Mth1 deficiency provides longer survival upon intraperitoneal crocidolite injection in female mice

Our plain-English summary of Mth1 deficiency provides longer survival upon intraperitoneal crocidolite injection in female mice, by S. Funahashi, Y. Okazaki, S. Akatsuka, et al (Free Radical Research, 2020).

The study

• Authors: S. Funahashi, Y. Okazaki, S. Akatsuka, T. Takahashi, K. Sakumi, Y. Nakabeppu, S. Toyokuni
• Journal: Free Radical Research
• Published: 2020;54(2-3):195-205
• Cited by: 6 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Exposure to asbestos fiber is central to mesothelial carcinogenesis. Recent sequencing studies on human and rodent malignant mesothelioma (MM) revealed frequently mutated genes, including CDKN2A, BAP1 and NF2. Crocidolite directly or indirectly catalyses the generation of hydroxyl radicals, which appears to be the major driving force for mesothelial mutations. DNA base modification is an oxidative DNA damage mechanism, where 8-hydroxy-2'-deoxyguanosine (8-OHdG) is the most abundant modification both physiologically and pathologically. Multiple distinct mechanisms work together to decrease the genomic level of 8-OHdG through the enzymatic activities of Mutyh, Ogg1 and Mth1. Knockout of one or multiple enzymes is not lethal but increases the incidence of tumors. Here, we used single knockout (KO) mice to test whether the deficiency of these three genes affects the incidence and prognosis of asbestos-induced MM. Intraperitoneal injection of 3 mg crocidolite induced MM at a fraction of 14.8% (4/27) in Mth1 KO, 41.4% (12/29) in Mutyh KO and 24.0% (6/25) in Ogg1 KO mice, whereas 31.7% (20/63) induction was observed in C57BL/6 wild-type (Wt) mice. The lifespan of female Mth1 KO mice was longer than that of female Wt mice (p = 0.0468). Whole genome scanning of MM with array-based comparative genomic hybridization revealed rare genomic alterations compared to MM in rats and humans. These results indicate that neither Mutyh deficiency nor Ogg1 deficiency promotes crocidolite-induced MM in mice, but the sanitizing nucleotide pool with Mth1 is advantageous in crocidolite-induced mesothelial carcinogenesis.

In plain English

In this animal experiment, the authors tested whether mice lacking one of three genes (Mth1, Mutyh or Ogg1) that limit the oxidative DNA damage 8-oxoG differed in response to crocidolite asbestos. Wild-type and knockout mice received two intraperitoneal injections of crocidolite, 3 mg in total, at 6 and 7 weeks of age, and were observed until 700 days after birth, with earlier euthanasia for sick mice and earlier endpoints for saline-injected knockouts. 196 mice were included. Among crocidolite-injected mice, malignant mesothelioma on the peritoneum developed in 4 of 27 Mth1 knockout mice (14.8%), 12 of 29 Mutyh knockout mice (41.4%), 6 of 25 Ogg1 knockout mice (24.0%) and 20 of 63 wild-type mice (31.7%). None of these differences from wild-type was statistically significant, and no mouse developed mesothelioma without crocidolite. Female Mth1 knockout mice lived significantly longer than female wild-type mice; males did not. The authors concluded that female Mth1 knockout mice showed delayed mesothelioma and longer lifespan, while Mutyh and Ogg1 knockout neither shortened survival nor significantly increased mesothelioma. They noted a larger number of mice might have made the lower Mth1 knockout incidence significant.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Animal experiment comparing knockout mice (lacking Mth1, Mutyh or Ogg1) with wild-type mice after intraperitoneal crocidolite injection
• Who was studied: 196 mice in total: C57BL6 wild-type mice and Mth1, Mutyh and Ogg1 knockout mice, injected with crocidolite or with saline, at Nagoya University Graduate School of Medicine, Japan. Group sizes are given in Table 1, which is not in the text.
• Exposure: Crocidolite (from the Union for International Cancer Control) suspended in saline at 5 mg/ml. Mice received two intraperitoneal injections of 0.3 ml at 6 and 7 weeks of age, 3 mg in total. Control mice received the same amount of saline.
• Main results:
  • Among crocidolite-injected mice, malignant mesothelioma developed in 14.8% (4/27) of Mth1 knockout mice, 41.4% (12/29) of Mutyh knockout mice, 24.0% (6/25) of Ogg1 knockout mice and 31.7% (20/63) of wild-type mice.
  • Mth1 knockout versus wild-type: mesothelioma incidence was lower but not statistically significant (Fisher's exact test P=0.122; relative risk 0.478, 95% CI 0.183-1.120).
  • Mutyh knockout versus wild-type: incidence was slightly higher but not statistically significant (P=0.480; relative risk 1.324, 95% CI 0.719-2.367).
  • Ogg1 knockout versus wild-type: incidence was slightly lower (P=0.607; relative risk 0.753, 95% CI 0.334-1.564).
  • No mice developed mesothelioma without crocidolite injection.
  • The mesotheliomas appeared as whitish masses of about 10 mm on the surface of the peritoneum.
  • Female Mth1 knockout mice lived significantly longer than female wild-type mice after crocidolite (P=0.0468).
  • Male Mth1 knockout mice did not live longer than male wild-type mice (P=0.2023).
  • Among mice that developed mesothelioma, the same longer-survival tendency was seen, but the differences were not significant.
  • Loss of Mutyh or Ogg1 did not significantly change lifespan after crocidolite, in males or females.
  • Female wild-type, Mth1 knockout and Mutyh knockout mice survived significantly longer than males of the same type; this was not the case for Ogg1 knockout mice.
  • Levels of 8-oxoG in normal mesothelium and in mesothelioma were not significantly higher in the knockout mice than in wild-type mice, as measured by immunohistochemistry.
  • Genome scanning (aCGH) of 20 mouse mesotheliomas found few changes. Cdkn2a/2b was deleted on both copies in only one wild-type case, and Nf2 showed loss of heterozygosity in only one wild-type case. No change was found in Bap1.
• The authors' conclusion: The authors concluded that female Mth1 knockout mice showed delayed crocidolite-induced mesothelioma and longer lifespan. They also concluded that Mutyh and Ogg1 knockout neither shortened survival nor significantly increased mesothelioma incidence, suggesting that this DNA-repair deficiency may not be critical in crocidolite-induced mesothelioma.
• Limitations the authors state:
  • The lower mesothelioma incidence in Mth1 knockout mice was not statistically significant; the authors suggested that more mice might have yielded significance.
  • Immunohistochemistry is less sensitive than biochemical methods for measuring 8-oxoG, which the authors said hampered statistical significance.
  • Mouse mesotheliomas were small and hard to separate from surrounding tissue, so tumor samples likely contained more non-tumor cells than rat tumors would. This may have affected the genome analysis.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Crocidolite.

Medical terms in this study, explained in our Lexicon: Crocidolite, Carcinogenesis, Malignant Mesothelioma, CDKN2A, BAP1, Hydroxyl Radical, 8-OHdG, Prognosis.

Related studies

• Changes in DNA 8-hydroxyguanine levels, 8-hydroxyguanine repair activity, and hOGG1 and hMTH1 mRNA expression in human lung alveolar epithelial cells induced by crocidolite asbestos — H.N. Kim, Y. Morimoto, et al. (2001)
• P53 mutations in tumours induced by intraperitoneal injection of crocidolite asbestos and benzo[a]pyrene in rats — K. Unfried, N. Kociok, et al. (1997)
• Differential diagnosis of malignant tumours in the abdominal cavity of rats after intraperitoneal injection of crocidolite or benzo[a]pyrene — J. Friemann, M. Varnai, et al. (1996)
• Global overexpression of divalent metal transporter 1 delays crocidolite-induced mesothelial carcinogenesis in male mice — S. Funahashi, Y. Okazaki, et al. (2018)
• Fibrous nanocellulose, crystalline nanocellulose, carbon nanotubes, and crocidolite asbestos elicit disparate immune responses upon pharyngeal aspiration in mice — E.J. Park, T.O. Khaliullin, et al. (2018)
• Asbestos surface provides a niche for oxidative modification — H. Nagai, T. Ishihara, et al. (2011)

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