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Quaternary ammoniums activate human dendritic cells and induce a specific T-cell response in vitro
No full textInternational audienceBackground: In many countries, neuro-muscular blocking agents (NMBAs) are the first cause of perioperative anaphylaxis. Epidemiological studies identified pholcodine, a quaternary ammonium-containing opiate as one of the sensitization sources. However, NMBA anaphylaxis exists in countries where pholcodine was unavailable, prompting the hypothesis of other sensitizing molecules, most likely quaternary ammonium compounds (QACs). Indeed, QACs are commonly used as disinfectants, antiseptics, preservatives, and detergents. Occupational exposure to QACs has been reported as a risk factor for NMBA anaphylaxis, but little is known about the sensitization mechanism and the capacity of these molecules to elicit an immune response. We aimed to establish the immunogenicity of QACs representative of the main existing chemical structures.Methods: We measured the sensitization potential of seven QACs (two polyquaterniums, three alkyl-ammoniums and two aromatic ammoniums) by using two standard dendritic cells (DCs) models (THP-1 cell line and monocyte derived-dendritic cells). The allergenicity of the sensitizing compounds was further tested in heterologous and autologous T-cell-DC co-culture models.Results: Amongst the seven molecules tested, four could modulate activation markers on DCs, and thus can be classified as chemical sensitizers (polyquaterniums-7 and -10, ethylhexadecyldimethylammonium and benzethonium). This activation was accompanied by the secretion of pro-inflammatory and maturation cytokines. Furthermore, activation by polyquaternium-7 could induce T-cell proliferation in heterologous and autologous coculture models, demonstrating that this molecule can induce a specific CD4+ T cell response.Conclusions: We provide evidence at the cellular level that some QACs can elicit an immune response, which could be in line with the hypothesis of these molecules' role in NMBA sensitization
Epigenetic footprints: Investigating placental DNA methylation in the context of prenatal exposure to phenols and phthalates
No full textInternational audienceBackground: Endocrine disrupting compounds (EDCs) such as phthalates and phenols can affect placental functioning and fetal health, potentially via epigenetic modifications. We investigated the associations between pregnancy exposure to synthetic phenols and phthalates estimated from repeated urine sampling and genome wide placental DNA methylation.Methods: The study is based on 387 women with placental DNA methylation assessed with Infinium MethylationEPIC arrays and with 7 phenols, 13 phthalates, and two non-phthalate plasticizer metabolites measured in pools of urine samples collected twice during pregnancy. We conducted an exploratory analysis on individual CpGs (EWAS) and differentially methylated regions (DMRs) as well as a candidate analysis focusing on 20 previously identified CpGs. Sex-stratified analyses were also performed.Results: In the exploratory analysis, when both sexes were studied together no association was observed in the EWAS. In the sex-stratified analysis, 114 individual CpGs (68 in males, 46 in females) were differentially methylated, encompassing 74 genes (36 for males and 38 for females). We additionally identified 28 DMRs in the entire cohort, 40 for females and 42 for males. Associations were mostly positive (for DMRs: 93% positive associations in the entire cohort, 60% in the sex-stratified analysis), with the exception of several associations for bisphenols and DINCH metabolites that were negative. Biomarkers associated with most DMRs were parabens, DEHP, and DiNP metabolite concentrations. Some DMRs encompassed imprinted genes including APC (associated with parabens and DiNP metabolites), GNAS (bisphenols), ZIM2;PEG3;MIMT1 (parabens, monoethyl phthalate), and SGCE;PEG10 (parabens, DINCH metabolites). Terms related to adiposity, lipid and glucose metabolism, and cardiovascular function were among the enriched phenotypes associated with differentially methylated CpGs. The candidate analysis identified one CpG mapping to imprinted LGALS8 gene, negatively associated with ethylparaben.Conclusions: By combining improved exposure assessment and extensive placental epigenome coverage, we identified several novel genes associated with the exposure, possibly in a sex-specific manner
Fast compressive Raman micro-spectroscopy to image and classify microplastics from natural marine environment
No full textInternational audienceThe fast and reliable detection of micron-sized plastic particles from the natural marine environment is an important topic that is mostly addressed using spontaneous Raman spectroscopy. Due to the long (>tens of ms) integration time required to record a viable Raman signal, measurements are limited to a single point per microplastic particle or require very long acquisition times (up to tens of hours). In this work, we develop, validate, and demonstrate a compressive Raman technology using binary spectral filters and single-pixel detection that can image and classify six types of marine microplastic particles over an area of 1 mm2 with a pixel dwell time down to 1.75 ms/pixel and a spatial resolution of 1 µm. This is x10–100 faster than reported in previous studies
Runoff microbiome quality assessment of a city center rainwater harvesting zone shows a differentiation of pathogen loads according to human mobility patterns
No full text3/2/1International audienceThe hygienic quality of urban surfaces can be impaired by multiple sources of microbiological contaminants. These surfaces can trigger the development of multiple bacterial taxa and favor their spread during rain events through the circulation of runoff waters. These runoff waters are commonly directed toward sewer networks, stormwater infiltration systems or detention tanks prior a release into natural water ways. With water scarcity becoming a major worldwide issue, these runoffs are representing an alternative supply for some usage like street cleaning and plant watering. Microbiological hazards associated with these urban runoffs, and surveillance guidelines must be defined to favor these uses. Runoff microbiological quality from a recently implemented city center rainwater harvesting zone was evaluated through classical fecal indicator bacteria (FIB) assays, quanti- tative PCR and DNA meta-barcoding analyses. The incidence of socio-urbanistic patterns on the organization of these urban microbiomes were investigated. FIB and DNA from Human-specific Bacteroidales and pathogens such as Staphylococcus aureus were detected from most runoffs and showed broad distribution patterns. 16S rRNA DNA meta-barcoding profilings further identified core recurrent taxa of health concerns like Acinetobacter, Mycobac- terium, Aeromonas and Pseudomonas, and divided these communities according to two main groups of socio- urbanistic patterns. One of these was highly impacted by heavy traffic, and showed recurrent correlation net- works involving bacterial hydrocarbon degraders harboring significant virulence properties. The tpm-based meta-barcoding approach identified some of these taxa at the species level for more than 30 genera. Among these, recurrent pathogens were recorded such as P. aeruginosa, P. paraeruginosa, and Aeromonas caviae. P. aeruginosa and A. caviae tpm reads were found evenly distributed over the study site but those of P. paraeruginosa were higher among sub-catchments impacted by heavy traffic. Health risks associated with these runoff P. paraeruginosa emerging pathogens were high and associated with strong cytotoxicity on A549 lung cells. Recurrent detections of pathogens in runoff waters highlight the need of a microbiological surveillance prior allowing their use. Good microbiological quality can be obtained for certain typologies of sub-catchments with good hygienic practices but not all. A reorganization of Human mobility and behaviors would likely trigger changes in these bacterial diversity patterns and reduce the occurrences of the most hazardous groups
Associations between pre- and post-natal exposure to phthalate and DINCH metabolites and gut microbiota in one-year old children
No full textInternational audienceThe gut microbiota is a collection of symbiotic microorganisms in the gastrointestinal tract. Its sensitivity to chemicals with widespread exposure, such as phthalates, is little known. We aimed to investigate the impact of perinatal exposure to phthalates on the infant gut microbiota at 12 months of age. Within SEPAGES cohort (Suivi de l'Exposition à la Pollution Atmosphérique durant la Grossesse et Effet sur la Santé), we assessed 13 phthalate metabolites and 2 di(isononyl) cyclohexane-1,2-dicarboxylate (DINCH) metabolites in repeated urine samples collected in pregnant women and their offspring. We obtained stool samples from 356 children at 12 months of age and sequenced the V3-V4 region of the 16S rRNA gene, allowing gut bacterial profiling. We used single-chemical (linear regressions) and mixture (BKMR, Bayesian Kernel Machine Regression) models to examine associations of phthalates and DINCH metabolites, with gut microbiota indices of α-diversity (specific richness and Shannon diversity) and the relative abundances of the most abundant microbiota phyla and genera. After correction for multiple testing, di(2-ethylhexyl) phthalate (ΣDEHP), diethyl phthalate (DEP) and bis(2-propylheptyl) phthalate (DPHP) metabolites 12-month urinary concentrations were associated with higher Shannon α-diversity of the child gut microbiota in single-chemical models. The multiple-chemical model (BKMR) suggested higher α-diversity with exposure to the phthalate mixture at 12 months, driven by the same phthalates. There were no associations between phthalate and DINCH exposure biomarkers at other time points and α-diversity after correction for multiple testing. ΣDEHP metabolites concentration at 12 months was associated with higher Coprococcus genus. Finally, ΣDEHP exposure at 12 months tended to be associated with higher phylum Firmicutes, an association not maintained after correction for multiple testing. Infancy exposure to phthalate might disrupt children's gut microbiota. The observed associations were cross-sectional, so that reverse causality cannot be excluded
In Silico Predictions of Endocrine Disruptors Properties
No full textInternational audienceEndocrine-disrupting chemicals (EDCs) are a broad class of molecules present in our environment that are suspected to cause adverse effects in the endocrine system by interfering with the synthesis, transport, degradation, or action of endogenous ligands. The characterization of the harmful interaction between environmental compounds and their potential cellular targets and the development of robust in vivo, in vitro, and in silico screening methods are important for assessment of the toxic potential of large numbers of chemicals. In this context, computer-aided technologies that will allow for activity prediction of endocrine disruptors and environmental risk assessments are being developed. These technologies must be able to cope with diverse data and connect chemistry at the atomic level with the biological activity at the cellular, organ, and organism levels. Quantitative structure-activity relationship methods became popular for toxicity issues. They correlate the chemical structure of compounds with biological activity through a number of molecular descriptors (e.g., molecular weight and parameters to account for hydrophobicity, topology, or electronic properties). Chemical structure analysis is a first step; however, modeling intermolecular interactions and cellular behavior will also be essential. The increasing number of three-dimensional crystal structures of EDCs' targets has provided a wealth of structural information that can be used to predict their interactions with EDCs using docking and scoring procedures. In the present review, we have described the various computer-assisted approaches that use ligands and targets properties to predict endocrine disruptor activities
Development of a crosswalk to convert French PCS2003 into international ISCO88 occupational classifications. Application to the Occupational Asthma-specific Job-Exposure Matrix (OAsJEM)
No full textInternational audienceIntroduction The problem of transcoding is recurrent when researchers wish to link occupational data from cohorts to Job-Exposure Matrices (JEMs) which were not set up in the same classifications. The Occupational Asthma-specific JEM (OAsJEM) is a JEM developed for assessing exposure to agents known at risk for asthma for jobs coded with ISCO88 occupation classification. To apply the OAsJEM in the CONSTANCES cohort, in which jobs and industries were coded with French PCS2003 and NAF2008 classifications respectively, we developed a crosswalk to convert jobs from PCS2003 into ISCO88 classification. Methods This work was carried out by 2 skilled coders and 1 novice coder who have worked independently by using different tools and transcoding strategies defined a priori. Consensus meetings were organized with skilled coders to define the final crosswalk. This work was elaborated in 2 steps: (i) for 38 ISCO88 codes classified as potentially exposed to cleaning and disinfection products by the OAsJEM, and (ii) for all jobs from the ISCO88 classification. A comparison between the 3 initial coder’s crosswalk proposals and the final crosswalk was made for the 38 ISCO codes in step (i). Results The final crosswalk provided 998 matches between the 482 4-digit PCS2003 codes, 308 4-digit ISCO88 codes, and 31 3-digit ISCO88 codes. Information regarding the NAF2008 industry classification was also used in some cases to improve the final crosswalk. For the selected 38 ISCO88 codes, the final crosswalk provided 110 combinations, but the number of proposed ISCO88–PCS2003 couples by each of the 3 coders varied greatly from 68 to 153. In addition, an important variability between the 3 coders were observed among the number of common combinations between the initial coder’s proposals and the final crosswalk (from 47% to 78%). Discussion We have developed a crosswalk specifically for an application of the OAsJEM in population-based surveys using the PCS2003 occupation classification. The development of this crosswalk is of great interest for the use of OAsJEM on the data of the CONSTANCES cohort and on any other survey with occupational data coded according to the French classifications. This OAsJEM crosswalk could be used by other teams to evaluate occupational exposures known to be at risk of asthma from occupational calendars coded with French classifications
Placental DNA methylation signatures of prenatal air pollution exposure and potential effects on birth outcomes: an analysis of three prospective cohorts
No full textInternational audienceBackground Pregnancy air pollution exposure (PAPE) has been linked to a wide range of adverse birth and childhood outcomes, but there is a paucity of data on its influence on the placental epigenome, which can regulate the programming of physiological functions and affect child development. This study aimed to investigate the association between prenatal air pollutant exposure concentrations and changes in placental DNA methylation patterns, and to explore the potential windows of susceptibility and sex-specific alterations. Methods This multi-site study used three prospective population-based mother-child cohorts: EDEN, PELAGIE, and SEPAGES, originating from four French geographical regions (Nancy, Poitiers, Brittany, and Grenoble). Pregnant women were included between 2003 and 2006 for EDEN and PELAGIE, and between 2014 and 2017 for SEPAGES. The main eligibility criteria were: being older than 18 years, having a singleton pregnancy, and living and planning to deliver in one of the maternity clinics in one of the study areas. A total of 1539 mother-child pairs were analysed, measuring placental DNA methylation using Illumina BeadChips. We used validated spatiotemporally resolved models to estimate PM 2<middle dot>5 , PM 10 , and NO 2 exposure over each trimester of pregnancy at the maternal residential address. We conducted a pooled adjusted epigenome-wide association study to identify differentially methylated 5'- C-phosphate-G-3' (CpG) sites and regions (assessed using the Infinium HumanMethylationEPIC BeadChip array, n=871), including sex-specific and sex-linked alterations, and independently validated our results (assessed using the Infinium HumanMethylation450 BeadChip array, n=668). Findings We identified four CpGs and 28 regions associated with PAPE in the total population, 469 CpGs and 87 regions in male infants, and 150 CpGs and 66 regions in female infants. We validated 35% of the CpGs available. More than 30% of the identified CpGs were related to one (or more) birth outcome and most significant alterations were enriched for neural development, immunity, and metabolism related genes. The 28 regions identified for both sexes overlapped with imprinted genes (four genes), and were associated with neurodevelopment (nine genes), immune system (seven genes), and metabolism (five genes). Most associations were observed for the third trimester for female infants (134 of 150 CpGs), and throughout pregnancy (281 of 469 CpGs) and the first trimester (237 of 469 CpGs) for male infants. Interpretation These findings highlight the molecular pathways through which PAPE might affect child health in a widespread and sex-specific manner, identifying the genes involved in the major physiological functions of a developing child. Further studies are needed to elucidate whether these epigenetic changes persist and affect health later in life
Les effets potentiels du fluorure de sodium sur la truite arc-en-ciel: Evaluation des effets potentiels du Fluorure de Sodium, substance perturbatrice endocrinienne suspectée, sur le système thyroïdien, l’immunité et le microbiote de la truite arc-en-ciel, Oncorhynchus mykiss
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