The Genetic Heterogeneity among Different Mouse Strains Impacts the Lung Injury Potential of Multiwalled Carbon Nanotubes

Abstract

Genetic variation constitutes an important variable impacting the susceptibility to inhalable toxic substances and air pollutants, as reflected by epidemiological studies in humans and differences among animal strains. While multi-walled carbon nanotubes (MWCNTs) are capable of causing lung fibrosis in rodents, it is unclear to what extent the genetic variation in different mouse strains influence the outcome. We chose four inbred mouse strains, including C57Bl/6, Balb/c, NOD/ShiLtJ and A/J, to test the pro-fibrogenic effects of a library of MWCNTs in vitro and in vivo. Ex vivo analysis of IL-1β production in bone marrow-derived macrophages (BMDMs) as molecular initiating event (MIE) were performed. The order of cytokine production (Balb/c > A/J > C57Bl/6 > NOD/ShiLtJ) in BMDMs was also be duplicated during assessment of IL-1β production in the bronchoalveolar lavage fluid of the same mouse strains 40 hr after oropharyngeal instillation of a representative MWCNT. Animal test after 21 days also confirmed a similar hierarchy in TGF-β1 production and collagen deposition in the lung. Statistical analysis confirmed a correlation between IL-1β production in BMDM and the lung fibrosis. All considered, these data demonstrate that genetic background indeed plays a major role in determining the pro-fibrogenic response to MWCNTs in the lung.

Use of a Mechanism-based Toxicological Approach to Analyze the Pulmonary Pro-Fibrogenic Effects of Air Pollution PM2.5 Particulates

“…We have previously demonstrated for silica and carbonaceous nanomaterials that the in vitro profibrogenic responses in THP-1 and BEAS-2B cells largely reflect their ability to generate similar biomarker responses in the bronchoalveolar lavage fluid (BALF) of mice receiving oropharyngeal aspiration. [22,26,32] The C57BL/6 mice were used for exposure to S1, S3, S5 and S6 PM2.5 particles, which correspondence to low, medium and high response level of pro-inflammatory and profibrogenic effects in vitro. The mice were sacrificed at 21 days after the oropharyngeal inspiration of the PM2.5 particles.…”

Creative use of analytical techniques and high-throughput technology to facilitate safety assessment of engineered nanomaterials

“…The third example is the work with the engineered carbonaceous nanomaterials (ECNs), which includes carbon nanotubes (CNTs), graphene and graphene oxides (GO) [20, 21, 106–109]. These materials have intrinsic electrical and optical characteristics, as well as the capability to finely tune the physicochemical properties such as size, durability, and surface chemistry, facilitating them to be widely used in biomedical and electronics industry.…”

“…In order to comprehensively compare tubes with different characteristics, it is necessary to develop predictive toxicology paradigms which could characterize and categorize CNTs, graphene, GO into the specific libraries based upon their unique properties, for example, CNTs of different synthesis methods, dispersal states, surface functionalization, and lengths, etc. [106–109, 117]. The key characterization methods are listed in Table 1.…”

Toxicological Profiling of Highly Purified Single‐Walled Carbon Nanotubes with Different Lengths in the Rodent Lung and Escherichia Coli

“…While it is generally accepted that long and stiff (micrometer scale) carbon nanotubes (CNTs) are more toxic than shorter or tangled tubes (nanometer scale) tubes, the data are based on materials of heterogeneous composition, without attempts to purify tubes of the same length or develop a tube‐length series that is based on the same starting material . Moreover, although it has been shown that tubes longer than 10 µm could act like fibers, with the ability to induce frustrated phagocytosis, our own studies have shown that SWCNTs and multiwalled carbon nanotubes (MWCNTs) at length scales well below those that cause frustrated phagocytosis, can induce acute and chronic lung injury …”

“…This purification method also yields sufficient tube quantities for performance of structure‐activity analysis, which allows one to address the role of individual tube properties to biological outcome . One of our preferred study approaches to assessing SWCNT and MWCNT properties is to study their profibrogenic effects in pulmonary cell types and the lung . Many of these studies have demonstrated that the long aspect ratio of these materials, rather than fiber‐like dimensions, play a role in triggering lysosomal damage and IL‐1β release in macrophages, which synergize with the ability of these materials to induce transforming growth factor (TGF)‐β1 production in lung epithelial cells .…”