Cobalt nanoparticles induce lung injury, DNA damage and mutations in mice

Abstract

BackgroundWe and other groups have demonstrated that exposure to cobalt nanoparticles (Nano-Co) caused oxidative stress and inflammation, which have been shown to be strongly associated with genotoxic and carcinogenic effects. However, few studies have reported Nano-Co-induced genotoxic effects in vivo. Here, we propose that Nano-Co may have high genotoxic effects due to their small size and high surface area, which have high capacity for causing oxidative stress and inflammation.Methods gpt delta transgenic mice were used as our in vivo study model. They were intratracheally instilled with 50 μg per mouse of Nano-Co. At day 1, 3, 7 and 28 after exposure, bronchoalveolar lavage (BAL) was performed and the number of neutrophils, CXCL1/KC level, LDH activity and concentration of total protein in the BAL fluid (BALF) were determined. Mouse lung tissues were collected for H&E staining, and Ki-67, PCNA and γ-H2AX immunohistochemical staining. 8-OHdG level in the genomic DNA of mouse lungs was determined by an OxiSelect™ Oxidative DNA Damage ELISA Kit, and mutant frequency and mutation spectrum in the gpt gene were also determined in mouse lungs at four months after Nano-Co exposure by 6-TG selection, colony PCR, and DNA sequencing.ResultsExposure of mice to Nano-Co (50 μg per mouse) resulted in extensive acute lung inflammation and lung injury which were reflected by increased number of neutrophils, CXCL1/KC level, LDH activity and concentration of total protein in the BALF, and infiltration of large amount of neutrophils and macrophages in the alveolar space and interstitial tissues. Increased immunostaining of cell proliferation markers, Ki-67 and PCNA, and the DNA damage marker, γ-H2AX, was also observed in bronchiolar epithelial cells and hyperplastic type II pneumocytes in mouse lungs at day 7 after Nano-Co exposure. At four months after exposure, extensive interstitial fibrosis and proliferation of interstitial cells with inflammatory cells infiltrating the alveolar septa were observed. Moreover, Nano-Co caused increased level of 8-OHdG in genomic DNA of mouse lung tissues. Nano-Co also induced a much higher mutant frequency as compared to controls, and the most common mutation was G:C to T:A transversion, which may be explained by Nano-Co-induced increased formation of 8-OHdG.ConclusionOur study demonstrated that exposure to Nano-Co caused oxidative stress, lung inflammation and injury, and cell proliferation, which further resulted in DNA damage and DNA mutation. These findings have important implications for understanding the potential health effects of nanoparticle exposure.

A Clearance Period After Soluble Lead Nanoparticle Inhalation did not Ameliorate the Negative Effects on Target Tissues Due to Decreased Immune Response

“…3A, Table S1). These findings were similar to what has been described in the inhalation experiment with other metal NPs: PbO [13], titanium oxide (TiO2) [25] and cobalt (Co) [26]. The damaged lung parenchyma included destroyed alveolar septa, with alveolar emphysema initiated in some areas.…”

A clearance period after soluble lead nanoparticle inhalation did not ameliorate the negative effects on target tissues due to decreased immune response

“…2 and 3, Table S1). These ndings were similar to what has been described in the inhalation experiment with other metal NPs: PbO [19], titanium oxide (TiO 2 ) [32] and cobalt (Co) [33]. The damaged lung parenchyma included destroyed alveolar septa, with alveolar emphysema initiated in some areas.…”

<p>Local Cellular Responses to Metallic and Ceramic Nanoparticles from Orthopedic Joint Arthroplasty Implants</p>

“…Similar to histological results from Co nanoparticle-induced lung injury, 98 , 99 assessments of retrieved tissues from patients with failed CoCr alloy hip prostheses demonstrated necrosis, as well as macrophagic and lymphocytic infiltrates. 95 – 97 This suggests cytotoxicity of wear products and macrophagic recruitment in periprosthetic tissue.…”