Toxicity evaluation following pulmonary exposure to an as-manufactured dispersed boron nitride nanotube (BNNT) material in vivo
NANOIMPACT
Authors: Xin, Xing; Barger, Mark; Roach, Katherine A.; Bowers, Lauren; Stefaniak, Aleksandr B.; Kodali, Vamsi; Glassford, Eric; Dunn, Kevin L.; Dunn, Kevin H.; Wolfarth, Michael; Friend, Sherri; Leonard, Stephen S.; Kashon, Michael; Porter, Dale W.; Erdely, Aaron; Roberts, Jenny R.
Abstract
Boron nitride nanotubes (BNNT) are multi-walled nanotubes composed of hexagonal B-N bonds and possess many unique physical and chemical properties, creating a rapidly expanding market for this newly emerging nanomaterial which is still primarily in the research and development stage. The shape and high aspect ratio give rise to concern for the potential toxicity that may be associated with pulmonary exposure, especially in an occupational setting. The goal of this study was to assess lung toxicity using an in vivo time course model. The sample was manufactured to be 5 nm wide and up to 200 m long, with similar to 50% purity covalently bound with hexagonal boron nitride (hBN) in the sample. Following preparation for in vivo studies, sonication of the material disrupted the longer tubes in the complex and the size distribution in dispersion medium (DM) of the structures was 13-23 nm in diameter and 0.6-1.6 mu m in length. Male C57BL/6 J mice were exposed to 4 or 40 mu g of BNNT or DM (vehicle control) by a single oropharyngeal aspiration. Pulmonary and systemic toxicity were investigated at 4 h, 1 d, 7 d, 1 mo and 2 mo post-exposure. Bronchoalveolar lavage (BAL) studies determined pulmonary inflammation (neutrophil influx) and cytotoxicity (lactate dehydrogenase activity) occurred at early time points and peaked at 7 d post-exposure in the high dose group. Histopathological analysis showed a minimal level of inflammatory cell infiltration in the high dose group with resolution over time and no fibrosis, and lung clearance analysis showed similar to 50% of the material cleared over the time course. The expression of inflammatoryand acute phase response-associated genes in the lung and liver were significantly increased by the high dose at 4 h and 1 d post-exposure. The increases in lung gene expression of Cxcl2, Ccl2, Il6, Cc122, Ccl11, and Spp1 were significant up to 2 mo but decreased with time. The low dose exposure did not result in significant changes in any toxicological parameters measured. In summary, the BNNT-hBN sample used in this study caused acute pulmonary inflammation and injury at the higher dose, which peaked by 7 d post-exposure and showed resolution over time. Further studies are needed to determine if physicochemical properties and purity will impact the toxicity profile of BNNT and to investigate the underlying mechanisms of BNNT toxicity.
Associations of IL6 rs1800795, BLK rs13277113, TIMP3 rs9621532, IL1RL1 rs1041973 and IL1RAP rs4624606 single gene polymorphisms with laryngeal squamous cell carcinoma
GENE
Authors: Pasvenskaite, Agne; Vilkeviciute, Alvita; Liutkeviciene, Rasa; Gedvilaite, Greta; Liutkevicius, Vykintas; Uloza, Virgilijus
Abstract
Objective: Survival rate of laryngeal squamous cell carcinoma (LSCC) patients is not improving. To understand more complete biology of LSCC, studies focused on identification of new specific and prognostic markers are performed. The aim of current study was to evaluate the impact of five different single nucleotide polymorphisms (SNP) (IL6 rs1800795, BLK rs13277113, TIMP3 rs9621532, IL1RL1 rs1041973 and IL1RAP rs4624606) on LSCC development. Material and methods: A total of 891 subjects (353 histologically verified LSCC patients and 538 healthy controls) were involved in this study. The genotyping was carried out using the real-time-PCR. Results: Statistical analysis revealed statistically significant associations between TIMP3 rs96215332 variants and LSCC in the codominant (OR = 0.600; 95% CI: 0.390-0.922; p = 0.020), overdominant (OR = 0.599; 95% CI: 0.390-0.922; p = 0.020) and additive (OR = 0.675; 95% CI: 0.459-0.991; p = 0.045) models. Also, significant variants of IL1RAP rs4624606 were determined in the codominant (OR = 1.372; 95% CI: 1.031-1.827; p = 0.030), overdominant (OR = 1.353; 95% CI: 1.018-1.798; p = 0.037) and additive (OR = 1.337; 95% CI: 1.038-1.724; p = 0.025) models. Conclusion: Results of the current study indicate significant associations between TIMP3 rs9621532 and IL1RAP rs4624606 gene polymorphisms and LSCC development.