Oxidatively damaged DNA in animals exposed to particles

Our plain-English summary of Oxidatively damaged DNA in animals exposed to particles, by P. Møller, P.H. Danielsen, K. Jantzen, et al (Critical Reviews in Toxicology, 2013).

The study

• Authors: P. Møller, P.H. Danielsen, K. Jantzen, M. Roursgaard, S. Loft
• Journal: Critical Reviews in Toxicology
• Published: 2013;43(2):96-118
• Type of article: Review
• Cited by: 61 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Exposure to combustion-derived particles, quartz and asbestos is associated with increased levels of oxidized and mutagenic DNA lesions. The aim of this survey was to critically assess the measurements of oxidatively damaged DNA as marker of particle-induced genotoxicity in animal tissues. Publications based on non-optimal assays of 8-oxo-7,8-dihydroguanine by antibodies and/or unrealistically high levels of 8-oxo-7,8-dihydroguanine (suggesting experimental problems due to spurious oxidation of DNA) reported more induction of DNA damage after exposure to particles than did the publications based on optimal methods. The majority of studies have used single intracavitary administration or inhalation with dose rates exceeding the pulmonary overload threshold, resulting in cytotoxicity and inflammation. It is unclear whether this is relevant for the much lower human exposure levels. Still, there was linear dose-response relationship for 8-oxo-7,8-dihydroguanine in lung tissue without obvious signs of a threshold. The dose-response function was also dependent on chemical composition and other characteristics of the administered particles, whereas dependence on species and strain could not be equivocally determined. Roles of cytotoxicity or inflammation for oxidatively induced DNA damage could not be documented or refuted. Studies on exposure to particles in the gastrointestinal tract showed consistently increased levels of 8-oxo-7,8-dihydroguanine in the liver. Collectively, there is evidence from animal experimental models that both pulmonary and gastrointestinal tract exposure to particles are associated with elevated levels of oxidatively damaged DNA in the lung and internal organs. However, there is a paucity of studies on pulmonary exposure to low doses of particles that are relevant for hazard/risk assessment.

In plain English

This was a review with meta-analysis of animal experiments. It asked whether particles, including asbestos, quartz, diesel exhaust particles and nanomaterials, raised levels of DNA damage caused by oxidation, measured mainly as a lesion called 8-oxodG. The authors identified 64 publications and grouped the laboratory methods as "optimal" or "non-optimal". In lung studies, non-optimal methods tended more often to report statistically significant effects. The effect size in lung tissue was 0.87 (95% confidence interval 0.31 to 1.43) for optimal assays and 1.14 (0.61 to 1.67) for non-optimal assays. In optimal-assay studies, dose fitted a straight-line relationship with 8-oxodG without obvious signs of a threshold. Asbestos fibers seemed to cause more damage, but this rested on one publication. For oral exposure, the pooled estimate showed higher liver 8-oxodG in exposed animals. However, repeated dietary diesel particle studies were not statistically significant, and in one study ambient-air and wood-combustion particles had no effect. The authors concluded that animal models gave compelling evidence linking lung and gut exposure to particles with elevated oxidatively damaged DNA. They noted that most lung studies used doses causing pulmonary overload and that realistic low-dose studies are scarce.

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 with meta-analysis of published animal experiments, testing seven hypotheses
• Who was studied: 64 publications reporting oxidatively damaged DNA in tissues of animals exposed to particles
• Exposure: Particles given by airway, gastrointestinal or other routes, including asbestos fibers, quartz, diesel exhaust particles, carbon black, titanium dioxide and nanomaterials. Three studies of intraperitoneal asbestos injection, used as a stand-in for pleural exposure, were grouped with pulmonary exposure.
• Main results:
  • In lung tissue studies, those using non-optimal assays tended more often to report statistically significant effects than those using optimal assays
  • Standardized mean difference for oxidatively damaged DNA in lung tissue: 0.87 (95% CI 0.31 to 1.43) for optimal-assay studies and 1.14 (95% CI 0.61 to 1.67) for non-optimal-assay studies
  • In optimal-assay lung studies, a range of particles fitted a linear relationship between mass dose and 8-oxodG induction without obvious signs of a threshold
  • Asbestos fibers seemed to generate a higher induction of 8-oxodG, based on one publication (Takata et al., 2009)
  • In one reviewed study, chrysotile asbestos markedly increased 8-oxodG in rat lungs, while the same dose of forsterite (1 mg/rat by intratracheal instillation) had no effect
  • In one reviewed study, crocidolite asbestos (0.5 to 2 mg by intratracheal instillation) increased 8-oxodG in Wistar rats and Syrian hamsters, whereas glass fibers had no effect
  • Among optimal-assay lung studies, the highest effect sizes were obtained with asbestos fibers and quartz
  • Of 31 studies using intratracheal instillation (or intraperitoneal injection), 26 showed statistically significant effects on oxidatively damaged DNA
  • Among inhalation studies, six reported a statistically significant outcome and five a null effect
  • Liver, oral exposure: the overall pooled effect size was statistically significant, indicating higher 8-oxodG in exposed animals than in unexposed controls
  • Liver, oral exposure: standardized mean difference 0.96 (95% CI 0.55 to 1.36) for single-exposure studies and 0.79 (95% CI 0.19 to 1.78) for repeated-exposure studies
  • Studies of repeated exposure to diesel exhaust particles showed statistically non-significant effects in the liver of mice and rats
  • In one study of intragastric exposure in rats, particles from ambient air in a village with many wood stoves, or from wood combustion, had no effect on liver 8-oxodG
• The authors' conclusion: The authors concluded that there is compelling evidence from animal models that both pulmonary and gastrointestinal exposure to particles are associated with elevated oxidatively damaged DNA in the lungs and internal organs
• Limitations the authors state:
  • Most pulmonary studies used doses associated with pulmonary overload in rats
  • There are few studies combining realistic low-dose exposures with enough animals
  • Intraperitoneal injection is not a physiological route, and high doses may have limited relevance to risk assessment
  • Comparing particles across studies by mass dose is an assumption that may introduce a limitation
  • The dose-response correlation values were calculated from group means and ignore variation within studies
  • Heterogeneity between studies may reflect publication bias
  • Differences between species and strains could not be determined
  • Older publications gave little information on particle characteristics

Topics

Medical terms in this study, explained in our Lexicon: DNA lesions, Genotoxicity, Inflammation, Dose-response relationship.

Related studies

• Carboxylated short single-walled carbon nanotubes but not plain and multi-walled short carbon nanotubes show in vitro genotoxicity — M. Mrakovcic, C. Meindl, et al. (2015)
• Oxidative and cytotoxic stress induced by inorganic granular and fibrous particles — S. Helmig, D. Walter, et al. (2018)
• A study of the effect of chrysotile fiber surface composition on genotoxicity in vitro — M.J. Keane, J.W. Stephens, et al. (1999)
• Cytotoxicity, oxidative stress and genotoxicity induced by glass fibers on human alveolar epithelial cell line A549 — V. Rapisarda, C. Loreto, et al. (2015)
• Does qualitative examination of Elongated Mineral Particles (EMP) recovered from human and animal lungs provide reliable information on their carcinogenic and other effects? — B.W. Case (2018)
• Tobacco smoke: involvement of reactive oxygen species and stable free radicals in mechanisms of oxidative damage, carcinogenesis and synergistic effects with other respirable particles — A. Valavanidis, T. Vlachogianni, et al. (2009)

Browse more research in Critical Reviews in Toxicology, or return to medical research.