Role of Iron in the Cellular Effects of Asbestos

Our plain-English summary of Role of Iron in the Cellular Effects of Asbestos, by E.A. Aust, L.G. Lund, C.C. Chao, et al (Inhalation Toxicology, 2000).

The study

• Authors: E.A. Aust, L.G. Lund, C.C. Chao, S.H. Park, R. Fang
• Journal: Inhalation Toxicology
• Published: 2000;12 Suppl 3:75-80
• Cited by: 15 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Research to understand how the physical characteristics of asbestos fibers impact the pathological effects has intensified in the past 10 years. The role that iron, intrinsic or acquired, may play has been the subject of many of these investigations. Asbestos catalyzes many of the same reactions that iron does, including lipid peroxidation and DNA damage. At physiological pH, mobilization of iron from the fibers by a low-molecular-weight chelator greatly enhances these reactions. Iron is also mobilized from asbestos fibers in human lung epithelial (A549) cells after the fibers are endocytized. The iron appears to move from a low-molecular-weight pool to nonferritin proteins and ferritin. The amount of iron in the low-molecular-weight pool was directly correlated with the toxicity of the asbestos. Glutathione (CSH) levels in these cells were dramatically reduced after asbestos treatment as a result of CSH efflux. This was not related to the iron associated with the fibers, but appeared to be due in some way to the silicate structure. The presence of the mobilized iron in the cells depleted of CSH creates a very oxidizing environment. Asbestos treatment of cells resulted in DNA oxidation, as assessed by formation of 8-hydroxy-2'-deoxyguanosine (8-oxo-dCJ. The DNA oxidation was dependent upon the iron associated with the fibers and the enzymatic generation of (•) NO by the cells. The induction of the inducible form of nitric oxide synthase (iNOS), responsible for the production of "NO, was dependent upon the presence of iron from the fibers and the decrease in CSH. One without the other did not lead to induction of iNOS. Asbestos was mutagenic in hgprt-gpt(+) V79 Chinese hamster lung cells. The mutagenicity was dependent upon iron, intrinsic or acquired. Addition of (•) NO synergistically increased the mutagenicity of the asbestos, suggesting that in cells that respond to asbestos by making (•) NO, the response will be enhanced. This also suggests that the responses will be enhanced in the presence of activated macrophages producing (•) NO or in the presence of cigarette smoke, because of the presence of (•) NO and iron chelators in the smoke.

In plain English

This article was a review, not a new study. It looked at how iron carried on asbestos fibers may contribute to the fibers' effects on cells, drawing mainly on earlier laboratory studies of crocidolite asbestos in cultured cells. In human lung epithelial (A549) cells, iron released from crocidolite into a low-molecular-weight fraction was directly related to how toxic the crocidolite was to the cells. Crocidolite lowered the cells' glutathione, a protective molecule, because the cells pumped it out. This did not depend on the fibers' iron and appeared to be related to the silicate crystal structure. Oxidative DNA damage rose with the crocidolite dose and required both iron and nitric oxide made by the cells. Iron and glutathione depletion together switched on the enzyme that makes nitric oxide, but neither did so alone. In Chinese hamster V79 cells, asbestos caused mutations that required iron, and a nitric oxide-generating compound increased them synergistically. The authors suggested that reactive species formed after asbestos is inhaled could increase damage to the cells lining the lung.

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: Review of earlier laboratory (cell culture) studies on iron associated with asbestos fibers
• Who was studied: Cultured cells in the reviewed studies: human lung epithelial (A549) cells and Chinese hamster V79 lung cells; no human or animal subjects
• Exposure: Asbestos, mainly crocidolite, including iron intrinsic to the fibers or acquired from culture medium; in some experiments a soluble iron compound (ferric ammonium citrate), a glutathione synthesis inhibitor (BSO), or a nitric oxide-generating compound (DETA/NO)
• Main results:
  • In A549 cells, the iron mobilized from crocidolite into a low-molecular-weight fraction was directly related to the cytotoxicity of the crocidolite (reported from Chao et al., 1994)
  • Glutathione levels in A549 cells fell with crocidolite treatment because the cells released (effluxed) it (reported from Golladay et al., 1997)
  • The glutathione decrease in A549 cells did not depend on iron associated with the fibers and appeared related to the silicate crystalline structure
  • Oxidative DNA damage (8-oxo-dG) in A549 cells increased with crocidolite dose and leveled off at the highest dose (reported from Chao et al., 1996)
  • Formation of 8-oxo-dG in A549 cells required iron and also depended on nitric oxide produced enzymatically by the cells
  • In A549 cells, soluble iron (FAC) alone or the glutathione synthesis inhibitor BSO alone did not induce iNOS, the enzyme that makes nitric oxide, but the two together did, without fibers (reported from Park and Aust, 1998b)
  • Asbestos was mutagenic in Chinese hamster V79 cells (reported from Park and Aust, 1998a)
  • In V79 cells, adding the nitric oxide-generating compound DETA/NO synergistically increased the mutations caused by crocidolite
• The authors' conclusion: The authors suggested that the reactive species formed after asbestos is inhaled could increase the damaging effects of asbestos in the epithelial cells lining the lung

Topics

Medical terms in this study, explained in our Lexicon: Ferritin, Glutathione (GSH), Silicate, Macrophage.

Related studies

• Participation of nitric oxide and iron in the oxidation of DNA in asbestos-treated human lung epithelial cells — C.C. Chao, S.H. Park, et al. (1996)
• Iron mobilization from crocidolite asbestos greatly enhances crocidolite-dependent formation of DNA single-strand breaks in phi X174 RFI DNA — L.G. Lund, A.E. Aust (1992)
• Iron mobilization from asbestos by chelators and ascorbic acid — L.G. Lund, A.E. Aust (1990)
• Iron associated with asbestos bodies is responsible for the formation of single strand breaks in phi X174 RFI DNA — L.G. Lund, M.G. Williams, et al. (1994)
• Regulation of nitric oxide synthase induction by iron and glutathione in asbestos-treated human lung epithelial cells — S.H. Park, A.E. Aust (1998)
• Tunneling nanotubes provide a unique conduit for intercellular transfer of cellular contents in human malignant pleural mesothelioma — E. Lou, S. Fujisawa, et al. (2012)

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