Asbestos and erionite fibres can induce mutations in human lymphocytes that result in loss of heterozygosity

Our plain-English summary of Asbestos and erionite fibres can induce mutations in human lymphocytes that result in loss of heterozygosity, by K. Both, D.W. Henderson, D.R. Turner (International Journal of Cancer, 1994).

The study

• Authors: K. Both, D.W. Henderson, D.R. Turner
• Journal: International Journal of Cancer
• Published: 1994;59(4):538-42
• Cited by: 20 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Although asbestos and erionite are proven human carcinogens, most studies have concluded that these fibres are not mutagenic to mammalian cells in vitro. We have studied the potential of these fibres and chrysotile fibres to induce mutations in human peripheral lymphocytes, using a mutation assay that measures mutation at the autosomal HLA-A locus. Exposure of lymphocytes in culture to 400 micrograms/ml of crocidolite or erionite for 72 hr did not result in a statistically significant increase in the mutation frequency (MF) in the HLA-A assay, although a trend towards increased MF was observed. Exposure to 400 micrograms/ml chrysotile resulted in no increase in MF; however a significant increase was observed at 50 micrograms/ml. Mutations in somatic cells can be classified according to their molecular basis. Molecular analysis of mutants obtained following exposure of lymphocytes to crocidolite and erionite demonstrated a statistically significant increase in the class of mutations arising from loss-of-heterozygosity (LOH) events involving the selection locus (HLA-A) and more distal loci. Mutations following exposure to crocidolite and erionite showed a greater frequency of LOH than did spontaneous mutants (p < 0.02 and p < 0.005 respectively). Mutants following exposure to chrysotile did not display a significant difference in LOH when compared with spontaneous mutants. Thus, although an increase in overall mutation frequency following fibre exposure did not achieve statistical significance, the modest increase seen following exposure to erionite and crocidolite is translated into a highly significant change in those components of the spectrum of mutations which result in LOH.

In plain English

This was a laboratory study of human white blood cells (lymphocytes) grown in dishes, not of people. The authors exposed lymphocytes from one blood donor for 72 hours to UICC crocidolite or erionite (a zeolite fibre), each at 400 micrograms per millilitre, or UICC chrysotile at 50 or 400 micrograms per millilitre. They measured mutations at the HLA-A gene and analysed 622 mutant clones. Crocidolite and erionite did not significantly raise overall mutation frequency, though a trend towards an increase appeared. Chrysotile at 50 micrograms per millilitre was moderately mutagenic. Mutants from crocidolite-exposed cells (p less than 0.020) and erionite-exposed cells (p less than 0.005) showed more loss of heterozygosity than spontaneous mutants. Loss of heterozygosity means losing one of two different versions of a chromosome stretch. With chrysotile at either concentration, the difference in loss of heterozygosity from spontaneous mutants was not statistically significant. The authors called the overall increase small, said assigning it biological significance was premature, but concluded their results suggest a role for asbestos both as a primary carcinogen and in cancer progression. They noted lymphocytes are not the cells asbestos fibres target.

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: Laboratory (in vitro) experiment on cultured human lymphocytes, using a mutation assay at the HLA-A locus followed by molecular analysis of mutant clones
• Who was studied: Peripheral-blood lymphocytes from a single donor who carried two different HLA-A types (A2/A3), studied at Flinders Medical Centre, Adelaide, South Australia; 622 mutant clones were analysed
• Exposure: UICC standard reference South African crocidolite at 400 micrograms per millilitre; erionite (not milled to UICC standards) at 400 micrograms per millilitre; UICC chrysotile at 50 or 400 micrograms per millilitre; all for 72 hours. Control cells were cultured without fibres.
• Main results:
  • Crocidolite and erionite at 400 micrograms per millilitre did not significantly increase mutation frequency compared with controls
  • Crocidolite and erionite showed a trend towards increased mutation that was not statistically significant
  • Chrysotile at 50 micrograms per millilitre was moderately mutagenic to the lymphocytes; chrysotile at 400 micrograms per millilitre produced no increase
  • 622 mutant clones were analysed for loss or retention of heterozygosity at three loci on chromosome 6
  • Mutants from cells exposed to 400 micrograms per millilitre crocidolite had a significantly higher frequency of loss of heterozygosity than spontaneous mutants (p less than 0.020)
  • Mutants from cells exposed to 400 micrograms per millilitre erionite had a greater frequency of loss of heterozygosity than controls (p less than 0.005)
  • For mutants from chrysotile-exposed cells, at either 50 or 400 micrograms per millilitre, the difference in loss of heterozygosity compared with spontaneous mutants was not statistically significant (p less than 0.800 in each case)
  • In most cases the loss of heterozygosity extended at least to the D6S89 locus near the end of the short arm of chromosome 6. Heterozygosity on the long arm was kept in all mutant clones.
• The authors' conclusion: The authors said the overall increase in mutations was small and it was premature to assign biological significance to it. They nevertheless concluded that, because loss of heterozygosity is a factor in cancer initiation and progression, their results suggest a role for asbestos both as a primary carcinogen and in cancer progression.
• Limitations the authors state:
  • Lymphocytes are not the cells that asbestos fibres target
  • The PCR-based method could not distinguish mitotic recombination from large deletions extending to the end of the chromosome
  • The increased mutation frequency seen with 50 micrograms per millilitre chrysotile may have been adventitious (a chance finding)
  • Whether monocytes (another blood cell type) acted as effectors of mutation was not resolved

Topics

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

Medical terms in this study, explained in our Lexicon: erionite, Chrysotile, Crocidolite, Statistical Significance.

Related studies

• Loss of heterozygosity in asbestos-induced mutations in a human mesothelioma cell line — K. Both, D.R. Turner, et al. (1995)
• Stability of mineral fibres in contact with human cell cultures. An in situ μXANES, μXRD and XRF iron mapping study — S. Pollastri, A.F. Gualtieri, et al. (2016)
• Assessment of asbestos body formation by high resolution FEG-SEM after exposure of Sprague-Dawley rats to chrysotile, crocidolite, or erionite — N.B. Gandolfi, A.F. Gualtieri, et al. (2016)
• Increased expression of epidermal growth factor receptor in rat pleural mesothelial cells correlates with carcinogenicity of mineral fibres — S.P. Faux, C.E. Houghton, et al. (2000)
• Erionite induces production of autoantibodies and IL-17 in C57BL/6 mice — C.N. Zebedeo, C. Davis, et al. (2014)
• Erionite and asbestos differently cause transformation of human mesothelial cells — P. Bertino, A. Marconi, et al. (2007)

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