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Differential mouse pulmonary dose and time course responses to titanium dioxide nanospheres and nanobelts.

ABSTRACT: Three anatase titanium dioxide (TiO(2)) nanoparticles (NPs) were prepared; nanospheres (NSs), short nanobelts (NB1), and long nanobelts (NB2). These NPs were used to investigate the effect of NP shape and length on lung toxicity. Mice were exposed (0-30 µg per mouse) by pharyngeal aspiration and pulmonary toxicity was assessed over a 112-day time course. Whole lung lavage data indicated that NB1- and NB2-exposed mice, but not NS-exposed mice, had significant dose- and time-dependent pulmonary inflammation and damage. Histopathological analyses at 112 days postexposure determined no interstitial fibrosis in any NS-exposed mice, an increased incidence in 30 µg NB1-exposed mice, and significant interstitial fibrosis in 30 µg NB2-exposed mice. At 112 days postexposure, lung burden of NS was decreased by 96.4% and NB2 by 80.5% from initial deposition levels. At 112 days postexposure, enhanced dark field microscopy determined that alveolar macro- phages were the dominant deposition site, but a fraction of NB1 and NB2 was observed in the alveolar interstitial spaces. For the 30 µg exposure groups at 112 days postexposure, confocal micro- scopy and immunofluorescent staining demonstrated that retained NB2 but not NS were present in the interstitium subjacent to the terminal bronchiole near the normal location of the smallest lymphatic capillaries in the lung. These lymphatic capillaries play a critical role in particle clearance, and the accumulation of NB2, but not NS, suggests possible impaired lymphatic clearance by the high aspect ratio particles. In summary, our data indicate that TiO(2) NP shape alters pulmonary responses, with severity of responses being ranked as NS < NB1 < NB2.

SUBMITTER: Porter DW

PROVIDER: S-EPMC3537123 | biostudies-literature | 2013 Jan

REPOSITORIES: biostudies-literature

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Differential mouse pulmonary dose and time course responses to titanium dioxide nanospheres and nanobelts.

Porter Dale W DW Wu Nianqiang N Hubbs Ann F AF Mercer Robert R RR Funk Kathleen K Meng Fanke F Li Jiangtian J Wolfarth Michael G MG Battelli Lori L Friend Sherri S Andrew Michael M Hamilton Raymond R Sriram Krishnan K Yang Feng F Castranova Vincent V Holian Andrij A

Toxicological sciences : an official journal of the Society of Toxicology 20120905 1

Three anatase titanium dioxide (TiO(2)) nanoparticles (NPs) were prepared; nanospheres (NSs), short nanobelts (NB1), and long nanobelts (NB2). These NPs were used to investigate the effect of NP shape and length on lung toxicity. Mice were exposed (0-30 µg per mouse) by pharyngeal aspiration and pulmonary toxicity was assessed over a 112-day time course. Whole lung lavage data indicated that NB1- and NB2-exposed mice, but not NS-exposed mice, had significant dose- and time-dependent pulmonary in ...[more]

PMID: 22956629

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Project description:Pulmonary exposure to high doses of nanoparticles (NP) leads to well characterized lung toxicity in addition to long-term NP retention. However, pulmonary NP accumulation and toxicity following low dose exposures are not well described. In the present study we sought to: (1) investigate particle retention in mouse lungs following intratracheal instillation of varying doses of nano-sized titanium dioxide (nano-TiO2) and (2) determine the effects of long-term particle accumulation on pulmonary systems. Female C57BL/6 mice were exposed to rutile nano-TiO2 (primary size of 20.6 nm and surface area of 107.7 m2/g) via single intratracheal instillations of 18, 54 and 162 µg/mouse and sampled 1, 3 and 28 days post-exposure. The deposition of nano-TiO2 in the lungs was assessed using Nanoscale Hyperspectral Microscope. DNA microarrays, pathway-specific real-time RT-PCR (qPCR) and gene-specific qPCR arrays, and tissue protein analyses were employed to characterize pulmonary responses. Hyperspectral mapping showed dose-dependent retention of nano-TiO2 in the lungs up to 28 days post-exposure time. Retention did not correlate with the extent of inflammatory neutrophil influx into the lungs. DNA microarray analysis showed altered expression of approximately 3000 genes across all treatment groups (±1.3 fold; p<0.1). Several inflammatory mediators changed in a dose- and time-dependent manner at both the mRNA and protein levels. Although the low dose exposure failed to induce observable inflammation, significant changes in the expression of genes and proteins associated with inflammation were observed. Moreover, diminished (or absent) neutrophil influx in the low and medium dose groups was correlated with negative regulation of genes associated with ion homeostasis and muscle regulation. Gene expression changes for several inflammatory mediators have previously been noted in mice exposed to the same nano-TiO2 via inhalation. Our results suggest that retention of nano-TiO2 in the absence of inflammation and effective clearance can perturb calcium and ion homeostasis, and affect smooth muscle activities over time.

Project description:Pulmonary exposure to high doses of nanoparticles (NP) leads to well characterized lung toxicity in addition to long-term NP retention. However, pulmonary NP accumulation and toxicity following low dose exposures are not well described. In the present study we sought to: (1) investigate particle retention in mouse lungs following intratracheal instillation of varying doses of nano-sized titanium dioxide (nano-TiO2) and (2) determine the effects of long-term particle accumulation on pulmonary systems. Female C57BL/6 mice were exposed to rutile nano-TiO2 (primary size of 20.6 nm and surface area of 107.7 m2/g) via single intratracheal instillations of 18, 54 and 162 M-BM-5g/mouse and sampled 1, 3 and 28 days post-exposure. The deposition of nano-TiO2 in the lungs was assessed using Nanoscale Hyperspectral Microscope. DNA microarrays, pathway-specific real-time RT-PCR (qPCR) and gene-specific qPCR arrays, and tissue protein analyses were employed to characterize pulmonary responses. Hyperspectral mapping showed dose-dependent retention of nano-TiO2 in the lungs up to 28 days post-exposure time. Retention did not correlate with the extent of inflammatory neutrophil influx into the lungs. DNA microarray analysis showed altered expression of approximately 3000 genes across all treatment groups (M-BM-11.3 fold; p<0.1). Several inflammatory mediators changed in a dose- and time-dependent manner at both the mRNA and protein levels. Although the low dose exposure failed to induce observable inflammation, significant changes in the expression of genes and proteins associated with inflammation were observed. Moreover, diminished (or absent) neutrophil influx in the low and medium dose groups was correlated with negative regulation of genes associated with ion homeostasis and muscle regulation. Gene expression changes for several inflammatory mediators have previously been noted in mice exposed to the same nano-TiO2 via inhalation. Our results suggest that retention of nano-TiO2 in the absence of inflammation and effective clearance can perturb calcium and ion homeostasis, and affect smooth muscle activities over time. This experiment consists of three different dosages of TiO2, e.g., low (18 ug), medium (54 ug) and high (162 ug), and one control. There are 3 time points for each treatment and control group, e.g., day 1, day 3 and day 28. Each dose or time point has 5-6 biological replicates. There are total 65 samples (arrays)

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Differential mouse pulmonary dose and time course responses to titanium dioxide nanospheres and nanobelts.

Publications

Differential mouse pulmonary dose and time course responses to titanium dioxide nanospheres and nanobelts.

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