Papers by Caroline Desvergne
HAL (Le Centre pour la Communication Scientifique Directe), Nov 13, 2012
International audiencePas de résum
Journal of Breath Research, Nov 28, 2022
The whitening and opacifying properties of titanium dioxide (TiO<sub>2</sub>) are com... more The whitening and opacifying properties of titanium dioxide (TiO<sub>2</sub>) are commonly exploited when it is used as a food additive (E171). However, the safety of this additive can be questioned as TiO<sub>2</sub> nanoparticles (TiO<sub>2</sub>-NPs) have been classed at potentially toxic. This study aimed to shed some light on the mechanisms behind the potential toxicity of E171 on epithelial intestinal cells, using two <i>in vitro</i> models: (i) a monoculture of differentiated Caco-2 cells and (ii) a coculture of Caco-2 with HT29-MTX mucus-secreting cells. Cells were exposed to E171 and two different types of TiO<sub>2</sub>-NPs, either acutely (6–48 h) or repeatedly (three times a week for 3 weeks). Our results confirm that E171 damaged these cells, and that the main mechanism of toxicity was oxidation effects. Responses of the two models to E171 were similar, with a moderate, but significant, accumulation of reactiv...
Archives of Toxicology, 2021
Silver nanoparticles (Ag NPs) are priority substances closely monitored by health and safety agen... more Silver nanoparticles (Ag NPs) are priority substances closely monitored by health and safety agencies. Despite their extensive use, some aspects of their toxicokinetics remain to be documented, in particular following inhalation, the predominant route of exposure in the workplace. A same experimental protocol and exposure conditions were reproduced two times (experiments E1 and E2) to document the kinetic time courses of inhaled Ag NPs. Rats were exposed nose-only to 20 nm Ag NPs during 6 h at a target concentration of 15 mg/m3 (E1: 218,341 ± 85,512 particles/cm3; E2, 154,099 ± 5728 particles/cm3). The generated aerosol showed a uniform size distribution of nanoparticle agglomerates with a geometric mean diameter ± SD of 79.1 ± 1.88 nm in E1 and 92.47 ± 2.19 nm in E2. The time courses of elemental silver in the lungs, blood, tissues and excreta were determined over 14 days following the onset of inhalation. Excretion profiles revealed that feces were the dominant excretion route and represented on average (± SD) 5.1 ± 3.4% (E1) and 3.3 ± 2.5% (E2) of the total inhaled exposure dose. The pulmonary kinetic profile was similar in E1 and E2; the highest percentages of the inhaled dose were observed between the end of the 6-h inhalation up to 6-h following the end of exposure, and reached 1.9 ± 1.2% in E1 and 2.5 ± 1.6% in E2. Ag elements found in the GIT followed the trend observed in lungs, with a peak observed at the end of the 6-h inhalation exposure and representing 6.4 ± 4.9% of inhaled dose, confirming a certain ingestion of Ag NPs from the upper respiratory tract. Analysis of the temporal profile of Ag elements in the liver showed two distinct patterns: (i) progressive increase in values with peak at the end of the 6-h inhalation period followed by a progressive decrease; (ii) second increase in values starting at 72 h post-exposure with maximum levels at 168-h followed by a progressive decrease. The temporal profiles of Ag elements in lymphatic nodes, olfactory bulbs, kidneys and spleen also followed a pattern similar to that of the liver. However, concentrations in blood and extrapulmonary organs were much lower than lung concentrations. Overall, results show that only a small percentage of the inhaled dose reached the lungs-most of the dose likely remained in the upper respiratory tract. The kinetic time courses in the gastrointestinal tract and liver showed that part of the inhaled Ag NPs was ingested; lung, blood and extrapulmonary organ profiles also suggest that a small fraction of inhaled Ag NPs progressively reached the systemic circulation by a direct translocation from the respiratory tract.
Environmental Science: Nano, 2020
At equal cumulated dose, a chronic exposure to silver nanoparticles produces more effects on macr... more At equal cumulated dose, a chronic exposure to silver nanoparticles produces more effects on macrophages than an acute exposure.
Journal of Breath Research, 2018
Proteomes, 2019
Metal-containing drugs have long been used in anticancer therapies. The mechansims of action of p... more Metal-containing drugs have long been used in anticancer therapies. The mechansims of action of platinum-based drugs are now well-understood, which cannot be said of drugs containing other metals, such as gold or copper. To gain further insights into such mechanisms, we used a classical proteomic approach based on two-dimensional elelctrophoresis to investigate the mechanisms of action of a hydroxyquinoline-copper complex, which shows promising anticancer activities, using the leukemic cell line RAW264.7 as the biological target. Pathway analysis of the modulated proteins highlighted changes in the ubiquitin/proteasome pathway, the mitochondrion, the cell adhesion-cytoskeleton pathway, and carbon metabolism or oxido-reduction. In line with these prteomic-derived hypotheses, targeted validation experiments showed that the hydroxyquinoline-copper complex induces a massive reduction in free glutathione and a strong alteration in the actin cytoskeleton, suggesting a multi-target action ...
Environmental Science: Nano, 2019
Repeated exposure to E171 or TiO2-NPs, in vitro, induce moderate inflammation and mucus secretion... more Repeated exposure to E171 or TiO2-NPs, in vitro, induce moderate inflammation and mucus secretion in intestinal cells.
Journal of Breath Research, 2018
To improve biomedical knowledge and to support biomarker discovery studies, it is essential to es... more To improve biomedical knowledge and to support biomarker discovery studies, it is essential to establish comprehensive proteome maps for human tissues and biofluids, and to make them publicly accessible. In this study, we performed an in-depth proteomics characterization of exhaled breath condensate (EBC), a sample obtained non-invasively by condensation of exhaled air that contains submicron droplets of airway lining fluid. Two pooled samples of EBC, each obtained from 10 healthy donors, were processed using a straightforward protocol based on sample lyophilization, in-gel digestion and liquid chromatography tandem-mass spectrometry analysis. Two 'technical' control samples were processed in parallel to the pooled samples to correct for exogenous protein contamination. A total of 229 unique proteins were identified in EBC among which 153 proteins were detected in both EBC pooled samples. A detailed bioinformatics analysis of these 153 proteins showed that most of the proteins identified corresponded to proteins secreted in the respiratory tract (lung, bronchi). Eight proteins were salivary proteins. Our dataset is described and has been made accessible through the ProteomeXchange database (dataset identifier: PXD007591) and is expected to be useful for future MS-based biomarker studies using EBC as the diagnostic specimen. Chronic obstructive pulmonary disease EBC Exhaled breath condensate FDR False discovery rate GO Gene ontology IBAQ Intensity-based absolute quantification LC-MS/MS Liquid chromatography tandem-mass spectrometry PEx Exhaled air endogenous particles SELDI Surface-enhanced laser desorption/ionization
Nanotoxicology, Jan 19, 2017
The whitening and opacifying properties of titanium dioxide (TiO2) are commonly exploited when it... more The whitening and opacifying properties of titanium dioxide (TiO2) are commonly exploited when it is used as a food additive (E171). However, the safety of this additive can be questioned as TiO2 nanoparticles (TiO2-NPs) have been classed at potentially toxic. This study aimed to shed some light on the mechanisms behind the potential toxicity of E171 on epithelial intestinal cells, using two in vitro models: (i) a monoculture of differentiated Caco-2 cells and (ii) a coculture of Caco-2 with HT29-MTX mucus-secreting cells. Cells were exposed to E171 and two different types of TiO2-NPs, either acutely (6-48 h) or repeatedly (three times a week for 3 weeks). Our results confirm that E171 damaged these cells, and that the main mechanism of toxicity was oxidation effects. Responses of the two models to E171 were similar, with a moderate, but significant, accumulation of reactive oxygen species, and concomitant downregulation of the expression of the antioxidant enzymes catalase, superox...
Journal of Breath Research, 2016
Aircraft engine exhaust increases the number concentration of nanoparticles (NP) in the surroundi... more Aircraft engine exhaust increases the number concentration of nanoparticles (NP) in the surrounding environment. Health concerns related to NP raise the question of the exposure and health monitoring of airport workers. No biological monitoring study on this profession has been reported to date. The aim was to evaluate the NP and metal exposure of airport workers using exhaled breath condensate (EBC) as a non-invasive biological matrix representative of the respiratory tract. EBC was collected from 458 French airport workers working either on the apron or in the offices. NP exposure was characterized using particle number concentration (PNC) and size distribution. EBC particles were analyzed using dynamic light scattering (DLS) and scanning electron microscopy coupled to x-ray spectroscopy (SEM-EDS). Multi-elemental analysis was performed for aluminum (Al), cadmium (Cd) and chromium (Cr) EBC contents. Apron workers were exposed to higher PNC than administrative workers (p < 0.001). Workers were exposed to very low particle sizes, the apron group being exposed to even smaller NP than the administrative group (p < 0.001). The particulate content of EBC was brought out by DLS and confirmed with SEM-EDS, although no difference was found between the two study groups. Cd concentrations were higher in the apron workers (p < 0.001), but still remained very low and close to the detection limit. Our study reported the particulate and metal content of airport workers airways. EBC is a potential useful tool for the non-invasive monitoring of workers exposed to NP and metals.
Nanotoxicology, 2016
Titanium dioxide nanoparticles (TiO 2 -NPs) are one of the most produced NPs in the world. Their ... more Titanium dioxide nanoparticles (TiO 2 -NPs) are one of the most produced NPs in the world. Their toxicity has been studied for a decade using acute exposure scenarios, i.e. high exposure concentrations and short exposure times. In the present study, we evaluated their genotoxic impact using long-term and low concentration exposure conditions. A549 alveolar epithelial cells were continuously exposed to 1-50 µg/mL TiO 2 -NPs, 86% anatase / 14% rutile, 24±6 nm average primary diameter, for up to two months. Their cytotoxicity, oxidative potential and intracellular accumulation were evaluated using MTT assay and reactive oxygen species measurement, transmission electron microscopy observation, micro-particle-induced X-ray emission and inductivelycoupled plasma mass spectroscopy. Genotoxic impact was assessed using alkaline and Fpg-modified comet assay, immunostaining of 53BP1 foci and the cytokinesis-blocked micronucleus assay. Finally, we evaluated the impact of a subsequent exposure of these cells to the alkylating agent methyl methanesulfonate. We demonstrate that long-term exposure to TiO 2 -NPs does not affect cell viability but causes DNA damage, particularly oxidative damage to DNA and increased 53BP1 foci counts, correlated with increased intracellular accumulation of NPs. In addition, exposure over 2 months causes cellular responses suggestive of adaptation, characterized by decreased proliferation rate and stabilization of TiO 2 -NP intracellular accumulation, as well as sensitization to MMS. Taken together, these data underline the genotoxic impact and sensitization effect of long-term exposure of lung alveolar epithelial cells to low levels of TiO 2 -NPs.
Nanoscale, 2015
TiO2-NPs, both anatase and rutile, accumulate in Caco-2 cells and up-regulate a battery of nutrie... more TiO2-NPs, both anatase and rutile, accumulate in Caco-2 cells and up-regulate a battery of nutrient transporters and efflux pumps, but do not cause overt mortality or DNA damage.
Toxicological Sciences, 2011
Measurements of 3-hydroxybenzo(a)pyrene (3-OHBaP) in urine has been proposed for the biomonitorin... more Measurements of 3-hydroxybenzo(a)pyrene (3-OHBaP) in urine has been proposed for the biomonitoring of exposure to benzo(a)pyrene (BaP) in workers. To allow a better understanding of the toxicokinetics of BaP and its key biomarker, a multicompartment model was developed based on rat data previously obtained by this group. According to the model, iv injected BaP is rapidly distributed from blood to tissues (t 1/2 5 3.65 h), with particular affinity for tissue lipid components and liver and lung proteins. BaP is then rapidly distributed to lungs, where significant tissue uptake occurs, followed by the skin, liver, and adipose tissues. Once in liver, BaP is readily metabolized, and 3-OHBaP is formed with a t 1/2 of 3.32 h. Lung metabolism of BaP was also accounted for, but its contribution to the whole kinetics was found to be negligible. Once formed, 3-OHBaP is distributed from blood to the various organs almost as fast as the parent compound (t 1/2 5 2.26 h). In kidneys, 3-OHBaP builds up as a result of the smaller rate of 3-OHBaP urinary excretion (t 1/2 5 4.52 h) as compared with its transfer rate from blood to kidneys (t 1/2 5 27.8 min). However, overall clearance of 3-OHBaP from the body is driven by its biliary transfer from liver to the gastrointestinal tract (t 1/2 5 3.81 h). The model provides a great fit to independent sets of published data on 3-OHBaP urinary excretion time course (x 2 5 0.019). This model proves useful in establishing the main biological determinants of the overall kinetics of these compounds.
Journal of Physics: Conference Series, 2011
In the context of the precautionary principle for engineered nanoparticles, a test able to verify... more In the context of the precautionary principle for engineered nanoparticles, a test able to verify the non exposure of individuals to nanoaerosols seems to be of great interest, especially for workers involved with nanomaterials. A novel method is proposed to detect the presence of nanoparticles in the nose. Different materials, including paper and polycarbonate, have been tested for their sampling efficiency towards ZnO nanoparticles. The detection of nanoparticles is performed by elemental analysis using Total Reflection X-Ray Fluorescence (TXRF). For an optimal sensitivity of the TXRF signal, samples have to be deposited on a smooth surface. Therefore, different materials have been compared as sample carrier. The results indicate that pure paper is the most efficient material for sampling nanoparticles (ZnO), while the use of polycarbonate, and even more flexible polyester, as sample carrier allows a better sensitivity for TXRF analysis. Therefore, the sampling device made of paper is digested under slightly acidic conditions in a microwave oven after collection, and the resulting solution is deposited on polyester for TXRF analysis. Internal calibration is performed thanks to an addition of Rb to the samples. The proposed method allows the chemical identification of nanoparticles deposited in the nose: a qualitative signature of a potential nanoaerosol inhalation.
Chemical Research in Toxicology, 2010
Biomarkers of exposure and effect were assessed in 40 male Sprague-Dawley rats injected intraveno... more Biomarkers of exposure and effect were assessed in 40 male Sprague-Dawley rats injected intravenously with 40 µmol/kg of benzo(a)pyrene (BaP) to determine which biomarkers are more representative of BaP-induced DNA damage in lung. Lung, liver, blood, and urine were collected at t ) 2, 4, 8, 16, 24, 33, 48, 72, and 360 h postdosing. Specific BaP-diol epoxide (BPDE)-DNA adducts, 8-hydroxy-7,8dihydro-2′-deoxyguanosine (8-OHdGuo), were measured in lung, liver, and mononucleated blood cells by high-performance liquid chromatography coupled to tandem mass spectrometry (HPLC-MS/MS). Urinary 8-OHdGuo and 8-hydroxy-7,8-dihydroguanosine (8-OHGuo) were also determined by HPLC-MS/MS, and urinary 3-hydroxybenzo(a)pyrene was measured by HPLC/fluorescence. Between 2 and 72 h postdosing, BPDE-DNA adducts were significantly increased in lung, liver, and mononucleated blood cells of BaP-treated rats as compared to controls, with the highest levels found in lung. 8-OHdGuo levels also increased in lung of BaP-treated rats with values reaching statistical significance at 2, 8, and 16 h postinjection. No influence of BaP treatment was found on 8-OHdGuo and 8-OHGuo urinary excretions. BPDE-DNA adducts in lung were strongly correlated to urinary 3-OHBaP (r ) 0.936 and p < 0.001) and to a lesser extent to blood BPDE-DNA adducts (r ) 0.636 and p < 0.001), the latter of which were correlated to each other (r ) 0.573 and p ) 0.002). Urinary 3-OHBaP and BPDE-DNA adducts in mononucleated blood cells appear as relevant biomarkers of BaP genotoxic exposure and are highly promising for health risk assessment in humans.
International audiencePas de résum
Journal of Physics: Conference Series, 2015
The use of engineered nanoparticles (NP) is more and more widespread in various industrial sector... more The use of engineered nanoparticles (NP) is more and more widespread in various industrial sectors. The inhalation route of exposure is a matter of concern (adverse effects of air pollution by ultrafine particles and asbestos). No NP biomonitoring recommendations or standards are available so far. The LBM laboratory is currently studying several approaches to develop bioindicators for occupational health applications. As regards exposure indicators, new tools are being implemented to assess potentially inhaled NP in non-invasive respiratory sampling (nasal sampling and exhaled breath condensates (EBC)). Diverse NP analytical characterization methods are used (ICP-MS, dynamic light scattering and electron microscopy coupled to energy-dispersive X-ray analysis). As regards effect indicators, a methodology has been developed to assess a range of 29 cytokines in EBCs (potential respiratory inflammation due to NP exposure). Secondly, collaboration between the LBM laboratory and the EDyp team has allowed the EBC proteome to be characterized by means of an LC-MS/MS process. These projects are expected to facilitate the development of individual NP exposure biomonitoring tools and the analysis of early potential impacts on health. Innovative techniques such as field-flow fractionation combined with ICP-MS and single particle-ICPMS are currently being explored. These tools are directly intended to assist occupational physicians in the identification of exposure situations.
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Papers by Caroline Desvergne