality, and empirical support were assessed using modified Bradford Hill considerations. The weight-of-evidence also included a lack of induced mutations in the duodenum after up to 90 days of Cr(VI) or captan exposure. The extensive evidence for this AOP, along with the knowledge that human exposures are orders of magnitude below those associated with KEs in this AOP, supports its use for regulatory applications, including hazard identification and risk assessment.

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Section: Alternative Modes Of Actionmentioning

confidence: 82%

Section: Alternative Modes Of Actionmentioning

confidence: 99%

Section: Alternative Modes Of Actionmentioning

confidence: 99%

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An adverse outcome pathway for small intestinal tumors in mice involving chronic cytotoxicity and regenerative hyperplasia: a case study with hexavalent chromium, captan, and folpet

Bhat

Cohen

Gordon³

et al. 2020

Critical Reviews in Toxicology

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“…As a result, G-to-T transversions, which are a landmark mutation of oxidative stress, were observed in tumor tissue, particularly in the 5′-TGAA-3′ sequence of the Apc gene, which encodes a component of the Wnt signaling pathway. Recently, our group showed that 90-day administration of 0.6 g/L potassium bromate in drinking water increased mutant frequency in the small intestine of gpt (guanine phosphoribosyltransferase) delta mice [ 7 ], in which the gpt gene of Escherichia coli carried on lambda EG10 phage DNA (80 copies per haploid) is integrated into the mouse genomic DNA as a target gene for detecting mutations in vivo [ 8 , 9 ]. Specifically, we found that the frequency of G-to-T transversion was increased, particularly in a 5′-TGAA-3′ sequence in the gpt gene [ 7 ].…”

Section: Introductionmentioning

confidence: 99%

“…Recently, our group showed that 90-day administration of 0.6 g/L potassium bromate in drinking water increased mutant frequency in the small intestine of gpt (guanine phosphoribosyltransferase) delta mice [ 7 ], in which the gpt gene of Escherichia coli carried on lambda EG10 phage DNA (80 copies per haploid) is integrated into the mouse genomic DNA as a target gene for detecting mutations in vivo [ 8 , 9 ]. Specifically, we found that the frequency of G-to-T transversion was increased, particularly in a 5′-TGAA-3′ sequence in the gpt gene [ 7 ]. Together, these observations suggest that G-to-T transversion in the 5′-TGAA-3′ sequence of the Apc gene is an initiating event of tumorigenesis in the small intestine via disruption of the Wnt signaling pathway.…”

Section: Introductionmentioning

confidence: 99%

Characteristic mutations induced in the small intestine of Msh2-knockout gpt delta mice

et al. 2021

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Background Base pair mismatches in genomic DNA can result in mutagenesis, and consequently in tumorigenesis. To investigate how mismatch repair deficiency increases mutagenicity under oxidative stress, we examined the type and frequency of mutations arising in the mucosa of the small intestine of mice carrying a reporter gene encoding guanine phosphoribosyltransferase (gpt) and in which the Msh2 gene, which encodes a component of the mismatch repair system, was either intact (Msh2+/+::gpt/0; Msh2-bearing) or homozygously knockout (KO) (Msh2−/−::gpt/0; Msh2-KO). Results Gpt mutant frequency in the small intestine of Msh2-KO mice was about 10 times that in Msh2-bearing mice. Mutant frequency in the Msh2-KO mice was not further enhanced by administration of potassium bromate, an oxidative stress inducer, in the drinking water at a dose of 1.5 g/L for 28 days. Mutation analysis showed that the characteristic mutation in the small intestine of the Msh2-KO mice was G-to-A transition, irrespective of whether potassium bromate was administered. Furthermore, administration of potassium bromate induced mutations at specific sites in gpt in the Msh2-KO mice: G-to-A transition was frequently induced at two known sites of spontaneous mutation (nucleotides 110 and 115, CpG sites) and at nucleotides 92 and 113 (3′-side of 5′-GpG-3′), and these sites were confirmed to be mutation hotspots in potassium bromate-administered Msh2-KO mice. Administration of potassium bromate also induced characteristic mutations, mainly single-base deletion and insertion of an adenine residue, in sequences of three to five adenine nucleotides (A-runs) in Msh2-KO mice, and elevated the overall proportion of single-base deletions plus insertions in Msh2-KO mice. Conclusions Our previous study revealed that administration of potassium bromate enhanced tumorigenesis in the small intestine of Msh2-KO mice and induced G-to-A transition in the Ctnnb1 gene. Based on our present and previous observations, we propose that oxidative stress under conditions of mismatch repair deficiency accelerates the induction of single-adenine deletions at specific sites in oncogenes, which enhances tumorigenesis in a synergistic manner with G-to-A transition in other oncogenes (e.g., Ctnnb1).

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Possible contribution of 8-hydroxydeoxyguanosine to gene mutations in the kidney DNA of gpt delta rats following potassium bromate treatment

Kuroda,

Ishii,

Takasu

et al. 2024

Mutation Research/Genetic Toxicology and Environmental Mutagene

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Oxidative-stress-driven mutagenesis in the small intestine of the gpt delta mouse induced by oral administration of potassium bromate

Cited by 10 publications

References 67 publications

An adverse outcome pathway for small intestinal tumors in mice involving chronic cytotoxicity and regenerative hyperplasia: a case study with hexavalent chromium, captan, and folpet

An adverse outcome pathway for small intestinal tumors in mice involving chronic cytotoxicity and regenerative hyperplasia: a case study with hexavalent chromium, captan, and folpet

Characteristic mutations induced in the small intestine of Msh2-knockout gpt delta mice

Possible contribution of 8-hydroxydeoxyguanosine to gene mutations in the kidney DNA of gpt delta rats following potassium bromate treatment

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