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School indoor air contaminated with polychlorinated biphenyls (PCBs) released from older building materials and paint pigments may pose health risks to children, as well as teachers and staff, by inhalation of PCBs. The health effects of long-term inhalation exposure to PCBs are poorly understood. We conducted a comprehensive toxicity assessment of 91-day repeated inhalation exposure to a lab-generated mixture of PCBs designed to emulate indoor school air, combining transcriptomics, metabolomics, and neurobehavioral outcomes. Female Sprague-Dawley rats were exposed to school air mixture (SAM+) at a concentration of 45.5±5.9 μg/m(3) Σ(209)PCB or filtered air 4 h/day, 6 days/week for 13 weeks using nose-only exposure systems. The congener-specific PCB body burden was quantified in major tissues using GC-MS/MS. Generated SAM+ vapor recapitulated the target school air profile with a similarity coefficient, cosθ of 0.91. PCB inhalation yielded 875–9930 ng/g Σ(209)PCB(lipid weight) levels in tissues with ascending order: brain

Additional file 7. Table S5. Performance data on NIST, LAMP, and QMEQAS analyses.

Additional file 2. Table S1. Total Cu in the lung (μg/mouse lung), total soluble Cu in the lung (μg/mouse lung), and % soluble Cu/ total Cu in the lung.

Additional file 5. Figure S2. Dissolution of CuO NPs in simulated biological fluids: Simulated gastric fluid (SGF, pH 1.5), artificial lysosomal fluid (ALF, pH 4.5), and simulated epithelial lung fluid (SELF, pH 7.4), n = 2. Percent dissolved Cu was calculated from dissolved Cu over total amount of CuO NPs.

Additional file 3. Table S2. Mean dried organ weights and body weights.

Additional file 1. Figure S1. Percentage of Inflammatory cell numbers in BAL fluid of mice exposed to CuO NPs in aerosols: (a) Neutrophils, (b) Macrophages, (c) Lymphocytes, and (d) Eosinophils at different time points throughout or after exposure (Red-highlighted area indicates time during CuO exposure). Statistical analysis for % Neutrophil, % Lymphocyte, and % Macrophage were performed using one-way ANOVA with Dunnett’s post hoc test, while % Eosinophils was performed by Kruskal-Wallis test. Data are expressed as mean ± SD (n = 5). **** P < 0.0001, **P < 0.01,*P < 0.05.

Additional file 6. Table S4. Reagents, sample composition, and calibrator concentrations for dosimetry analysis using ICP-MS.

Additional file 8. Table S6. Composition of simulated fluid including ALF (pH = 4.5), SELF (pH = 7.4), and SGF (pH = 1.5) for 500 mL solution preparation for each fluid.

Background It has been shown that copper oxide nanoparticles (CuO NPs) induce pulmonary toxicity after acute or sub-acute inhalation exposures. However, little is known about the biodistribution and elimination kinetics of inhaled CuO NPs from the respiratory tract. The purposes of this study were to observe the kinetics of pulmonary inflammation during and after CuO NP sub-acute inhalation exposure and to investigate copper (Cu) biodistribution and clearance rate from the exposure site and homeostasis of selected trace elements in secondary organs of BALB/c mice. Results Sub-acute inhalation exposure to CuO NPs led to pulmonary inflammation represented by increases in lactate dehydrogenase, total cell counts, neutrophils, macrophages, inflammatory cytokines, iron levels in bronchoalveolar lavage (BAL) fluid, and lung weight changes. Dosimetry analysis in lung tissues and BAL fluid showed Cu concentration increased steadily during exposure and gradually declined after exposure. Cu elimination from the lung showed first-order kinetics with a half-life of 6.5 days. Total Cu levels were significantly increased in whole blood and heart indicating that inhaled Cu could be translocated into the bloodstream and heart tissue, and potentially have adverse effects on the kidneys and spleen as there were significant changes in the weights of these organs; increase in the kidneys and decrease in the spleen. Furthermore, concentrations of selenium in kidneys and iron in spleen were decreased, pointing to disruption of trace element homeostasis. Conclusions Sub-acute inhalation exposure of CuO NPs induced pulmonary inflammation, which was correlated to Cu concentrations in the lungs and started to resolve once exposure ended. Dosimetry analysis showed that Cu in the lungs was translocated into the bloodstream and heart tissue. Secondary organs affected by CuO NPs exposure were kidneys and spleen as they showed the disruption of trace element homeostasis and organ weight changes.

Encapsulating genetic material into biocompatible polymeric microparticles is a means to improving gene transfection while simultaneously decreasing the tendency for inflammatory responses; and can be advantageous in terms of delivering material directly to the lungs via aerosolization for applications such as vaccinations. In this study, we investigated the advantages of using polymeric microparticles carrying the luciferase reporter gene in increasing transfection efficiency in the readily transfectable HEK293 cell line and the difficult to transfect RAW264.7 cell line. The results indicated that there was a limit to the ratio of nitrogen in polyethylenimine (PEI) to phosphate in DNA (N/P ratio) beyond which further increases in transgene expression no longer, or only marginally, occurred. Microparticles encapsulating PEI:DNA nanoplexes induced cellular toxicity in a dose-dependent manner. PEGylation increased transgene expression, likely related to enhanced degradation of particles. Furthermore, intra-tracheal instillation in rats allowed us to investigate the inflammatory response in the lung as a function of PEGylation, porosity, and size. Porosity did not influence cell counts in bronchoalveolar lavage fluid in the absence of PEG, but in particles containing PEG, non-porous particles recruited fewer inflammatory cells than their porous counterparts. Finally, both 1 μm and 10 μm porous PLA-PEG particles recruited more neutrophils than 4 μm particles. Thus, we have shown that PEGylation and lack of porosity are advantageous for faster release of genetic cargo from microparticles and a reduced inflammatory response, respectively. Supplementary Information The online version contains supplementary material available at 10.1208/s12249-021-01932-z.

Cellulose nanofibers (CNFs) are an emerging engineered nanomaterial that are utilized in a variety of applications, including as a replacement for urea-formaldehyde, and other adhesives, as the binding agent in manufactured fiber and particle boards. To ensure the health and well-being of those producing, installing, or otherwise using cellulose nanofiber boards (CNFBs) it is imperative that the particulate matter (PM) produced during CNFB manipulation be evaluated for toxicity. We developed and internally verified a generation system to examine the PM produced by sanding CNFB using aluminum oxide sandpaper. With 80-grit sandpaper our system produced a low dispersity aerosol, as determined by a scanning mobility particle sizer and an optical particle counter, with a geometric mean of 28 nm (GSD = 1.60). ICP-MS evaluation showed little difference in metal concentrations between CNFB PM and nonsanded CNFB stock. We then used the system to simultaneously generate and expose both male and female C57BL/6J mice acutely for 4 hours at a concentration of 7.9 mg/m(3). Sham-exposed controls were treated similarly but without sanding the CNFB. Analysis of bronchoalveolar lavage (BAL) fluid biomarkers showed no signs of inflammatory response at either 4- or 24-hours post exposure. Further, BAL cell viability, number of total cells, and pulmonary cellular recruitment were not significantly changed between the sham-exposed controls and CNFB-exposed mice. Histology further confirmed no pulmonary toxicity as a result of CNFB PM inhalation. We conclude that inhalation of a high concentration of the PM from manipulation of a CNFB did not produce acute toxic responses within 24 hours of exposure.

Characterizations and in vitro toxicity screening were performed on metal oxide engineered nanomaterials (ENMs) independently comprising ZnO, CuO, CeO(2), Fe(2)O(3), WO(3), V(2)O(5), TiO(2), Al(2)O(3) and MgO. Nanomaterials that exhibited the highest toxicity responses in the in vitro screening assays (ZnO, CuO, and V(2)O(5)) and the lesser explored material WO(3) were tested for acute pulmonary toxicity in vivo. Female and male mice (C57Bl/6J) were exposed to aerosolized metal oxide ENMs in a nose-only exposure system and toxicity outcomes (biomarkers of cytotoxicity, immunotoxicity, inflammation, and lung histopathology) at 4 and 24 h after the start of exposure were assessed. The studies were performed as part of the NIEHS Nanomaterials Health Implications Research consortium with the purpose of investigating the effects of ENMs on various biological systems. ENMs were supplied by the Engineered Nanomaterials Resource and Coordination Core. Among the ENMs studied, the highest toxicity was observed for CuO and ZnO NPs in both in vitro and in vivo acute models. Compared to sham-exposed controls, there was a significant increase in bronchoalveolar lavage neutrophils and proinflammatory cytokines and a loss of macrophage viability at both 4 h and 24 h for ZnO and CuO but not seen for V(2)O(5) or WO(3). These effects were observed in both female and male mice. The cell viability performed after in vitro exposure to ENMs and assessment of lung inflammation after acute inhalation exposure in vivo were shown to be sensitive endpoints to predict ENM acute toxicity.

Airborne engineered nanomaterials (ENMs) can readily enter the human body through inhalation potentially leading to adverse health effects such as cardiovascular and pulmonary diseases. Our group has previously utilized and validated an integrated low flow system capable of generating and depositing airborne ENMs directly onto cells at an air-liquid interface (ALI). To further improve this ALI method for an even closer representation of the in vivo system, a co-culture model containing epithelial, endothelial and macrophage cell lines (A549, EA.hy 926, and THP-1 differentiated macrophages) was established and validated for testing ENMs toxicity. In the co-culture model, cells were exposed to citrate-capped gold (Au), 15% silver on silica (Ag-SiO(2)) and copper oxide (CuO) ENMs under the same protocol (4 h ALI exposure with a target concentration of 3.5 mg/m(3)) and compared to responses with A549 cells only or THP-1 differentiated cells only. The toxicological profile was assessed by measuring cell viability, reactive oxygen species (ROS) production, lactate dehydrogenase (LDH) release, and interleukin (IL)-8 concentration. Results showed that 15% Ag-SiO(2) induced more oxidative stress-related toxicity in the co-culture than in A549 cells alone. Both 15% Ag-SiO(2) and CuO exposure produced significantly higher levels of IL-8 in the co-culture compared with A549 cells alone. Citrate-capped Au was largely inert. Further exposures of CuO on macrophages alone provided evidence of cell-cell interaction in the co-culture model. In addition, the co-culture model exhibited a similar response to primary human bronchial epithelial cells in terms of ROS and IL-8 responses after CuO exposure, suggesting a more advanced refinement of the conventional model for in vitro inhalation study.

Exposure to arsenic (As) and manganese (Mn) from contaminated food, drinking water and dust are linked to a host of adverse health effects. The recent discovery of unmonitored community exposures to hazardous levels of metals, as seen in the Flint Water Crisis and East Chicago, have demonstrated a need for novel biomonitoring methods utilizing samples other than whole blood. Here, we present a method utilizing clotted erythrocyte fraction samples, a blood component commonly archived in biorepositories, to predict whole blood levels of As and Mn. This method would allow for innovative retrospective assessments of environmental exposures in previously unused samples. Whole blood and clotted erythrocyte fraction samples were simultaneously collected from 84 participants in the Airborne Exposure to Semivolatile Organic Pollutants (AESOP) cohort study of mother-child dyads in East Chicago. Clotted erythrocyte fraction samples were prepared by alkaline dilution and subsequently analyzed using inductively coupled plasma-mass spectrometry. A strong linear relationship was observed between whole blood and clotted erythrocyte fraction with Pearson correlation coefficients (r, p 0.001) of 0.74, and 0.82 for As and Mn, respectively. Modeled whole blood Mn levels predicted from clotted erythrocyte fractions evaluated at a test threshold representing the NHANES median of 9.7 μg/L, were found to have diagnostic sensitivity of 88% and specificity of 71%. Clotted erythrocyte partitioning of As was tested on a wide range of oral gavage doses using a rat model. Results from this investigation demonstrate clotted erythrocyte fraction samples are a viable alternative biological sample for retrospective public health surveillance of environmental exposure to As and Mn.

Hexavalent chromium [Cr(VI)] is a well-known carcinogen that can cause several types of cancer including lung cancer. NF-E2-related factor 2 (Nrf2), the redox sensitive transcription factor, can protect normal cells from a variety of toxicants and carcinogens by inducing the expression of cellular protective genes and maintaining redox balance. However, Nrf2 also protects cancer cells from radio- and chemo-therapies and facilitates cancer progression. Although Cr(VI) treatment has been demonstrated to upregulate Nrf2 expression, the mechanisms for Nrf2 regulation upon chronic Cr(VI) exposure remain to be elucidated. We found that Nrf2 was upregulated in BEAS-2B cells exposed to Cr(VI) from 1 to 5 months, and also in Cr(VI)-induced transformed (Cr-T) cells with Cr(VI) treatment for 6 months. We showed that KEAP1, the classic negative regulator of Nrf2, was downregulated after Cr(VI) exposure for 4 months, suggesting that Nrf2 induction by Cr(VI) treatment is through KEAP1 decrease at late stage. To further decipher the mechanisms of Nrf2 upregulation at early stage of Cr(VI) exposure, we demonstrated that miR-27a and miR-27b were redox sensitive miRNAs, since reactive oxygen species (ROS) scavengers induced miR-27a/b expression. After Cr(VI) exposure for 1 month, the expression levels of miR-27a/b was dramatically decreased. The changes of miR-27a/b and their target Nrf2 were confirmed in vivo by mouse model intranasally exposed to Cr(VI) for 12 weeks. Nrf2 was a direct target of miR-27a/b, which acted as tumor suppressors in vitro and in vivo to inhibit tumorigenesis and cancer development of Cr-T cells. The results suggested that the inhibition of miR-27a/b was responsible for Nrf2 upregulation at both early stage and late stage of Cr(VI) exposure. This novel regulation of Nrf2 upon chronic Cr(VI) exposure through redox-regulated miR-27a/b will provide potential targets for preventing and treating Cr(VI)-induced carcinogenesis in the future.