Dose-Response Relationships in Expression of Biomarkers of Cell Proliferation in in vitro Assays and Inhalation Experiments

Our plain-English summary of Dose-Response Relationships in Expression of Biomarkers of Cell Proliferation in in vitro Assays and Inhalation Experiments, by A. Shukla, P. Vacek, B.T. Mossman (Nonlinearity in Biology, Toxicology, Medicine, 2004).

The study

• Authors: A. Shukla, P. Vacek, B.T. Mossman
• Journal: Nonlinearity in Biology, Toxicology, Medicine
• Published: 2004;2(2):117-28
• Cited by: 12 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Asbestos is a group of naturally occurring mineral fibers which are associated in occupational settings with increased risks of malignant mesothelioma (MM), lung cancers, and pulmonary fibrosis (asbestosis). The six recognized types of asbestos fibers (chrysotile, crocidolite, amosite, tremolite, anthophyllite, and actinolite) are different chemically and physically and may have different dose-response relationships in the development of various asbestos-associated diseases. For example, epidemiologic and lung fiber content studies suggest that the pathogenic potential and durability of crocidolite is much greater than chrysotile asbestos in the causation of human MM. We have used isolated mesothelial cells, the target cells of MM, as well as epithelial cells of the lung, the target cells of lung cancers, in vitro to elucidate the dose-response relationships in expression of early response protooncogenes and other genes critical to cell proliferation and malignant transformation in cells exposed to crocidolite and chrysotile asbestos, as well as a number of nonpathogenic fibers and particles. These studies reveal distinct dose-response patterns with different types of asbestos, suggesting a threshold for effects of chrysotile both in in vitro studies and inhalation experiments. The different patterns of gene expression have been confirmed in lungs of rats exposed by inhalation to these types of asbestos. Experiments also suggest no observed adverse effect levels after evaluation of lung injury, inflammation, and fibrosis at lower concentrations of both types of asbestos.

In plain English

This article was a short overview by the authors of their laboratory's research on how crocidolite and chrysotile asbestos affect cell growth (proliferation), which the authors linked to cancer development. Its introduction reviewed other researchers' studies. In cell experiments, a low concentration of crocidolite (0.1 µg per square centimetre of dish) increased growth of normal rat pleural mesothelial cells, while higher concentrations reduced growth. An SV40-transformed human mesothelial cell line did not show this increase. In a mouse lung epithelial cell line, individual fos/jun genes responded to crocidolite in different, nonlinear patterns. The authors also summarized earlier rat inhalation experiments using a high and a low concentration of each fiber. Increased cell proliferation was seen only at the high concentrations. Fibrotic lesions and hydroxyproline, a collagen marker, rose after 20 days of crocidolite inhalation. They were seen in both asbestos groups after a further 20 days in clean air. The genes c-jun and odc rose in rat lungs only at high crocidolite. The authors concluded that, fiber for fiber, chrysotile was less apt than crocidolite to cause cell proliferation and increased fos/jun expression.

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: Overview of the authors' own laboratory work: in vitro cell experiments plus a summary of earlier rat inhalation experiments, with a background review of other studies
• Who was studied: Fischer 344 rats exposed by inhalation (rat data compiled from Quinlan et al., 1994, 1995 and BeruBe et al., 1996; number of rats not given). Cell types studied: normal rat pleural mesothelial (RPM) cells, SV40-transformed human mesothelial cells (MET5A line), and a murine C10 alveolar type II lung epithelial cell line
• Exposure: Crocidolite and chrysotile asbestos. In rats, time-weighted average concentrations in mg/m3 air, with fibers longer than 5 microns per cc air (by PCM) in brackets: crocidolite high 8.25 [2800] and low 0.16 [60]; chrysotile high 8.23 [2457] and low 0.18 [32]. Animals were evaluated at 5 and 20 days of exposure and 20 days after a 20-day exposure ended. In cells, a range of crocidolite concentrations was used.
• Main results:
  • In normal rat pleural mesothelial cells, crocidolite increased proliferation (colony forming efficiency) at 0.1 µg/cm2 dish. Higher concentrations caused dose-related decreases (growth inhibition).
  • SV40-transformed human mesothelial cells (MET5A) were resistant to the proliferative effects of asbestos
  • In C10 lung epithelial cells exposed to crocidolite for 24 hours, dose-response patterns of individual fos/jun (AP-1) family genes were different and nonlinear
  • In rats, increased proliferation of mesothelial or epithelial cells was observed only at the highest asbestos concentrations
  • In rats, mesothelial cell proliferation in response to crocidolite was protracted compared with the early epithelial cell responses to both asbestos types
  • Fibrotic lesions and raised hydroxyproline were seen only after 20 days of crocidolite inhalation. They appeared in both asbestos groups after an additional 20 days in clean air.
  • In whole-lung tissue from rats, c-jun and odc were increased only at high concentrations of crocidolite
• The authors' conclusion: The authors concluded that short-term rodent inhalation experiments and in vitro studies indicate that, on a fiber-to-fiber basis, chrysotile is less apt than crocidolite to cause cell proliferation and increased fos/jun protooncogene expression

Topics

Medical terms in this study, explained in our Lexicon: Dose-response relationship, Biomarker, Mineral Fiber, Malignant Mesothelioma, Lung Cancer, Pulmonary Fibrosis, Chrysotile, Crocidolite.

Related studies

• Patterns of inflammation, cell proliferation, and related gene expression in lung after inhalation of chrysotile asbestos — T.R. Quinlan, K.A. BéruBé, et al. (1995)
• In vitro response of rat pleural mesothelial cells to talc samples in genotoxicity assays (sister chromatid exchanges and DNA repair) — S. Endo-Capron, A. Renier, et al. (1993)
• Towards predicting the lung fibrogenic activity of nanomaterials: experimental validation of an in vitro fibroblast proliferation assay — G. Vietti, S. Ibouraadaten, et al. (2013)
• Osteopontin mRNA expression by rat mesothelial cells exposed to multi-walled carbon nanotubes as a potential biomarker of chronic neoplastic transformation in vitro — S. Sridharan, A. Taylor-Just, et al. (2021)
• Silica binds serum proteins resulting in a shift of the dose-response for silica-induced chemokine expression in an alveolar type II cell line — E.G. Barrett, C. Johnston, et al. (1999)
• Patterns of c-fos and c-jun proto-oncogene expression, apoptosis, and proliferation in rat pleural mesothelial cells exposed to erionite or asbestos fibers — C.R. Timblin, G.D. Guthrie, et al. (1998)

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