Project description:An estimated 1% or less of the nanoparticles (NPs) deposited in lungs translocate to systemic circulation and enter other organs; however this estimation may not be accurate considering the low sensitivity of the existing in vivo NP detection methods. Moreover, the biological outcomes of such low levels of translocation are not elucidated. The objectives of the present study were to employ a Nano-scale Hyperspectral Microscope to spatially observe and spectrally profile NPs in tissues, and characterize the effects of NPs in blood, liver and heart following pulmonary deposition and subsequent translocation from lungs. Adult female C57BL/6 mice were exposed via intratracheal instillation to 18 and 162 µg per mouse of industrially relevant non-doped titanium dioxide nanoparticles (nano-TiO2). Using the Nano-scale Hyperspectral Microscope translocation to heart and liver was confirmed at both doses and to blood at the highest dose at 24 hours post-exposure time-point. The analysis of biological effects using DNA microarrays, RT-qPCR and ELISA revealed activation of complement cascade and inflammatory process in heart and specific activation of complement factor 3 in blood, potentially suggestive of activation of early innate immune response essential for particle opsonisation and clearance. The liver showed subtle response with changes in the expression of few genes associated with acute phase genes. This study establishes a direct link between particle translocation and systemic effects. An estimated 1% or less of the nanoparticles (NPs) deposited in lungs translocate to systemic circulation and enter other organs; however this estimation may not be accurate considering the low sensitivity of the existing in vivo NP detection methods. Moreover, the biological outcomes of such low levels of translocation are not elucidated. The objectives of the present study were to employ a Nano-scale Hyperspectral Microscope to spatially observe and spectrally profile NPs in tissues, and characterize the effects of NPs in blood, liver and heart following pulmonary deposition and subsequent translocation from lungs. Adult female C57BL/6 mice were exposed via intratracheal instillation to 18 and 162 µg per mouse of industrially relevant non-doped titanium dioxide nanoparticles (nano-TiO2). Using the Nano-scale Hyperspectral Microscope translocation to heart and liver was confirmed at both doses and to blood at the highest dose at 24 hours post-exposure time-point. The analysis of biological effects using DNA microarrays, RT-qPCR and ELISA revealed activation of complement cascade and inflammatory process in heart and specific activation of complement factor 3 in blood, potentially suggestive of activation of early innate immune response essential for particle opsonisation and clearance. The liver showed subtle response with changes in the expression of few genes associated with acute phase genes. This study establishes a direct link between particle translocation and systemic effects. This experiment consists of one dose of nano-TiO2 (162 ug) and one control. There are 2 time points for each treatment and control group, e.g., day 1 and day 28. Each dose or time point has 5-6 biological replicates. There are total 22 samples (arrays)

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.

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Pulmonary retention of titanium dioxide nanoparticles and biological outcomes following low dose instillation in mice

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