Global overexpression of divalent metal transporter 1 delays crocidolite-induced mesothelial carcinogenesis in male mice

Our plain-English summary of Global overexpression of divalent metal transporter 1 delays crocidolite-induced mesothelial carcinogenesis in male mice, by S. Funahashi, Y. Okazaki, T. Nishiyama, et al (Free Radical Research, 2018).

The study

• Authors: S. Funahashi, Y. Okazaki, T. Nishiyama, H. Ohyoshi, H. Yasui, K. Nishida, S. Matsui, S. Toyokuni
• Journal: Free Radical Research
• Published: 2018;52(9):1030-1039
• Cited by: 5 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Exposure to asbestos fiber is central to mesothelial carcinogenesis, for which iron overload in or near mesothelial cells is a key pathogenic mechanism. Alternatively, iron chelation therapy with deferasirox or regular phlebotomy was significantly preventive against crocidolite-induced mesothelial carcinogenesis in rats. However, the role of iron transporters during asbestos-induced carcinogenesis remains elusive. Here, we studied the role of divalent metal transporter 1 (DMT1; Slc11a2), which is a Fe(II) transporter, that is present not only on the apical plasma membrane of duodenal cells but also on the lysosomal membrane of every cell, in crocidolite-induced mesothelial carcinogenesis using DMT1 transgenic (DMT1Tg) mice. DMT1Tg mice show mucosal block of iron absorption without cancer susceptibility under normal diet. We unexpectedly found that superoxide production was significantly decreased upon stimulation with crocidolite both in neutrophils and macrophages of DMT1Tg mice, and the macrophage surface revealed higher iron content 1 h after contact with crocidolite. Intraperitoneal injection of 3 mg crocidolite ultimately induced malignant mesothelioma in ∼50% of both wild-type and DMT1Tg mice (23/47 and 14/28, respectively); this effect was marginally (p = 0.069) delayed in DMT1Tg mice, promoting survival. The promotional effect of nitrilotriacetic acid was limited, and the liver showed significantly higher iron content both in DMT1Tg mice and after crocidolite exposure. The results indicate that global DMT1 overexpression causes decreased superoxide generation upon stimulation in inflammatory cells, which presumably delayed the promotional stage of crocidolite-induced mesothelial carcinogenesis. DMT1Tg mice with low-stamina inflammatory cells may be helpful to evaluate the involvement of inflammation in various pathologies.

In plain English

This was an animal experiment in mice. The authors compared ordinary (wild-type) mice with mice genetically altered to overproduce an iron transporter, DMT1. Mice received crocidolite asbestos injected into the abdomen and were watched until 600 days after birth. Some also received weekly injections of nitrilotriacetic acid (NTA), which the authors found had a limited effect. Mesothelioma developed in 23 of 47 crocidolite-treated wild-type mice and 14 of 28 crocidolite-treated DMT1 mice. No mice developed mesothelioma without crocidolite. In males, DMT1 mice survived marginally longer, but the difference was not statistically significant (p = 0.069). In females this tendency was not seen. In laboratory tests, DMT1 mouse neutrophils made less reactive oxygen at the highest crocidolite dose. Their macrophages made more at 1 hour after stimulation but less from 2 hours on. The tumors were sarcomatoid or biphasic, with none of the epithelioid type. The authors concluded that DMT1 mice showed a delay in crocidolite-induced mesothelioma that appeared linked to a weaker inflammatory response. They noted the study's power to detect a difference was only 47.4% and they could not add animals.

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 using genetically altered (DMT1 transgenic) and wild-type mice, with laboratory tests on their blood and immune cells
• Who was studied: 132 male and female mice in total: C57BL6 wild-type mice and DMT1 transgenic (heterozygous) mice, split into groups, observed until 600 days after birth
• Exposure: Two injections into the abdomen of 0.3 ml of crocidolite suspension (5 mg/ml), given at 6 and 7 weeks of age (3 mg in total). Some mice also received NTA (80 mg/kg) or saline once a week from 10 to 26 weeks of age.
• Main results:
  • Mesothelioma developed in 23 of 47 crocidolite-treated wild-type mice and 14 of 28 crocidolite-treated DMT1 transgenic mice
  • None of the mice without crocidolite developed mesothelioma. The five tumors found in untreated mice were sarcomas.
  • In males, overall survival was marginally longer in DMT1 transgenic mice than in wild-type mice (p = 0.069, not statistically significant). The study's detection power was 47.4%, and 103 mice per group would have been needed for 90% power.
  • In female mice, the longer-survival tendency was not observed
  • In the blood test, reactive oxygen production after crocidolite was significantly lower in DMT1 transgenic mice at the highest crocidolite concentration tested. It was also significantly lower after the iron-free stimulant zymosan.
  • Macrophages from DMT1 transgenic mice had significantly lower basal reactive oxygen production. After LPS stimulation they produced significantly more than wild-type macrophages at 1 hour, but less at 2 hours and thereafter.
  • After crocidolite exposure, macrophage reactive oxygen production was slightly higher in DMT1 transgenic mice at 1 hour, but significantly higher in wild-type mice at 2 hours
  • Macrophages from DMT1 transgenic mice had significantly higher surface iron 1 hour after exposure to crocidolite
  • Mesotheliomas were sarcomatoid (86.5%) or biphasic (13.5%); no epithelioid subtype was seen
  • Liver iron was significantly higher in DMT1 transgenic mice than in wild-type mice
  • NTA had a limited promotional effect
• The authors' conclusion: The authors concluded that DMT1 transgenic mice showed a delay in crocidolite-induced mesothelial carcinogenesis. They concluded this appeared to be mediated by a decreased inflammatory response, mainly in macrophages.
• Limitations the authors state:
  • The experiment's detection power was 47.4%, and the authors could not increase the number of animals per group
  • The mouse tumors had no pure epithelioid subtype, which the authors note is the major subtype in human mesothelioma. They called this species difference still a puzzle.

Topics

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

Medical terms in this study, explained in our Lexicon: Crocidolite, Carcinogenesis, Mesothelial Cells, Superoxide, Macrophage, Malignant Mesothelioma, Inflammation.

Related studies

• Iron addiction with ferroptosis-resistance in asbestos-induced mesothelial carcinogenesis: Toward the era of mesothelioma prevention — S. Toyokuni (2019)
• Dual preventive benefits of iron elimination by desferal in asbestos-induced mesothelial carcinogenesis — L. Jiang, S.H. Chew, et al. (2016)
• Mth1 deficiency provides longer survival upon intraperitoneal crocidolite injection in female mice — S. Funahashi, Y. Okazaki, et al. (2020)
• Susceptibility of p53-deficient mice to induction of mesothelioma by crocidolite asbestos fibers — J.M. Marsella, B.L. Liu, et al. (1997)
• Crocidolite asbestos-induced signal pathway dysregulation in mesothelial cells — H. Wang, A. Gillis, et al. (2011)
• Ferroptosis-dependent extracellular vesicles from macrophage contribute to asbestos-induced mesothelial carcinogenesis through loading ferritin — F. Ito, K. Kato, et al. (2021)

Browse more research in Free Radical Research, or return to medical research.