Meta-Analysis of Integrated Proteomic and Transcriptomic Data Discerns Structure-Activity Relationship of Carbon Materials with Different Morphologies

Our plain-English summary of Meta-Analysis of Integrated Proteomic and Transcriptomic Data Discerns Structure-Activity Relationship of Carbon Materials with Different Morphologies, by V.I. Dumit, Y.C. Liu, A. Bahl, et al (Advanced Science, 2024).

The study

• Authors: V.I. Dumit, Y.C. Liu, A. Bahl, P. Kohonen, R.C. Grafström, P. Nymark, C. Müller-Graf, A. Haase, M. Pink
• Journal: Advanced Science
• Published: 2024;11(9):e2306268
• Type of article: Meta-analysis
• Cited by: 11 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

The Fiber Pathogenicity Paradigm (FPP) establishes connections between fiber structure, durability, and disease-causing potential observed in materials like asbestos and synthetic fibers. While emerging nanofibers are anticipated to exhibit pathogenic traits according to the FPP, their nanoscale diameter limits rigidity, leading to tangling and loss of fiber characteristics. The absence of validated rigidity measurement methods complicates nanofiber toxicity assessment. By comprehensively analyzing 89 transcriptomics and 37 proteomics studies, this study aims to enhance carbon material toxicity understanding and proposes an alternative strategy to assess morphology-driven toxicity. Carbon materials are categorized as non-fibrous, high aspect ratio with shorter lengths, tangled, and rigid fibers. Mitsui-7 serves as a benchmark for pathogenic fibers. The meta-analysis reveals distinct cellular changes for each category, effectively distinguishing rigid fibers from other carbon materials. Subsequently, a robust random forest model is developed to predict morphology, unveiling the pathogenicity of previously deemed non-pathogenic NM-400 due to its secondary structures. This study fills a crucial gap in nanosafety by linking toxicological effects to material morphology, in particular regarding fibers. It demonstrates the significant impact of morphology on toxicological behavior and the necessity of integrating morphological considerations into regulatory frameworks.

© 2023 The Authors. Advanced Science published by Wiley-VCH GmbH.

In plain English

This study did not test asbestos, which appears only as background. The authors re-analyzed 126 datasets (89 transcriptomic, 37 proteomic) from public repositories plus their own experiments, covering lung-focused studies in human, mouse and rat cells, tissue and lavage fluid. They sorted the materials into four groups. The groups were non-fibrous materials (Carbon Black, fullerenes, graphene) and high aspect ratio materials shorter than the nanotube Mitsui-7, which were examined separately. The other two were fibers at least as long as Mitsui-7, split by diameter (used as a stand-in for rigidity) into rigid (30 nm or more) and tangled (below 30 nm). A lung inflammation pathway was altered in 60% of rigid-fiber datasets and in none of the tangled or non-fibrous ones. A random forest computer model had a specificity higher than 85% for separating rigid fibers from each of the other two groups, but could not separate tangled fibers from non-fibrous materials. One thin, short nanotube, NM-400, produced changes resembling those of rigid fibers, and the model predicted it to be rigid. The authors suggested fiber bundles might explain this. They concluded that a diameter below the rigidity threshold is not enough to assume low toxicity, while noting that their analysis does not directly assess toxicity.

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: Meta-analysis: harmonized re-analysis of transcriptomic and proteomic datasets from public repositories, supplemented by the authors' own experimental results, followed by a random forest machine-learning model to predict material shape
• Who was studied: 126 datasets (89 transcriptomic from Gene Expression Omnibus, 37 proteomic from PRIDE Archive), supplemented by the authors' own experimental results. The studies were in mice, rats or humans with lungs as the research focus. They included in vitro cell studies and in vivo animal studies (lung tissue and, in rats, bronchoalveolar lavage fluid).
• Exposure: Carbon nanomaterials: non-fibrous materials (Carbon Black, fullerenes, graphene), multi-walled and single-walled carbon nanotubes, and other high aspect ratio carbon materials (including Mitsui-7, NM-400, NM-401, Baytubes). Materials at least as long as Mitsui-7 (average 3.8 μm) were classed as fibers. In the decision tree, fibers with a diameter of 30 nm or more were classed as rigid and those under 30 nm as tangled. Diameter was used as a proxy for rigidity. No asbestos was studied.
• Main results:
  • The rigid-fiber, tangled-fiber and non-fibrous groups contained 47, 20 and 9 datasets respectively
  • The in-house 'lung inflammation' pathway was altered in 60% of the rigid carbon fiber datasets
  • Tangled carbon fibers and non-fibrous carbon materials showed no alteration of the lung inflammation pathway
  • In cross-validation, the random forest model had a specificity higher than 85% for distinguishing rigid fibers from tangled fibers and from non-fibrous carbon materials
  • The model could not distinguish tangled fibers from non-fibrous carbon materials
  • NM-400 (NRCWE26), with an average length below 900 nm and a diameter of 11 nm, caused strong cellular changes comparable to rigid carbon fibers
  • The random forest model predicted NM-400 to be a rigid fiber despite its diameter and length
  • The model predicted Baytubes, of similar morphology to NM-400, to be a tangled fiber
• The authors' conclusion: The authors concluded that different carbon material shapes cause different cellular alterations. They also concluded that a fiber diameter below the expected rigidity threshold is not sufficient to assume low toxicity, as seen for NM-400. They suggested this might be explained by secondary structures (aligned bundles).
• Limitations the authors state:
  • The analysis does not directly assess toxicity
  • High aspect ratio materials shorter than Mitsui-7 were left out of the rigidity analysis for lack of size distribution information
  • The authors describe their structural findings as preliminary evidence

Topics

Medical terms in this study, explained in our Lexicon: Meta-Analysis, Aspect Ratio (Length-to-diameter ratio).

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