Evaluation of anti-nuclear antibodies and kidney pathology in Lewis rats following exposure to Libby amphibole asbestos

Our plain-English summary of Evaluation of anti-nuclear antibodies and kidney pathology in Lewis rats following exposure to Libby amphibole asbestos, by K.D. Salazar, C.B. Copeland, C.E. Wood, et al (Journal of Immunotoxicology, 2013).

The study

• Authors: K.D. Salazar, C.B. Copeland, C.E. Wood, J.E. Schmid, R.W. Luebke
• Journal: Journal of Immunotoxicology
• Published: 2013;10(4):329-33
• Cited by: 13 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

The prevalence of anti-nuclear antibodies (ANA) and self-reported systemic autoimmune diseases were increased in residents of Libby, MT, as was the incidence of ANA in Lewis rats exposed to Libby amphibole (LA) asbestos. However, rats induced to develop rheumatoid arthritis (RA) did not develop autoantibodies associated with RA, nor was RA exacerbated by LA exposure, suggesting that increased ANA expression might be related to some other autoimmune process. Libby residents self-reported increased numbers of physician-diagnosed cases of systemic lupus erythematosus (SLE). Thus, the goal of this study was to determine if the increased incidence of ANA in Lewis rats exposed to LA is related to the development of SLE-like disease. Female Lewis rats were intratracheally instilled bi-weekly for 13 weeks with total doses of 0.15, 0.5, 1.5, or 5.0 mg of LA or 0.5 or 1.5 mg of a positive control fiber, amosite. ANA incidence was significantly increased in all asbestos dose groups, although no dose response was observed. The occurrence of proteinuria was increased in LA 0.5, LA 5.0, and amosite 0.5 dose groups; however, the microscopic appearance of the kidneys was normal, no binding of autoimmune complexes to glomerular surfaces was observed, and antibodies to double-stranded DNA were not elevated. Therefore, an increased prevalence of ANA in rats exposed to asbestos does not appear to correlate with disease markers typically observed in SLE. Analysis of ANA specificity for extractable nuclear antigens (ENA) determined that 98% of ENA(+) samples were specific for the Jo-1 antigen. Autoantibodies to Jo-1 have been reported in patients with interstitial lung disease, suggesting that autoantibodies to Jo-1 may be a biomarker for asbestos-related pulmonary disease.

In plain English

This animal experiment tested whether Libby amphibole (LA) asbestos produces SLE-like autoimmune disease in female Lewis rats. Rats (8 per group, experiments run in duplicate with pooled data) received seven intratracheal instillations bi-weekly over 13 weeks, giving total doses of 0, 0.15, 0.5, 1.5 or 5.0 mg LA, or 0.5 or 1.5 mg amosite as a positive control fiber. Serum was collected before dosing and every 4 weeks thereafter. The authors reported that all doses of amosite and LA, except LA 0.15 and LA 1.5, significantly increased the number of anti-nuclear antibody (ANA) positive animals, with no dose-dependent increase; at week 28, 5 of 16 vehicle rats were ANA positive compared with 11 of 15 at LA 5.0. Proteinuria rose in some groups at some time points, but kidney histology showed no treatment-related changes, no glomerular IgG or complement C3 deposition was seen, and antibodies to double-stranded DNA were not affected. Only LA 1.5 significantly increased extractable nuclear antigen (ENA) positivity; 44 of 45 (98%) of rats with ENA-specific antibodies were specific for Jo-1. The authors concluded that increased ANA does not predict SLE-like disease in Lewis rats, and that increased anti-Jo-1 may indicate interstitial lung disease.

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 (controlled intratracheal instillation study in rats, performed in duplicate with pooled data)
• Who was studied: Female Lewis rats, 8 per group (pooled group sizes of 15-16), 8-9 weeks old at first dosing, followed 28 weeks, at the US EPA laboratory, Research Triangle Park, NC
• Exposure: Intratracheal instillation, bi-weekly over 13 weeks (seven instillations), of total doses of 0, 0.15, 0.5, 1.5 or 5.0 mg Libby amphibole (a mixture of winchite 84%, richterite 11%, tremolite 6%) or 0.5 or 1.5 mg amosite as positive control fiber
• Main results:
  • All amosite and LA doses except LA 0.15 and LA 1.5 significantly increased the number of ANA-positive animals (Fisher's exact test, p less than 0.05); Table 1 gives week-28 counts of 5 of 16 for vehicle, 11 of 15 for LA 0.5, 11 of 15 for LA 5.0, 12 of 16 for amosite 0.5 and 11 of 16 for amosite 1.5
  • No dose-dependent increase in the number of ANA-positive rats was seen for either fiber by the final week
  • The predominant ANA staining pattern was speckled (66 of 68), with two of 68 nucleolar and no cytoplasmic staining
  • Antibodies to double-stranded DNA were not affected by LA or amosite exposure at 28 weeks
  • Only the LA 1.5 group showed a significant increase in ENA-positive animals (11 of 16, versus 5 of 16 in vehicle, Table 2) and in anti-Jo-1-positive animals (11 of 16)
  • Among rats with ENA-specific antibodies, 44 of 45 (98%) were specific for the Jo-1 antigen
  • Proteinuria was significantly increased versus vehicle in LA 0.5, LA 1.5 and LA 5.0 at Week 19 and in LA 0.15, LA 0.5, LA 5.0 and amosite 0.5 at Week 25; the slopes for LA 0.5, LA 5.0 and amosite 0.5 differed from vehicle, and no dose response was observed
  • Kidney microscopy showed no treatment-related changes, and no complement C3 or IgG deposition was seen in any treatment group
• The authors' conclusion: The authors concluded that the increased ANA incidence after asbestos exposure in the Lewis rat does not predict SLE-like systemic autoimmune disease, that increased antibodies to Jo-1 may indicate interstitial lung disease after LA exposure, and that the Lewis rat is not recommended as a model for studying Libby amphibole and systemic autoimmunity in humans
• Limitations the authors state:
  • The authors said the absence of a dose response may reflect measuring the incidence rather than the titers of autoantibodies
  • The authors noted that ANA increased without ENA at several doses, indicating the ANA were specific for antigens not covered by the assay kits used
  • The authors stated there is no generally accepted urine protein threshold indicating renal damage in the rat
  • The authors said direct comparison with earlier mouse studies is complicated by differences in animal model, dosing material and exposure schedule
  • The authors reported that LOAEL and NOAEL values could not be determined because the replicate studies showed no dose-responsive pattern

Mines named here

Asbestos mines this study is about. Each mine's page says who ran it, when it worked, and what it produced.

• Libby vermiculite mine, Montana

All asbestos mines

Topics

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

Medical terms in this study, explained in our Lexicon: Pathology, Libby amphiboles, Amosite, Interstitial Lung Disease, Biomarker.

Related studies

• Effects of Libby amphibole asbestos exposure on two models of arthritis in the Lewis rat — K.D. Salazar, C.B. Copeland, et al. (2012)
• Persistent effects of Libby amphibole and amosite asbestos following subchronic inhalation in rats — S.H. Gavett, C.U. Parkinson, et al. (2016)
• Long-term response of rats to single intratracheal exposure of Libby amphibole or amosite — J.M. Cyphert, D.J. Padilla-Carlin, et al. (2012)
• Renal, vascular and cardiac fibrosis in rats exposed to passive smoking and industrial dust fibre amosite — P. Boor, S. Casper, et al. (2009)
• Mesothelial cell and anti-nuclear autoantibodies associated with pleural abnormalities in an asbestos exposed population of Libby MT — L.S. Marchand, S. St-Hilaire, et al. (2012)
• Pulmonary inflammatory and fibrotic responses in Fischer 344 rats after intratracheal instillation exposure to Libby amphibole — D.J. Padilla-Carlin, M.C. Schladweiler, et al. (2011)

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