Safety assessment of nanomaterials: proteomics predicts biomarkers of exposure to silica nanoparticles

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  • Published: Dec 1, 2010
  • Author: Steve Down
  • Channels: Proteomics
thumbnail image: Safety assessment of nanomaterials: proteomics predicts biomarkers of exposure to silica nanoparticles

Nanomaterials: shrinking in size but growing in influence

As nanomaterials become smaller, their uses increase and they are now part of everyday life, more so than many people will realise. Apart from being deployed in industrial, biomedical, and electronic applications, it is perhaps more surprising to find that they are added to such everyday commodities as cosmetics, personal care products and food.

The principal use of nanoparticles in cosmetics is as UV filters, preservatives and colorants. One of the common applications in foods in the USA is as an additive to salt, where up to 2 wt.% of amorphous silica is added to common salt.

While the number of applications is on the increase, the safety aspects of nanomaterials have largely been ignored. There is a growing body of evidence that nanomaterials could be toxic to humans, setting alarm bells ringing in the EU, the WHO and the OECD. The European Food Safety Authority declared recently that "there are limited data on oral exposure to nanomaterials and any consequent toxicity, as well as limited methods to characterise, detect, and measure nanomaterials in food/feed."

The toxicological profiles of nanomaterials cannot be extrapolated from those of their equivalent non-nano forms due to their widely contrasting properties. The EFSA has stated that a case by case approach is needed.


The toxicity of nanomaterials: a proteomics approach

In Japan, a research team had reported that silica nanoparticles of size 70 nm caused severe liver damage in mice whereas larger particles of 300 and 1000 nm had no effect. Repeated administration of the 70-nm particles went on to induce hepatic fibrosis. The same team also found that silica nanoparticles can penetrate mouse skin.

These findings back up other toxicological reports on nanoparticles, so the Japanese researchers decided to extend their own studies to see if nanomaterials induce changes in the proteome of infected species that could be used as indicators or predictors of exposure and toxicity.

Yasuo Yoshioka, Yasuo Tsutsumi and colleagues from Osaka University and the National Institute of Biomedical Innovation, Osaka, chose to test silica nanoparticles because they are one of the most common types of nanomaterials in use. In the first instance, they treated mice intravenously with 70-nm nanoparticles, or with saline as a control, and took blood samples at varying intervals for testing.

The plasma was depleted of the abundant albumin and immunoglobulins in case they masked some of the less abundant proteins before being subjected to SDS-PAGE and protein staining. One protein band of molecular mass 37 kDa was more abundant in the control plasma and it was identified by trypsin digestion and LC-tandem mass spectrometry as haptoglobin.

Levels of haptoglobin were only slightly increased following treatment with 300-nm nano-silica and unchanged by 100-nm nanosilica. This size effect suggests that haptoglobin is a biomarker for exposure to nanosized silica particles.

The effect was also dose-dependent, the haptoglobin concentration increasing markedly for doses of 0.8 mg/mouse but remaining unchanged from the saline-induced levels for 0.05 and 0.2 mg/mouse.

Following a single dose of 70- or 300-nm particles, but not 1000-nm particles, the haptoglobin levels maximised 24 hours later and remained elevated after 3 days, before falling to normal levels at 7 days.

Two other proteins, C-reactive protein and serum amyloid A, behaved in a similar fashion to haptoglobin, becoming elevated by 70- and 300-nm silica particles but not by 1000-nm particles, and maximising after 6 and 24 hours, respectively.


Acute-phase proteins: potential biomarkers of exposure to nanoparticles

All three of these affected proteins are typical acute-phase proteins that are induced in the body following infection and inflammation, so their responses to nanoparticles are not surprising. For instance, haptoglobin is a biomarker of pancreatic cancer and C-reactive protein and serum amyloid A are used in the prognosis of breast cancer.

This led the researchers to declare that "these diagnostic systems using acute phase proteins for human health would be useful for predicting the risk of exposure to nanomaterials as well as their likely toxicities." The varying times taken to reach their maximum levels also suggest that "the predictive quality of these biomarkers would be improved when they are used in combination."

Due to the widespread application of nanomaterials, it is impossible to avoid exposure to them either through medicines, personal care products and foodstuffs, via their release into the environment. Routes of exposure will also vary. Further testing by the team on intranasal exposure to 30- and 70-nm silica particles revealed that the former raised the levels of the three protein markers, but the larger nanoparticles did not. So, different routes of exposure appear to have different effects.

Tests with surface-modified 70-nm silica nanoparticles showed no change in the levels of the three acute-phase proteins, indicating that the toxic effects are being suppressed by the surface changes.

So, the acute-phase proteins could be useful biomarkers, especially in combination, for deciphering the toxic effects of silica nanoparticles. There are many different types of nanoparticles in circulation, such as titanium dioxide, fullerenes, nanotubes and metals, so the team have now begun to extend their work to see if acute-phase proteins are affected by these too.

The research team also believe that their work will form the basis of future predictive tests for estimating the toxicity of new nanomaterials based on their physicochemical properties with the overall aim of developing safer materials.



The views represented in this article are solely those of the author and do not necessarily represent those of John Wiley and Sons, Ltd.

 
 
 
Silica nanoparticles of different sizes induce increased levels of acute-phase proteins in the plasma of mice in a size-dependent manner following iv treatment. These proteins will be valuable indicators of exposure and could help to develop safer nanomaterials

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