HAL du Programme national de recherche environnement-santé-travail (PNR EST)
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Constitutive Androstane Receptor: A Peripheral and a Neurovascular Stress or Environmental Sensor
No full textInternational audienceXenobiotic nuclear receptors (NR) are intracellular players involved in an increasing number of physiological processes. Examined and characterized in peripheral organs where they govern metabolic, transport and detoxification mechanisms, accumulating data suggest a functional expression of specific NR at the neurovascular unit (NVU). Here, we focus on the Constitutive Androstane Receptor (CAR), expressed in detoxifying organs such as the liver, intestines and kidneys. By direct and indirect activation, CAR is implicated in hepatic detoxification of xenobiotics, environmental contaminants, and endogenous molecules (bilirubin, bile acids). Importantly, CAR participates in physiological stress adaptation responses, hormonal and energy homeostasis due to glucose and lipid sensing. We next analyze the emerging evidence supporting a role of CAR in NVU cells including the blood-brain barrier (BBB), a key vascular interface regulating communications between the brain and the periphery. We address the emerging concept of how CAR may regulate specific P450 cytochromes at the NVU and the associated relevance to brain diseases. A clear understanding of how CAR engages during pathological conditions could enable new mechanistic, and perhaps pharmacological, entry-points within a peripheral-brain axis
Exposure of pregnant women to organophosphate insecticides and child motor inhibition at the age of 10–12 years evaluated by fMRI
No full textInternational audienceBackground: Organophosphate pesticides (OP) are widely used for both agricultural and domestic purposes. Epidemiological studies suggest neurotoxicity in children after exposure to organophosphates pesticides (OP) at low levels but possible mechanism is still unclear.Objectives: We aimed at investigating the effects of prenatal exposure to OPs on inhibitory control of 10-12 year-old-children assessed by a motor inhibition task during functional magnetic resonance imaging (fMRI).Methods: Ninety-five children from the PELAGIE cohort (Brittany-France, from 2002) underwent a fMRI examination during which inhibition was assessed by a Go/No-Go task. Task performance was assessed by average response latency, commission rate and composite performance score (PS). Whole brain activation was estimated by modeling the hemodynamic response related to inhibition demand and successful inhibition. OP exposure was assessed by measuring six dialkylphosphate (DAP) metabolites in the urine of women in early pregnancy (<19 WG). Concentrations were summed to obtain overall levels of diethylphosphate (DE), dimethylphosphate (DM) and total non-specific metabolites (DAP), standardized to homogenize sampling conditions and categorized into levels of exposure: low (reference), moderate or high. Regression models were adjusted for potential cofounders considered by restriction and statistical criteria.Results: Moderate levels of DAP were associated with a decreased commission rate (β = -6.65%, p = 0.04), indicating improved performance. Increasing levels of DM and DE were associated with decreased brain activity in the left inferior and bilateral superior frontal regions during successful inhibition. We did not observe any differential activation related to inhibitory demands.Discussion: These results suggest that prenatal OPs may be associated with altered pattern of brain activity in regions related to inhibition among children and need to be confirmed by additional studies
Psychosocial work exposures of the job strain model and cardiovascular mortality in France: results from the STRESSJEM prospective study
No full textInternational audienceObjectives The study aims to explore the prospective associations of the psychosocial work exposures of the job strain model with cardiovascular mortality, including mortality for ischemic heart diseases (IHD) and stroke, using various time-varying exposure measures in the French working population of employees. Methods The study was based on a cohort of 798 547 men and 697 785 women for which job history data from 1976 to 2002 were linked to mortality data and causes of death from the national death registry. Psychosocial work exposures from the validated job strain model questionnaire were assessed using a job-exposure matrix (JEM). Three time-varying measures of exposure were studied: current, cumulative, and recency-weighted cumulative exposure. Cox proportional hazards models were used to examine the associations between psychosocial work exposures and cardiovascular mortality. Results Within the 1976-2002 period, there were 19 264 cardiovascular deaths among men and 6181 among women. Low decision latitude, low social support, job strain, iso-strain, passive job, and high strain were associated with cardiovascular mortality. Most of these associations were also observed for IHD and stroke mortality. The comparison between the different exposure measures suggested that current exposure may be more important than cumulative (or past) exposure. The population fractions of cardiovascular mortality attributable to job strain were 5.64% for men and 6.44% for women. Conclusions Psychosocial work exposures of the job strain model may play a role in cardiovascular mortality. The estimated burden of cardiovascular mortality associated with these exposures underlines the need for preventive policies oriented toward the psychosocial work environment
Gold-based therapy : from past to present
No full textInternational audienceDespite an abundant literature on gold nanoparticles use for biomedicine, only a few of the gold-based nanodevices are currently tested in clinical trials, and none of them are approved by health agencies. Conversely, ionic gold has been used for decades to treat human rheumatoid arthritis and benefits from 70-y hindsight on medical use. With a view to open up new perspectives in gold nanoparticles research and medical use, we revisit here the literature on therapeutic gold salts. We first summarize the literature on gold salt pharmacokinetics, therapeutic effects, adverse reactions, and the present repurposing of these ancient drugs. Owing to these readings, we evidence the existence of a common metabolism of gold nanoparticles and gold ions and propose to use gold salts as a “shortcut” to assess the long-term effects of gold nanoparticles, such as their fate and toxicity, which remain challenging questions nowadays. Moreover, one of gold salts side effects (i.e., a blue discoloration of the skin exposed to light) leads us to propose a strategy to biosynthesize large gold nanoparticles from gold salts using light irradiation. These hypotheses, which will be further investigated in the near future, open up new avenues in the field of ionic gold and gold nanoparticles-based therapies
Single-Molecule Sensing of DNA Intercalating Drugs in Water
No full textInternational audienceThe occurrence of pharmaceutical residues in surface water is raising environmental concern. To accompany the evolution of measures for natural resources protection, sensing methods enabling sensitive and rapid water quality monitoring are needed. We recently managed the parallelization of the Tethered Particle Motion (TPM), a single molecule technique, sensitive to the conformational changes of DNA. Here, we investigate the capacity of high throughput TPM (htTPM) to detect drugs that intercalate into DNA. As a proof-of-concept we analyze the htTPM signal for two DNA intercalating dyes, namely, YOYO-1 and SYTOX orange. The efficient detection of intercalating drugs is then demonstrated with doxorubicin. We further evaluate the possibility to detect carbamazepine, an antiepileptic massively prescribed and persistent in water, which had been described to interact with DNA through intercalation. Our results corroborated by other techniques show that, in fact, carbamazepine is not a DNA intercalator. The comparison of the results obtained with different aqueous buffers and solutions allows us to identify optimal conditions for the monitoring of intercalation compounds by htTPM
Environmental exposures related to parental habits in the perinatal period and the risk of Wilms' tumor in children
No full textInternational audienceIntroduction Wilms' tumor is the most frequently diagnosed renal tumor in children. Little is known about its etiology. The aim of this study was to investigate the potential role of specific exposures related to parental habits such as parental smoking, maternal alcohol consumption and the use of household pesticides during pregnancy.Methods The ESTELLE study was a nationwide case-control study that included 117 Wilms' tumor cases and 1100 control children from the general French population, frequency-matched by age and gender. Unconditional logistic regression was used to estimate odds ratios and 95 % confidence intervals.Results After controlling for matching variables and potential confounders, the maternal use of any type of pesticide during pregnancy was associated with the risk of Wilms' tumor in children (OR 1.6 [95 % CI 1.1-2.3]). Insecticides were the most commonly reported type of pesticide and there was a positive association with their use (OR 1.7 [95 % CI 1.1-2.6]. The association was stronger when they were used more often than once a month (OR 1.9 [95 % CI 1.2-3.0]. Neither maternal smoking during pregnancy nor paternal smoking during preconception/pregnancy was associated with a risk of Wilms' tumor (ORs 1.1[95 % CI 0.7-1.8] and 1.1 [95 % CI 0.7-1.7], respectively). No association was observed with maternal alcohol intake during pregnancy (OR 1.2 [95 % CI 0.8-2.0]).Conclusion Our findings suggest an association between the maternal use of household pesticides during pregnancy and the risk of Wilms' tumor
Foetal exposure to heavy metals and risk of atopic diseases in early childhood
No full textInternational audienceBackground: Accumulating evidence suggests that in utero exposures can influence the development of the immune system and thus contribute to disease development. Studies investigating the association between prenatal exposures to heavy metals and atopic diseases, however, are scarce.Methods: Children from the EDEN birth cohort were prospectively followed up using parental questionnaires with validated questions on asthma, allergic rhinitis, eczema, and food allergy symptoms. The questionnaires were administered every 4 months during the children's first year, and then every year until the age of 5, with a final survey at the age of 8. Serum concentrations of lead (Pb), cadmium (Cd), and manganese (Mn) were assessed in maternal blood samples collected during mid-pregnancy and in cord blood of 651 mother-children pairs. Hazard ratios (HR) for the incidence of each atopic disease in relation to the exposure to metals were calculated using Cox proportional hazard models.Results: Levels of Cd in cord blood were associated with greater risk of asthma (hazard ratio [95% confidence interval] for upper vs lower quartile: 1.81 [1.00-3.29]), eczema (1.60 [1.09-2.35]), and food allergy (3.17 [1.36-7.38]), while Mn levels in maternal serum were associated with eczema (1.55 [1.05-2.28]). These associations were similar in males and females and were confirmed using log concentrations of metals as exposures.Conclusions: Our results support the hypothesis that fetal exposure to heavy metals may affect the development of asthma, eczema, and food allergy in childhood and suggest that timing of exposure in utero may have a role in these associations
Mise en place d’un site atelier interdisciplinaire pour l’évaluation des effets multiples (environnementaux et sociétaux) d’une contamination chimique complexe des écosystèmes aquatiques : le cas d’un petit cours d’eau vosgien (Cleurie)
No full textNational audienceEn France, de nombreux cours d’eau présentent des concentrations en pesticides proches des NQE. Mais les indicateurs biologiques actuels ne permettent pas toujours de révéler les effets de ce type de pression complexe avec des effets subtils (pression faible épisodique, récurrente) ou indirects (effets trophiques…). Des indicateurs plus sensibles doivent donc être développés pour statuer sur les effets toxiques potentiels et évaluer leurs conséquences sur le fonctionnement des écosystèmes.La contamination observée depuis plusieurs années dans la rivière Cleurie constitue un cadre de travail idéal pour étudier ce type de contamination complexe. En raison d’activités industrielles (textiles), ce petit cours d’eau vosgien de tête de bassin versant forestier présente des concentrations élevées de pesticides (dont le glyphosate et son principal produit de dégradation, l’acide aminométhylphosphonique – AMPA) mais inférieures aux normes environnementales. De fortes concentrations d’azurants optiques sont également fréquemment observées, induisant un changement de coloration de l’eau spectaculaire. Les données disponibles, basées sur les indicateurs classiques (diatomées, invertébrés), indiquent pourtant une relativement bonne qualité de l’eau le long du linéaire. Du fait que les rejets soient localisés au niveau d’une zone naturelle d'intérêt écologique (site Natura 2000), que la Cleurie est une rivière très pêchée et que ces entreprises constituent une source essentielle d’emplois dans la vallée, ce site représente un cas d’étude sensible du point de vue socio-économique. Dans ce contexte, ce projet interdisciplinaire vise à évaluer les effets multiples (environnementaux et sociétaux) de la contamination des écosystèmes aquatiques par les pesticides, dans le cadre du site pilote de la Cleurie. Il regroupe les expertises complémentaires de différents partenaires de la Zone Atelier Moselle (ZAM), en écologie et écotoxicologie aquatiques, chimie analytique (matière organique, pesticides), géographie (hydrologie) et sociologie (controverses environnementales). Nos objectifs sont d’identifier des indicateurs/marqueurs globaux permettant de caractériser (1) la pression toxique in situ ainsi que (2) ses effets sur un compartiment clé du milieu aquatique (biofilms) mais également (3) la circulation des savoirs scientifiques produits entre les différents acteurs (scientifiques, pouvoirs publics, citoyens…) impliqués dans une controverse locale mais qui s’inscrit dans celle plus générale et ancienne sur la toxicité des pesticides. Cette présentation portera sur les premiers résultats obtenus dans le cadre de cette approche intégrée
Cyanobacteria and cyanotoxins in estuarine water and sediment
No full textInternational audienceWhile transfer of freshwater cyanobacteria to estuaries has been observed worldwide, the associated transfer of cyanotoxins is less often reported, in particular the sediment contribution. During fall 2018, we monitored the co-occurrence of cyanobacteria and microcystin (MC) in both the water column and in surface sediments at five stations along a river continuum, from a freshwater reservoir to the coastal area in Brittany, France. Cyanobacteria dominated the phytoplankton community in the water column with high densities at the freshwater sites. Microcystis cells and intracellular MC transfer to estuarine and marine sites were observed with decreasing concentrations in accordance with flow dilution. Extracellular MC showed the opposite trend and increased from upstream to downstream in accordance with the lysing of the cells at elevated salinities. Surface sediment samples contained high densities of colonial Microcystis in freshwater and with decreasing concentrations along the salinity gradient, similar to cells concentrations in the water column. Intracellular MC was detected in sediment at all sites except at the marine outlet suggesting the survival of intact cells. Extracellular MC concentrations in sediment were up to five times higher than intracellular concentrations suggesting incomplete MC degradation. mcyB genes were present at all sites, while mcyA genes were absent at the marine outlet suggesting the presence of toxic strains along the estuary. The high densities of intact colonies of potentially toxic Microcystis in the estuarine sediment strongly suggest that sediments can act as an inoculum of cyanobacteria and cyanotoxins in estuaries
Environmental radiofrequency electromagnetic field levels in a department of pediatrics
No full textInternational audiencePreterm neonates constitute a vulnerable population that is highly sensitive to its environment. Given the increased use of wireless communication devices (mobile and digital enhanced cordless telecommunications, WiFi networks, etc.), neonates hospitalized in a department of pediatrics are potentially exposed to radiofrequency electromagnetic fields (RF-EMF). Strikingly, data on RF-EMF levels in pediatric units have not previously been published. The objective of the present study was thus to quantify the RF-EMF levels in a 34-bed tertiary department of pediatrics with a neonatal critical care unit (NCCU) and a neonatal intensive care unit (NICU). To this end, we used triaxle antenna dosimeters to map the RF-EMF levels in the environment and to measure spot emissions from medical devices. In a first set of experiments, RF-EMF levels at 144 points in the staff area and in the children's rooms in the NCCU and NICU were evaluated over a 24-h period. In a second set of measurements performed in a Faraday chamber, we measured the RF-EMF levels emitted by the medical devices to which neonates are potentially exposed in the department of pediatrics. The RF-EMF levels were significantly higher in the NCCU than in the NICU (p < 0.05). Although the two units did not differ significantly with regard to the average maximum values, the single greatest value recorded in the NCCU (6 V/m GSM + UMTS 900 (UL) frequency band, in the staff area) was more than twice that recorded in the NICU (3.70 V/m in the UMTS 2100 (UL) frequency band, in the children's rooms). The NCCU and NICU did not differ significantly with regard to the time during which the RF-EMF level at each measurement point was more than two standard deviations above its mean. The RF-EMF level was significantly higher during the day than during the night (p < 0.001). The various medical devices used in the NICU did not emit detectable amounts of RF. Overall, RF-EMF levels in the NCCU and NICU were very low. It is probable that the RF-EMFs measured here were primarily generated by the parents' and staff members' activities, rather than by medical devices. However, a combination of low-level, chronic exposure with transient, elevated peak values in a vulnerable population of preterm neonates may be of particular concern. In a department of pediatrics, decreasing preterm neonates’ exposure to RF-EMFs should primarily involve a limitation on the use of wireless communication devices by staff members and parents