Asbestos exposure affects poly(ADP-ribose) polymerase-1 activity: role in asbestos-induced carcinogenesis

Our plain-English summary of Asbestos exposure affects poly(ADP-ribose) polymerase-1 activity: role in asbestos-induced carcinogenesis, by M. Tomasetti, M. Amati, L. Nocchi, et al (Mutagenesis, 2011).

The study

• Authors: M. Tomasetti, M. Amati, L. Nocchi, F. Saccucci, E. Strafella, S. Staffolani, L.M. Tarquini, D. Carbonari, R. Alleva, B. Borghi, J. Neuzil, M. Bracci, L. Santarelli
• Journal: Mutagenesis
• Published: 2011;26(5):585-91
• Cited by: 14 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Asbestos is known to induce malignant mesothelioma (MM) and other asbestos-related diseases. It is directly genotoxic by inducing DNA strand breaks and cytotoxic by promoting apoptosis in lung target cells. Poly(ADP-ribose) polymerase-1 (PARP1) is a nuclear zinc-finger protein with a function as a DNA damage sensor. To determine whether PARP1 is involved in asbestos-induced carcinogenesis, PARP1 expression and activity as well as DNA damage and repair were evaluated in circulating cells of asbestos-exposed subjects, MM patients and age-matched controls. PARP1 expression and activity were also evaluated in pleural biopsies of MM patients and compared with normal tissue. Accumulation of the pre-mutagenic 8-hydroxy-2'-deoxyguanosine and elevated PARP1 expression were found both in asbestos-exposed subjects and MM patients. Although PARP1 was highly expressed, its activity was relatively low. Low DNA repair efficiency was observed in lymphocytes from MM patients. High expression of PARP1 associated with low PARP activity was also found in MM biopsies. To mimic PARP1 dysfunction, PARP1 expression and activity were induced in immortalised mesothelial cells by their exposure to asbestos in the presence of a PARP1 inhibitor, which resulted in transformation of the cells. We propose that exposure to asbestos inhibits the PARP1 activity possibly resulting in higher DNA instability, thus causing malignant transformation.

In plain English

This laboratory study from Ancona, Italy, examined PARP1, a protein that senses DNA damage. The authors compared blood lymphocytes from 42 people with a history of asbestos exposure, 25 patients with malignant mesothelioma and 30 age-matched controls never exposed to asbestos. They also tested small numbers of mesothelioma and normal tissue biopsies, and exposed immortalised mesothelial cells to crocidolite asbestos with or without a PARP1-blocking drug. In exposed subjects, PARP1 gene expression was 4-fold higher than in controls, but PARP1 activity was lower. In mesothelioma patients, expression was 2.6-fold higher and most of the protein was in a cut (cleaved) form. Both groups had significantly more 8OHdG, a marker of oxidative DNA damage. DNA repair was significantly slower in mesothelioma patients and only slightly slower in exposed subjects. Tumour tissue had about 12-fold higher PARP1 gene expression than normal tissue, but lower PARP1 activity. Crocidolite-exposed cells with PARP1 blocked formed more colonies, a sign of malignant change. The authors proposed that asbestos inhibits PARP1 activity, possibly causing DNA instability and malignant transformation.

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 comparison of blood cells from three groups (asbestos-exposed subjects, mesothelioma patients, unexposed controls), plus a comparison of mesothelioma and normal tissue biopsies and a cell-culture experiment
• Who was studied: 42 people with a history of asbestos exposure (40 men, 2 women) enrolled at the Institute of Occupational Medicine, Ancona, Italy; 25 malignant mesothelioma patients (21 men, 4 women) diagnosed on pleural biopsies at the University Hospital of Ancona; 30 age-matched controls never exposed to asbestos (19 men, 11 women). Tissue: 4 mesothelioma and 4 normal mesothelium biopsies. 11 (26%) of the exposed subjects had evidence of asbestos-related disease (fibrosis and pleural plaques).
• Exposure: Human subjects: occupational exposure to asbestos dust for an average of 23.3 years (fiber type not stated). Cell experiments: crocidolite asbestos fibres at 10 micrograms per square centimetre, with or without the PARP1 inhibitor 3-aminobenzamide.
• Main results:
  • In lymphocytes of asbestos-exposed subjects, PARP1 gene expression was 4-fold higher than in controls (P less than 0.001)
  • Despite high expression, PARP1 activity in lymphocytes of asbestos-exposed subjects was low compared with controls (P less than 0.0001)
  • In mesothelioma patients, PARP1 gene expression in lymphocytes was 2.6-fold higher than in controls (P less than 0.0001), but most of the PARP1 protein was in the cleaved form
  • In mesothelioma tumour biopsies, PARP1 levels were about 12-fold higher than in normal tissue (Figure 2A, which shows PARP1 mRNA, that is gene expression); increased PARP1 protein was also shown by western blot, without a fold figure; PARP1 activity was lower than in normal tissue
  • Asbestos-exposed subjects and mesothelioma patients both had significantly higher lymphocyte 8OHdG (oxidative DNA damage) levels than controls
  • Repair of hydrogen peroxide-induced DNA breaks in lymphocytes: rate 48 plus or minus 34 AU/min in controls, 42 plus or minus 26 AU/min in exposed subjects (a slight delay), and 17 plus or minus 5 AU/min in mesothelioma patients (a significant delay, P less than 0.05)
  • Across the combined groups, PARP1 activity positively correlated with the rate of DNA repair (R = 0.248, P less than 0.05); none of the measures were influenced by age, sex, smoking or duration of asbestos exposure
  • In immortalised mesothelial cells exposed to crocidolite, PARP inhibition blocked the rejoining of DNA strand breaks and was accompanied by increased colony formation, which the authors took as indicating a malignant phenotype
• The authors' conclusion: The authors proposed that asbestos exposure inhibits PARP1 activity, possibly resulting in greater DNA instability and so causing malignant transformation.

Topics

Medical terms in this study, explained in our Lexicon: Asbestos Exposure, Carcinogenesis, Malignant Mesothelioma, Apoptosis, Mesothelial Cells, Malignant Transformation.

Related studies

• Modulation of cell and DNA damage by poly(ADP)ribose polymerase in lung cells exposed to H(2)O(2) or asbestos fibres — T. Ollikainen, A. Puhakka, et al. (2000)
• Synthesis of poly(ADP-ribose) in asbestos treated rat pleural mesothelial cells in culture — H.Y. Dong, A. Buard, et al. (1995)
• Cigarette smoke and asbestos activate poly-ADP-ribose polymerase in alveolar epithelial cells — D.W. Kamp, M. Srinivasan, et al. (2001)
• mRNA expression patterns in different stages of asbestos-induced carcinogenesis in rats — H. Sandhu, W. Dehnen, et al. (2000)
• The role of iNOS-mediated DNA damage in infection- and asbestos-induced carcinogenesis — Y. Hiraku, S. Kawanishi, et al. (2010)
• Asbestos promotes morphological transformation and elevates expression of a gene family invariably induced by tumor promoters in C3H/10T1/2 cells — C.L. Parfett, R. Pilon, et al. (1996)

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