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Transgenic fish are powerful models that can provide mechanistic information regarding the endocrine activity of test chemicals. In this study, our objective was to use a newly developed transgenic zebrafish line expressing eGFP under the control of the cyp19a1a promoter in the OECD Fish Short Term Reproduction Assay (Test Guideline 229) to provide additional mechanistic information on tested substances. For this purpose, we exposed adult transgenic zebrafish to a reference substance of the TG 229, i.e. prochloraz (PCZ; 1.7, 17.2 and 172.6 µg/L). In addition to “classical” endpoints used in the TG 229 (reproductive outputs, vitellogenin), the fluorescence intensity of the ovaries was monitored at 4 different times of exposure using in vivo imaging. Our data revealed that the highest PCZ concentration significantly decreased the number of eggs laid per female per day and the concentrations of vitellogenin in females, reflecting the decreasing E2 synthesis due to the inhibition of the ovarian aromatase activities. At 7 and 14 days, GFP intensities in ovaries were similar over the treatment groups but significantly increased after 21 days at 17.2 and 172.6 µg/L. A similar profile was observed for the endogenous cyp19a1a expression measured by qPCR thereby confirming the reliability of the GFP measurement for assessing aromatase gene expression. The overexpression of the cyp19a1a gene likely reflects a compensatory response to the inhibitory action of PCZ on aromatase enzymatic activities. These experiments showed that the physiological responses observed in control and PCZ-exposed cyp19a1aeGFP transgenic zebrafish (E2, VTG, reproduction) are similar to those of wild-type zebrafish, both qualitatively and quantitatively. Besides, the cyp19a1a-eGFP model reliably informs on the time- and concentrationdependent effects of PCZ on ovarian aromatase through in vivo GFP fluorescence of the ovaries, thereby providing novel mechanistic information without increasing the number of animals needed. Overall, the cyp19a1a-eGFP transgenic zebrafish line proved to be a relevant model to study the effects of EDCs in fish, which might also be wisely used to refine mechanism-based assays such as OECD TG 229.

International audience; Regulatory assays available from the OECD for the testing of chemicals, such as endocrine disrupting chemicals (EDC) testing (TG229, TG230), can be performed with zebrafish without any recommendation regarding the strain that should be used. In addition to endpoints defined in the TG, transgenic fish could inform on mechanisms underlying EDC effects. By avoiding interference with pigmentation during imaging, use of casper background may improve tests sensitivity. In the present study, we compared 4 zebrafish lines (wild type AB, casper, cyp19a1a-eGFP and cyp19a1a-eGFP-casper) to determine whether transgene insertion and mutations could modify their basal physiology and their response to pollutant, thereby impeding their use for EDC testing. We thus compared the behavior (anxiety, sociability) and reproductive parameters (circulating vitellogenin (VTG) concentrations, female fecundity, egg viability) of control fish of the 4 lines and evaluated their responses to a model pollutant, e.g. clotrimazole. Sociability was evaluated by monitoring the time spent near congeners in a shuttle box while anxiety was evaluated using the novel tank diving test. No difference was observed between lines for either sociability or anxiety level. Concerning reproduction, no significant difference in the number of eggs laid per female, in the viability of eggs or in the female circulating VTG concentrations was noted between the 4 lines studied. Clotrimazole exposure (28 days; 250 µg/L) had similar effects in the 4 zebrafish lines despite a slightly higher sensitivity in wild type AB. Clotrimazole led to a masculinization of one part of the females, an inhibition of VTG, an inhibition of aromatase A expression (GFP measurement and qPCR) and an induction of 11-ketotestosterone. In summary, no critical difference in the behavior, reproductive parameters and response to pollutant was found between the 4 zebrafish lines, indicating that the transgene insertion and the mutations did not modify basal physiology of the fish. Therefore, their use in OECD tests for the study of EDC appears to be relevant. Further work will be conducted on strains sensitivity by evaluating dose-response effects of pollutants.

Within the Water Framework Directive Common Implementation Strategy (WFD CIS) context, the derivation of Environmental Quality Standards (EQS) is framed by recommendations given in the European Technical Guidance Document for Deriving EQS (TGD EQS, E.C., 2018). This guidance recommends the use of data that are deemed relevant and reliable. Those are most often generated using standardised test methods, but not confined to standard studies and species. The concern raised by endocrine disruption should be tackled in diverse regulatory frameworks, among which the WFD. In this context, endocrine disruption (ED) is quoted several times as an issue in the TGD EQS but recommendations as this regards are not prescriptive. Our study attempts to assess how far can the ECHA/EFSA Guidance for the identification of endocrine disruptors (ECHA/EFSA, 2018) and its weight of evidence approach may be used within the context of the derivation of EQS for tebuconazole.The work consisted in (i) gathering ED toxicity data for aquatic wildlife and mammals not included in the initial dataset underlying the current EQS, (ii) assembling them in a database as lines of evidence of toxicity adressing endocrine activity in order to assess as rigorously as possible the ED potential of tebuconazole and finally (iii) analysing these data to evaluate how far they allowed to improve reliability of the current EQS for tebuconazole.The collection of data allowed to assemble more than 200 lines of evidence consisting in vivo mammals data (52%), in vivo wildlife data (34%) and in vitro mechanistics data (14%).The assessment did not allow to conclude on the ED potential of tebuconazole for wildlife strictly applying the guidance, whereas this ED potential was demonstrated for mammals for which at least two modes of action analysis enabled to conclude on the link between endocrine activity and adversity.Wildlife toxicity assessment would need more in-depth analysis, inter alia to collate and analyse invertebrates toxicity data in order to assess other taxa than fish and amphibians which are already well-represented in the dataset.This analysis allowed implementation of the weight of evidence approach of non-standard toxicity test within the assessment in order to strenghten relevancy and reliability of its EQS. It gives a good opportunity to evaluate how ECHA/EFSA guidance may be used in another regulatory context for which it is meant and allows highlighting the pros and cons of this exercise.

International audience; Given the large number of mobile phone users and the increasing exposure to radiofrequency electromagnetic field (RF-EMF) worldwide, we aimed to study the effect of RF-EMF related to mobile phones on heart rate variability (HRV). Twenty-six healthy young adults participated in two experimental sessions with a double-blind, randomized and counter-balanced crossover design. During each session, participants were exposed for 26 min to a sham or real 900 MHz RF-EMF, generated by a commercial dual-band Global System for Mobile technology (GSM) mobile phone. We recorded an electrocardiogram at rest during the exposure. We evaluated HRV by time- and frequency-domain analysis. Evaluation of time-domain HRV parameters revealed a statistically significant increase of the standard deviation of interbeat intervals (SDNN) during the real exposure. Other time-domain parameters were not affected. Analysis in the frequency-domain demonstrated that total spectral power and low-frequency band (LF) absolute power were significantly increased during exposure (p = .046 and p = .043, respectively). However, other parameters were not affected. In conclusion, it seems that most HRV parameters were not affected by GSM signal exposure in our study. The weak effect observed on HRV frequency-domain is likely to represent a random occurrence rather than a real effect.

Corrigendum: Aquatic Toxicology, Volume 247, June 2022, Pages 106166 https://doi.org/10.1016/j.aquatox.2022.106166 WOS:000799284400001; International audience; Transgenic fish are powerful models that can provide mechanistic information regarding the endocrine activity of test chemicals. In this study, our objective was to use a newly developed transgenic zebrafish line expressing eGFP under the control of the cyp19a1a promoter in the OECD Fish Short Term Reproduction Assay (TG 229) to provide additional mechanistic information on tested substances. For this purpose, we exposed adult transgenic zebrafish to a reference substance of the TG 229, i.e. prochloraz (PCZ; 1.7, 17.2 and 172.6 μg/L). In addition to “classical” endpoints used in the TG 229 (reproductive outputs, vitellogenin), the fluorescence intensity of the ovaries was monitored at 4 different times of exposure using in vivo imaging. Our data revealed that 172.6 μg/L PCZ significantly decreased the number of eggs laid per female per day and the concentrations of vitellogenin in females, reflecting the decreasing E2 synthesis due to the inhibition of the ovarian aromatase activities. At 7 and 14 days, GFP intensities in ovaries were similar over the treatment groups but significantly increased after 21 days at 17.2 and 172.6 μg/L. A similar profile was observed for the endogenous cyp19a1a expression measured by qPCR thereby confirming the reliability of the GFP measurement for assessing aromatase gene expression. The overexpression of the cyp19a1a gene likely reflects a compensatory response to the inhibitory action of PCZ on aromatase enzymatic activities. Overall, this study illustrates the feasibility of using the cyp19a1a-eGFP transgenic line for assessing the effect of PCZ in an OECD test guideline while providing complementary information on the time- and concentration-dependent effects of the compound, without disturbing reproduction of fish. The acquisition of this additional mechanistic information on a key target gene through in vivo fluorescence imaging of the ovaries was realized without increasing the number of individuals.

Communication technologies based on radiofrequency (RF) propagation bring great benefits to our daily life. However, their rapid expansion raises concerns about possible impacts on public health. At intensity levels below the threshold to produce thermal effects, RF exposure has also recently been reported to elicit biological effects, resembling reactions to cold. The objective of the present study was to investigate the effects of non-thermal RF on body temperature in mice and the related mechanisms. 3-months-old C57BL/6 J mice were exposed to a continuous RF signal at 900 MHz, 20 ± 5 V.m−1 for 7 consecutive days, twice per day during the light phase, for one hour each time. The SAR was 0.16 ± 0.10 W.kg−1. We showed that body temperature patterns in mice change synchronously with the RF exposure periods. Average body temperature in the light phase in the exposed group was higher than in the control group. The expression of the TRPM8 gene was not affected by RF in trigeminal ganglia. Furthermore, the injection of a TRPM8 antagonist did not induce a temperature decrease in exposed mice, as this was the case for sham-controls. These findings indicate that 900 MHz RF exposure at non-thermal level produce a physiological effect on body temperature in mice. However, the involvement of TRPM8 receptors in the mechanism by which RF induced changes in body temperature of mice which remains to be further explored. It must then be assessed if this effect is extrapolable to man, and if this could lead to consequences on health.

(1) Background: Mercury is a threat for the aquatic environment. Nonetheless, the entrance of Hg into food webs is not fully understood. Macrophytes are both central for Hg entry in food webs and are seen as good candidates for biomonitoring and bioremediation; (2) Methods: We review the knowledge gained on the uptake and effects of inorganic Hg (IHg) and methyl-Hg (MMHg) in the macrophyte Elodea nuttallii found in temperate freshwaters; (3) Results: E. nuttallii bioaccumulates IHg and MMHg, but IHg shows a higher affinity to cell walls. At the individual level, IHg reduced chlorophyll, while MMHg increased anthocyanin. Transcriptomics and metabolomics in shoots revealed that MMHg regulated a higher number of genes than IHg. Proteomics and metabolomics in cytosol revealed that IHg had more effect than MMHg; (4) Conclusions: MMHg and IHg show different cellular toxicity pathways. MMHg’s main impact appears on the non-soluble compartment, while IHg’s main impact happens on the soluble compartment. This is congruent with the higher affinity of IHg with dissolved OM (DOM) or cell walls. E. nuttallii is promising for biomonitoring, as its uptake and molecular responses reflect exposure to IHg and MMHg. More generally, multi-omics approaches identify cellular toxicity pathways and the early impact of sublethal pollution.

International audience; AIMS: Metformin exerts anti-inflammatory and immunosuppressive effects. We addressed the impact of prior metformin use on prognosis in patients with type 2 diabetes hospitalised for COVID-19. METHODS: CORONADO is a nationwide observational study that included patients with diabetes hospitalised for COVID-19 between March 10 and April 10, 2020 in 68 French centres. The primary outcome combined tracheal intubation and/or death within 7 days of admission. A Kaplan-Meier survival curve was reported for death up to day 28. The association between metformin use and outcomes was then estimated in a logistic regression analysis after applying a propensity score inverse probability of treatment weighting approach. RESULTS: Among the 2449 patients included, 1496 were metformin users and 953 were not. Compared with non-users, metformin users were younger with a lower prevalence of diabetic complications, but had more severe features of COVID-19 on admission. The primary endpoint occurred in 28.0% of metformin users (vs 29.0% in non-users, P = 0.6134) on day 7 and in 32.6% (vs 38.7%, P = 0.0023) on day 28. The mortality rate was lower in metformin users on day 7 (8.2 vs 16.1%, P \textless 0.0001) and on day 28 (16.0 vs 28.6%, P \textless 0.0001). After propensity score weighting was applied, the odds ratios for primary outcome and death (OR [95%CI], metformin users vs non-users) were 0.838 [0.649-1.082] and 0.688 [0.470-1.007] on day 7, then 0.783 [0.615-0.996] and 0.710 [0.537-0.938] on day 28, respectively. CONCLUSION: Metformin use appeared to be associated with a lower risk of death in patients with diabetes hospitalised for COVID-19.

BackgroundData on the effects of extremely low frequency electromagnetic fields (ELF-EMF) on pregnancy outcomes are inconclusive.ObjectiveTo study the relation between maternal cumulative exposure to ELF-EMF during pregnancy and the risk of prematurity or small for gestational age (SGA) in a pooled analysis of two French birth cohorts.MethodsElfe and Epipage2 are both population-based birth cohorts initiated in 2011 and included 18 329 and 8400 births, respectively. Health data and household, mother and child characteristics were obtained from medical records and questionnaires at maternity and during follow-up. A job exposure matrix was used to assess cumulative exposure to ELF-EMF during three periods: (1) until 15 weeks of gestation, (2) until 28 weeks of gestation and (3) until 32 weeks of gestation. Analyses were restricted to single live births in mainland France and to mothers with documented jobs (N=19 894). Adjusted logistic regression models were used.ResultsAccording to the period studied, 3.2%–4% of mothers were classified as highly exposed. Results were heterogeneous. Increased risks of prematurity were found among low exposed mothers for the three periods, and no association was observed among the most exposed (OR1=0.92 (95% CI 0.74 to 1.15); OR2=0.98 (95% CI 0.80 to 1.21); OR3=1.14 (95% CI 0.92 to 1.41)). For SGA, no association was observed with the exception of increased risk among the low exposed mothers in period 2 and the most exposed in period 3 (OR=1.25 (95% CI 1.02 to 1.53)).ConclusionSome heterogeneous associations between ELF-EMF exposure and prematurity and SGA were observed. However, due to heterogeneity (ie, their independence regarding the level of exposure), associations cannot be definitely explained by ELF-EMF exposure.

International audience; Le croisement des deux approches - mesure biologique et modélisation - doit être mené conjointement afin de permettre l’amélioration de l’efficacité des outils d’aide à la décision pour réduire les expositions.

The World Health Organization and the French Health Safety Agency (ANSES) recognize that the expressed pain and suffering of electromagnetic field hypersensitivity syndrome (EHS) people are a lived reality requiring daily life adaptations to cope. Mechanisms involving glutamatergic N-methyl d-aspartate (NMDA) receptors were not explored yet, despite their possible role in hypersensitivity to chemicals. Here, we hypothesized that radiofrequency electromagnetic field (RF-EMF) exposures may affect pain perception under a modulatory role played by the NMDA receptor. The rats were exposed to RF-EMF for four weeks (five times a week, at 0 (sham), 1.5 or 6 W/kg in restraint) or were cage controls (CC). Once a week, they received an NMDA or saline injection before being scored for their preference between two plates in the two-temperatures choice test: 50 &deg, C (thermal nociception) versus 28 &deg, C. Results in the CC and the sham rats indicated that latency to escape from heat was significantly reduced by &minus, 45% after NMDA, compared to saline treatment. Heat avoidance was significantly increased by +40% in the 6 W/kg, compared to the sham exposed groups. RF-EMF effect was abolished after NMDA treatment. In conclusion, heat avoidance was higher after high brain-averaged specific absorption rate, affording further support for possible effect of RF-EMF on pain perception. Further studies need to be performed to confirm these data.

BackgroundBreast cancer is the most frequent cancer in women in industrialized countries. Lifestyle and environmental factors, particularly endocrine-disrupting pollutants, have been suggested to play a role in breast cancer risk. Current epidemiological studies, although not fully consistent, suggest a positive association of breast cancer risk with exposure to several International Agency for Research on Cancer Group 1 air-pollutant carcinogens, such as particulate matter, polychlorinated biphenyls (PCB), dioxins, Benzo[a]pyrene (BaP), and cadmium. However, epidemiological studies remain scarce and inconsistent. It has been proposed that the menopausal status could modify the relationship between pollutants and breast cancer and that the association varies with hormone receptor status. ObjectiveThe XENAIR project will investigate the association of breast cancer risk (overall and by hormone receptor status) with chronic exposure to selected air pollutants, including particulate matter, nitrogen dioxide (NO2), ozone (O3), BaP, dioxins, PCB-153, and cadmium. MethodsOur research is based on a case-control study nested within the French national E3N cohort of 5222 invasive breast cancer cases identified during follow-up from 1990 to 2011, and 5222 matched controls. A questionnaire was sent to all participants to collect their lifetime residential addresses and information on indoor pollution. We will assess these exposures using complementary models of land-use regression, atmospheric dispersion, and regional chemistry-transport (CHIMERE) models, via a Geographic Information System. Associations with breast cancer risk will be modeled using conditional logistic regression models. We will also study the impact of exposure on DNA methylation and interactions with genetic polymorphisms. Appropriate statistical methods, including Bayesian modeling, principal component analysis, and cluster analysis, will be used to assess the impact of multipollutant exposure. The fraction of breast cancer cases attributable to air pollution will be estimated. ResultsThe XENAIR project will contribute to current knowledge on the health effects of air pollution and identify and understand environmental modifiable risk factors related to breast cancer risk. ConclusionsThe results will provide relevant evidence to governments and policy-makers to improve effective public health prevention strategies on air pollution. The XENAIR dataset can be used in future efforts to study the effects of exposure to air pollution associated with other chronic conditions. International Registered Report Identifier (IRRID)DERR1-10.2196/15167

The quality and relevance of nanosafety studies constitute major challenges to ensure their key role as a supporting tool in sustainable innovation, and subsequent competitive economic advantage. However, the number of apparently contradictory and inconclusive research results has increased in the past few years, indicating the need to introduce harmonized protocols and good practices in the nanosafety research community. Therefore, we aimed to evaluate if best-practice training and inter-laboratory comparison (ILC) of performance of the 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay for the cytotoxicity assessment of nanomaterials among 15 European laboratories can improve quality in nanosafety testing. We used two well-described model nanoparticles, 40-nm carboxylated polystyrene (PS-COOH) and 50-nm amino-modified polystyrene (PS-NH2). We followed a tiered approach using well-developed standard operating procedures (SOPs) and sharing the same cells, serum and nanoparticles. We started with determination of the cell growth rate (tier 1), followed by a method transfer phase, in which all laboratories performed the first ILC on the MTS assay (tier 2). Based on the outcome of tier 2 and a survey of laboratory practices, specific training was organized, and the MTS assay SOP was refined. This led to largely improved intra- and inter-laboratory reproducibility in tier 3. In addition, we confirmed that PS-COOH and PS-NH2 are suitable negative and positive control nanoparticles, respectively, to evaluate impact of nanomaterials on cell viability using the MTS assay. Overall, we have demonstrated that the tiered process followed here, with the use of SOPs and representative control nanomaterials, is necessary and makes it possible to achieve good inter-laboratory reproducibility, and therefore high-quality nanotoxicological data. European Commission | Ref. EC FP7 QualityNano (INFRA-2010-1.1.31- 262163) Fonds National de la Recherche of Luxembourg | Ref. NANION (FNR / 12 / SR / 4009651) Direction générale opérationnelle de l’Economie, de l’Emploi et de la Recherche (Walloon, Belgium) | Ref. ‘QNano’ (2011-14) n. 1117448 Norwegian Research Council | Ref. NorNANoREG 239199/070

The absorption of exposure to radiofrequency (RF) emitted by wireless devices leads to a high specific absorption rate in the skin. Ultraviolet (UV) radiation can induce several damages to the skin. The aim of this study was to examine whether combined, consecutive exposure to solar UV radiation and 1950 MHz RF exposure of third generation (3G) mobile system have any effect on inflammation processes in the skin. Under in vitro experiments, the inflammation process was examined by cytokines (IL-1&alpha, IL-6, and IL-8) and MMP-1 enzyme secretion on 3D full thickness human skin model. The RF exposure was applied before or after UV irradiation, in order to study either the possible cooperative or protective effects of exposure to RF and UV. We did not find changes in cytokines due to exposure to RF alone. The RF exposure did not enhance the effects of UV radiation. There was a statistically not-significant decrease in cytokines when the skin tissues were pre-exposed to RF before being exposed to 4 standard erythemal dose (SED) UV compared to UV exposure alone. We found that RF exposure reduced the previously UV-treated MMP-1 enzyme concentration. This study might support the evaluation of the effects on the skin exposed to microwave radiation of 5G mobile technology.

High-power microwaves are used to inhibit electronics of threatening military or civilian vehicles. This work aims to assess health hazards of high-power microwaves and helps define hazard threshold levels of modulated radiofrequency exposures such as those emitted by the first generations of mobile phones.Rats were exposed to the highest possible field levels, under single acute or repetitive exposures for eight weeks. Intense microwave electric fields at 1 MV/m of nanoseconds duration were applied from two sources at different carrier frequencies of 10 and 3.7 GHz. The repetition rate was 100 pps, and the duration of train pulses lasted from 10 s to twice 8 min. The effects were studied on the central nervous system, by labelling brain inflammation marker GFAP and by performing different behavioural tests: rotarod, T-maze, beam-walking, open-field, and avoidance test. Long-time survival was measured in animals repeatedly exposed, and anatomopathological analysis was performed on animals sacrificed at two years of life or at death if earlier. One group was sham exposed.Few effects were observed on behaviour. With acute exposure, an avoidance reflex was shown at very high, thermal level (22 W/kg); GFAP was increased some days after exposure. Most importantly, with repeated exposures, survival time was 4-month shorter in the exposed group, with eleven animals exhibiting a large sub-cutaneous tumour, compared to two in the sham group. A residual X-ray exposure was also present in the beam (0.8 Gy), which is not a bias for the observed result.High power microwaves below thermal level in average, can increase cancer incidence and decrease survival time in rats, without clear effects on behaviour. The parameters of this effect need to be explored further, and a more precise dosimetry to be performed.

Pharmaceutical substances are ubiquitous in the aquatic environment and their concentration levels typically range from ng/L up to several μg/L. Furthermore, as those compounds are designed to be highly biologically active, assessing their impacts on non-target organisms is important. Here, we conducted a mesocosm experiment testing a mixture of five pharmaceuticals (diclofenac, carbamazepine, irbesartan, acetaminophen and naproxen) on fish, three-spined stickleback (Gasterosteus aculeatus). The mixture concentration levels were chosen on the basis of the contamination of the Meuse river in Belgium which had been measured previously during a monitoring campaign undertaken in 2015 and 2016. Three nominal mixture concentration levels were tested: the lowest concentration level mixture was composed by environmentally-relevant concentrations that approximate average realistic values for each pharmaceuticals (Mx1); the two other levels were 10 and 100 times these concentrations. Although no impact on stickleback prey was observed, the mixture significantly impaired the survival of female fish introduced in the mesocosms at the highest treatment level without causing other major differences on fish population structure. Impacts on condition factors of adults and juveniles were also observed at both individual and population levels. Using a modelling approach with an individual-based model coupled to a bioenergetic model (DEB-IBM), we concluded that chronic exposure to environmentally-relevant concentrations of five pharmaceuticals often detected in the rivers did not appear to strongly affect the three-spined stickleback populations. Mechanisms of population regulation may have counteracted the mixture impacts in the mesocosms.

International audience; Background: There are few data concerning patients with Crohn's disease (CD) complicated by a stricture of the upper gastrointestinal tract (UGT). Aims: We evaluated the outcome and management of CD patients complicated by a stricture of the UGT. Methods: We performed a retrospective multicenter study including all CD patients with a non-passable symptomatic UGT stricture on endoscopy. Primary outcome measure was surgery-free survival from diagnosis of stricture. Efficacy of medical, endoscopic, and surgical treatments, and identification of predictors of surgery were also evaluated. Results: 60 CD patients with an UGT stricture were included. 60% of the strictures were located in the duodenum. With a median follow-up of 5.5 (IQR: 3.0-12.0) years since stricture diagnosis, surgical-free survival was 75% and 64% at 1 and 5 years, respectively. At the end of the follow up, 27 (45%) patients underwent surgery. 77 endoscopic procedures were performed in 30 patients with an immediate success of 81% and a clinical benefit in 84% of the procedures. In multivariate analysis, anti-TNF treatment initiation was associated with a reduced risk of surgery. Conclusion: CD UGT strictures are mainly located in the duodenum. Medical and endoscopic treatments allow to avoid surgery in half of the patients (C) 2020 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

Background Alzheimer's disease (AD) is the most common type of neurodegenerative disease leading to dementia. Several studies suggested that mobile phone radiofrequency electromagnetic field (RF-EMF) exposures modified AD memory deficits in rodent models. Objective Here we aimed to test the hypothesis that RF-EMF exposure may modify memory through corticosterone and oxidative stress in the Samaritan rat model of AD. Methods Long-Evans male rats received intracerebroventricular infusion with ferrous sulphate, amyloid-beta 1-42 peptide, and buthionine-sufloximine (AD rats) or with vehicle (control rats). To mimic cell phone use, RF-EMF were exposed to the head for 1 month (5 days/week, in restraint). To look for hazard thresholds, high brain averaged specific absorption rates (BASAR) were tested: 1.5 W/Kg (15 min), 6 W/Kg (15 min), and 6 W/Kg (45 min). The sham group was in restraint for 45 min. Endpoints were spatial memory in the radial maze, plasmatic corticosterone, heme oxygenase-1 (HO1), and amyloid plaques. Results Results indicated similar corticosterone levels but impaired memory performances and increased cerebral staining of thioflavine and of HO1 in the sham AD rats compared to the controls. A correlative increase of cortical HO1 staining was the only effect of RF-EMF in control rats. In AD rats, RF-EMF exposures induced a correlative increase of hippocampal HO1 staining and reduced corticosterone. Discussion According to our data, neither AD nor control rats showed modified memory after RF-EMF exposures. Unlike control rats, AD rats showed higher hippocampal oxidative stress and reduced corticosterone with the higher BASAR. This data suggests more fragility related to neurodegenerative disease toward RF-EMF exposures.

In this paper we consider the transport of a chemical species in a two phase system with exchange of matter at the interface (so-called active dispersion). The boundary conditions at the interface between the two phases existing within the pore space are either of thermodynamic equilibrium or of reactive type. Saturation changes with the exchange of matter at the interface. The medium itself is characterized by different levels of heterogeneity starting from the pore-scale. In this work, problems related to pore-scale to Darcy-scale upscaling and then to Darcy-scale to Large-scale upscaling are considered. The first upscaling [1] leads to different problems depending on the boundary conditions and various assumptions, in particular the role of the total mass exchange rate, non-standard terms, etc. The role of geometry, reaction rate on dispersion and tortuosity is investigated for simple 1D/2D/3D unit cells. The second upscaling is only considered for the case of a local non-equilibrium Darcyscale model in the case of small variations of density and viscosity with concentration. It leads to a complex coupled problem between Darcy-scale deviations and large-scale averaged values. In particular, the solution exhibits memory and history effects. An algorithm is proposed to solve for the case of small Damköhler numbers (the Diffusive Damköler for low Péclet numbers or the convective Damköhler for high Péclet numbers). The resulting large-scale model is of the non-equilibrium type. The algorithm allows for the calculation of large-scale effective properties such as large-scale relative permeability, large-scale mass exchange coeffcients as a function of the large-scale phase saturation. References [1] J. Guo, M. Quintard and F. Laouafa, Dispersion in Porous Media with Heterogeneous Nonlinear Reactions, Transport in Porous Media, 109, pp. 541-570, 2015.

International audience; The development of predictive, sensitive and reliable biomarkers is of crucial importance for aquatic biomonitoring to assess the effects of chemical substances on aquatic organisms, especially when it comes to combined effects with other stressors (e.g. temperature). The first purpose of the present study was to evaluate the single and combined effects of 90 days of exposure to an environmental cadmium concentration (0.5 μg. L−1) and two water temperatures (16 and 21 °C) on different parameters. These parameters are involved in (i) the antioxidant system (superoxide dismutase activity –SOD– and total glutathione levels –GSH–), (ii) the energy metabolism, i.e. energy reserves (glycogen, lipids, proteins) and digestive enzymes (trypsin, amylase, intestinal alkaline phosphatase–IAP–), and (iii) biometric parameters (weight, length, Fulton’s condition factor, and the gonadosomatic index –GSI–) of threespine stickleback (Gasterosteus aculeatus). The second purpose was to determine the interest of the three digestive enzymes as biomarkers in comparison with the other parameters. The higher temperature (21 °C) impacted the anti-oxidant and energy reserve parameters. In liver, GSH levels increased on day 60, while SOD decreased on days 15 and 90, with a significant decrease of protein and lipid energy reserves on day 90. In muscle, the higher temperature decreased SOD activity only on day 90. G. aculeatus biometric parameters were also impacted by the higher temperature, which limited stickleback growth after 90 days of exposure. In female sticklebacks, the GSI peaked on day 60 and decreased sharply on day 90, while the highest values were reached at day 90 in the control groups, suggesting impaired reproduction in sticklebacks raised at 21 °C. These results suggest that 21 °C is an upper-limit temperature for long-term physiological processes in sticklebacks. In contrast, very low-concentration cadmium exposure had no effect on classical biomarkers (energy reserves, antioxidant parameters, biometric parameters). However, digestive enzymes showed an interesting sensitivity to cadmium, which was emphasized by high temperature. The activity of the three digestive enzymes decreased significantly on day 90 when sticklebacks were exposed to cadmium alone, while the decrease was stronger and was recorded earlier (from day 15) when they were exposed to the cadmium-temperature combination. Compared to conventional measurements, digestive enzymes responded rapidly. This could be an important advantage for them to be used as early warning tools to reflect the health status of organisms, particularly for trypsin and IAP activities.

International audience; It is prerequisite to characterize nanoparticles in dispersions in particular with respect to their size and size distribution before they can be used in toxicological testing. This requires robust methods with high reproducibility. The aim of this study was to apply interlaboratory comparisons using Dynamic Light Scattering (DLS), in order to evaluate the reproducibility of nanoparticle size determinations. DLS is well established in most nanotoxicological laboratories. Due to the fact that this technique appears easy to use it has become a standard technique nowadays. Still, reproducibility and in particular differences between different commercial instruments have not been addressed systematically before. Our aim was to develop a robust standard operating procedure (SOP). Therefore, at the beginning, experiments were performed with dispersions of rather monodisperse and spherical particles in water. Significant differences were observed between the results obtained with different commercial instruments for DLS, especially when fitting the data using mathematical inversion methods. As a consequence of the different settings applied when fitting the data, significant errors could be made especially when working with dilute dispersions of very small particles. Here we have identified options how to overcome possible issues. However, It should be noted, that in practice, nanoparticles may have significant polydispersities and/or be non-spherical. The potential of the DLS technique in this situation should be noted that in nanoparticles may have significant polydispersities and/or be non-spherical. The potential of the DLS technique in this situation is evaluated. A combination of two different techniques (DLS and electron microscopy for instance) is recommended to fully interpret the results.

Safety testing of nanoparticles (NPs) relies on robust, predictive, and reproducible methods. Integrated test strategies usually start with the assessment of in vitro cytotoxicity. Methods for this purpose are only partially established for NPs. The aim of this study was to evaluate three cytotoxicity assays for their applicability to NPs in several human cell models representing the most important NP target organs and to compare cell responses. The assays covered different biological principles, i.e. ATP content, redox metabolism, and membrane permeability, as well as different read-out principles, i.e. luminescence, colorimetry, and fluorescence. For all assays standard operating procedures were developed. A549 and NCI-H441 lung epithelial cells in single and in co-culture with THP-1 derived macrophages served as lung epithelial models. Normal human epidermal keratinocytes and in vitro reconstituted human epidermis were employed as skin models. Undifferentiated and differentiated Caco-2 gut epithelial cells were applied as gut epithelial models. Primary CD34-derived dendritic cells (CD34-DCs) served as an immune model. We used well-characterized model NPs, i.e. 50 nm amine-modified and 50 nm carboxyl-modified polystyrene NPs (PS-NH2 and PS-COOH, respectively). PS-COOH NPs showed no effect in any test while PS-NH2 displayed cytotoxicity in most cell models. CD34-DCs was the most sensitive cell model tested. The tetrazolium-based MTS assay was the most robust assay in our study, applicable to all cell models investigated. Therefore, this assay could become an integral part of a NP testing strategy. Other assays might be also useful, depending on the cell model or the type of investigation.

International audience; The relevance of a biomarker for biomonitoring programs was influenced both by the knowledge on biomarker natural inter-individual and site variabilities and by the sensitivity of the biomarker towards environmental perturbations. To minimize data misinterpretation, robustness reference values for biomarkers were important in biomonitoring programs. Specific three-spined stickleback, Gasterosteus aculeatus, immune reference ranges for field studies had been determined based on laboratory data and one reference station (Contentieuse river at Houdancourt). In this study, data obtained in one uncontaminated and three contaminated sites were compared to these reference ranges as a validation step before considering them for larger scale biomonitoring programs. When the field reference range were compared to data from the uncontaminated station (Béronelle), only few deviations were shown. In this way, data coming from uncontaminated station (Béronelle) was integrated in the field reference ranges to improve the evaluation of site variability. The new field reference ranges provided better discrimination of sites and spanned a larger range of fish lengths than the initial reference ranges. Furthermore, the results suggest lysosomal presence during several months and phagocytosis capacity in autumn may be the most relevant immunomarkers towards identifying contaminated sites. In the future, combining this reference value approach with active biomonitoring could facilitate the obtention of data in multiple stream conditions.

International audience; Aquatic organisms are exposed to mixtures of chemicals that may interact. Mixtures of atrazine (ATR) and chlorpyrifos (CPF) may elicit synergic effects on the permanent inhibition of acetylcholinesterase (AChE) in certain aquatic organisms, causing severe damage. Mechanistic mathematical models of toxicokinetics and toxicodynamics (TD) may be used to better characterize and understand the interactions of these two chemicals. In this study, a previously published generic physiologically-based toxicokinetic (PBTK) model for fish was adapted to ATR and CPF. A sub-model of the kinetics of one of the main metabolites of CPF, chlorpyrifos-oxon (CPF-oxon), was included, as well as a TD model. Inhibition of two esterases, AChE and carboxylesterase, by ATR, CPF and CPF-oxon, was modeled using TD modeling of quantities of total and inactive esterases. Specific attention was given to the parameterization and calibration of the model to accurately predict the concentration and effects observed in the fish using Bayesian inference and published data from fathead minnow (Pimephales promelas), zebrafish (Dunn) rerio) and common carp (Cyprinus carpio L.). A PBTK-TD for mixtures was used to predict dose-response relationships for comparison with available adult fish data. Synergistic effects of a joint exposure to ATR and CPU could not be demonstrated in adult fish.

International audience; Acer 35 EC is a widely used insecticide (a binary mixture of lambda-cyhalothrin and acetamiprid) in pest control in many West African countries, particularly in the cotton culture in north Benin. The aim of this study was to investigate the chronic effects of Acer 35 EC on Nile tilapia Oreochromis niloticus juveniles using a multi-biomarker approach under laboratory conditions. For this purpose, fish were exposed to sublethal concentrations of Acer 35 EC (0, 1 and 10% of LC50- 96 h value). After 28 and 56 days of exposure, several biomarkers were measured in males and females including enzymatic activities related to detoxification and oxidative stress, neurotoxicity and immune responses, sex steroid hormones (testosterone, 17β-estradiol and 11-keto-testosterone) and histological alterations of liver, kidney and gonads. An Integrated Biomarker Response (IBR) was then calculated. The results showed a reduction of cholinesterase activity in muscles, and intercellular superoxide anion production in both sexes. Female steroidogenesis and gametogenesis were affected, especially testosterone levels and oocyte growth. More alterations were observed in liver after exposure to Acer 35 EC. In both sexes, IBR values were higher after 56 days than after 28 days of exposure. In conclusion, based on a large set of biomarkers and IBR values, the chronic exposure to low doses of insecticide Acer 35 EC seems to impair different physiological functions in Nile tilapia juveniles on a time-dependent manner, with a stronger impact on females than on males.

Adverse outcome pathways (AOPs) are a recent toxicological construct that connects, in a formalized, transparent and quality-controlled way, mechanistic information to apical endpoints for regulatory purposes. AOP links a molecular initiating event (MIE) to the adverse outcome (AO) via key events (KE), in a way specified by key event relationships (KER). Although this approach to formalize mechanistic toxicological information only started in 2010, over 200 AOPs have already been established. At this stage, new requirements arise, such as the need for harmonization and re-assessment, for continuous updating, as well as for alerting about pitfalls, misuses and limits of applicability. In this review, the history of the AOP concept and its most prominent strengths are discussed, including the advantages of a formalized approach, the systematic collection of weight of evidence, the linkage of mechanisms to apical end points, the examination of the plausibility of epidemiological data, the identification of critical knowledge gaps and the design of mechanistic test methods. To prepare the ground for a broadened and appropriate use of AOPs, some widespread misconceptions are explained. Moreover, potential weaknesses and shortcomings of the current AOP rule set are addressed (1) to facilitate the discussion on its further evolution and (2) to better define appropriate vs. less suitable application areas. Exemplary toxicological studies are presented to discuss the linearity assumptions of AOP, the management of event modifiers and compensatory mechanisms, and whether a separation of toxicodynamics from toxicokinetics including metabolism is possible in the framework of pathway plasticity. Suggestions on how to compromise between different needs of AOP stakeholders have been added. A clear definition of open questions and limitations is provided to encourage further progress in the field. © 2017, Springer-Verlag GmbH Germany.

International audience; The global dynamic spread of chemical contamination through the aquatic environment calls for the development of biomarkers of interest. Reproduction is a key element to be considered because it is related to the sustainability of species. Spermatogenesis is a complex process that leads to the formation of mature germ cells, whose steps and impairments need to be finely described in ecotoxicological analyses. The physiological process has been commonly described by histological analyses of gonads in different taxa. In the present paper, we describe the development of a novel technique to characterize spermatogenesis based on the analysis of the DNA content of germ cells by flow cytometry, using a DNA-intercalating agent. This new biomarker, referred to as an index of sexual maturity, proved relevant to describe the seasonal reproductive cycle of the zebra mussel, Dreissena polymorpha (Pallas, 1771), used as a sentinel species in the biomonitoring of continental waters and sensitive to highlight the reprotoxicity of carbamazepine (an anti-epileptic pharmaceutical) tested under ecosystemic conditions (mesocosms).

Contamination of aquatic ecosystems is considered as one of the main threats to global freshwater biodiversity. Within the European Water Framework Directive (EU-WFD) a particular attention is dedicated to assess ecological risks of surface water contamination and mitigation of chemical pressures on aquatic ecosystems. In this work, we evaluated ecological risks of surface water contamination for fish populations in four EU-WFD rivers through an integrative approach investigating three Lines of Evidence (chemical contamination, biomarker responses as early warning signals of contamination impacting individuals and ecological analyses as an indicator of fish community disturbances). This work illustrates through 4 case studies the complementary role of biomarkers, chemical and ecological analyses which, used in combination, provide fundamental information to understand impacts of chemical pressures that can affect fish population dynamics. We discuss the limitations of this approach and future improvements needed within the EU-WFD to assess ecological risk of river contamination for fish populations.

International audience; Tracer tests are frequently used to delineate catchment area of water supply springs in karstic zones. In the karstic chalk of Normandy, the main tracers used are fluorescent: uranine, sulforhodamine B, naphtionate, and Tinopal®. In this area, a statistical analysis shows that less than half of the injected tracers joins the monitored restitution points and enters the drinking water system where they undergo chlorination. Most of the injected tracers is absorbed in the rock matrix or is thrown out of the aquifer via karstic springs: then it can join superficial waters where it is degraded due to the sun and air action. The paper presents firstly the laboratory degradation of a first batch of fluorescent tracers in contact with chlorine, in order to simulate their passage through a water treatment system for human consumption. A second batch of the same tracers is subjected to agents of natural degradation: ultraviolet illumination, sunlight and air sparging. Most tracers is degraded, and toxicity and ecotoxicity tests (on rats, daphniae and algae) are performed on degradation byproducts. These tests do not show any acute toxicity but a low to moderate ecotoxicity. In conclusion, the most used fluorescent tracers of the Normandy karstic chalk and their artificial and natural degradation byproducts do not exhibit significant toxicity to humans and the aquatic environment, at the concentrations generally noted at the restitution points.

Contexte : Les données spatiales environnementales produites dans le cadre de projets de recherche, de la surveillance des milieux ou des populations peuvent être réutilisées pour évaluer l’exposition des populations sur les territoires. Pour une caractérisation fine des expositions environnementales, un premier verrou réside dans la capacité à rassembler au sein d'un même système d’analyse un ensemble de données combinant le mode de vie des populations et la contamination locale des milieux environnementaux sur des résolutions spatiales appropriées et des territoires étendus (échelles régionales). Méthodes : L’objectif est de décliner sur les territories une approche intégrée de modélisation de l’exposition aux substances chimiques sur des résolutions spatio-temporelles fines. D'une part, elle permet d’intégrer des bases de données environnementales (eau, air, sol, alimentation) et de les agréger sur des supports géographiques communs. D'autre part, elle permet d'estimer l’exposition des populations jusqu'à l'exposition interne à l'organe cible à partir du croisement des modèles de transport, de transfert, d'exposition multimedia et toxicocinétique pour caractériser le continuum source-environnement-homme. Résultats : Pour illustrer cette approche, le cas d'étude porte sur l'exposition au chlorpyrifos de la population générale dans l'ancienne région Picardie pour une année type (2013). Les zones d’expositions les plus élevées sont à proximité des parcelles sur lesquelles la substance est potentiellement plus épandue. La voie majoritaire correspond à la voie d’ingestion. Les cartographies obtenues permettent de confronter les doses internes aux données de biosurveillance (MecoExpo, HypoMeco, Elfe). Conclusions : Cette démarche intégrée d'évaluation de l'exposition fournit des éléments d'interprétation des inégalités environnementales dans une visée d'aide à la décision pour réduire les expositions. Cependant, la caractérisation de l'exposition comporte de nombreuses incertitudes au regard des données de mesures et des hypothèses de modélisation qui la sous-tend. Le besoin de mobiliser des données supplémentaires et de mieux évaluer les phénomènes de transfert devient nécessaire pour améliorer la représentativité des estimations.

International audience

Erratum in : Correction: Liquid biopsies for omics-based analysis in sentinel mussels. [PLoS One. 2019]; International audience; Liquid biopsy of plasma is a simple and non-invasive technology that holds great promise in biomedical research. It is based on the analysis of nucleic acid-based biomarkers with predictive potential. In the present work, we have combined this concept with the FTA technology for sentinel mussels. We found that hemocytes collected from liquid biopsies can be readily fixed on FTA cards and used for long-term transcriptome analysis. We also showed that liquid biopsy is easily adaptable for metagenomic analysis of bacterial profiles of mussels. We finally provide evidence that liquid biopsies contained circulating cell-free DNA (ccfDNA) which can be used as an easily accessible genomic reservoir. Sampling of FTA-fixed circulating nucleic acids is stable at room temperature and does not necessitate a cold-chain protection. It showed comparable performance to frozen samples and is ideally adapted for sampling in remote areas, most notably in polar regions threatened by anthropogenic activities. From an ethical point of view, this minimally-invasive and non-lethal approach further reduces incidental mortality associated with conventional tissue sampling. This liquid biopsy-based approach should thus facilitate biobanking activities and development of omics-based biomarkers in mussels to assess the quality of aquatic ecosystems.

Developing population models is of great interest as these models enable to extrapolate toxicity observed at the molecular or individual levels to the population level, and thus improve environmental risk assessment of chemical substances. For this purpose, accounting for natural variations of environmental conditions and prey dynamics along with the chemical stress is needed. In this study, an individual-based model (IBM) coupled to a Dynamic Energy Budget (DEB) model was developed in order to predict three-spined stickleback population dynamics in semi-controlled stream experiments (in mesocosms). Datasets obtained in mesocosms offer the opportunity to develop and evaluate the model predictions. The most sensitive parameters of the DEB-IBM were identified by sensitivity analyses and were calibrated based on data from two independent mesocosm experiments. The predictive capacities of our model were subsequently evaluated using three independent mesocosm datasets under different environmental scenarios. Finally, our model was applied to a theoretical case of toxic effects to show an example of application of the model in a regulatory context. While the most uncertain population processes (in particular, competition for food in mesocosms) in our three-spined stickleback DEB-IBM could be modelled more accurately, our model can already serve to assess the impacts of toxicants at the population level by improving the analyses of mesocosm experiments, in decreasing the uncertainty of the experimental results. Therefore, in a second step, it could be used to predict the consequences on viability of a population exposed to a contaminant under various environmental and exposure scenarios.

Bisphenol A, a well-known endocrine-disrupting chemical, is ubiquitously present in an aquatic environment. Its impacts at populational level on three-spined sticklebacks have been studied in a long-term mesocosm experiment at low-dose BPA, however the causes explaining the observed effects have remained unclear. Here, we used an individual-based model coupled to a Dynamic Energy Budget model for (i) assessing the potential of modelling to predict impacts on population viability from organism ecotoxicological endpoints and (ii) provide insights on the mechanisms of BPA toxicity in the artificial streams. To do that, both direct and indirect effects of BPA on three-spined sticklebacks were incorporated in the model. BPA impacts on the physiological processes of fish have been identified based on literature data and effects on stickleback preys have been t into account using sampling data from exposed mesocosms. Simulations were made with the model integrating dose-responses only calibrated on literature data to assess the predictive capacity of the model. Then, simulations were made with a re-calibration of the toxic parameters on the populational data to better understand the observed BPA impacts found in mesocosms. Results showed that direct BPA effects on fish (impacts on gonad formation, growth, male reproductive behavior, eggs and larvae survival) mostly explained the three-spined stickleback population structure in mesocosms, but indirect effects were not negligible. Hence, this study showed the potential of modelling in risk assessment to predict the impacts on the fish population viability from behavioural and physiological effects measured on organism in controlled conditions.

Endocrine disruptors (EDs) are a major concern because of their effects on the main physiological functions, particularly on the reproductive function.In vertebrates, reproduction is under the control of a neuroendocrine axis called hypothalamic-pituitary-gonadal (HPG) axis. It includes various actors atthe brain (gonadotropin releasing hormones (GnRH) and kisspeptins), pituitary (gonadotropic hormones) and gonadal (sex steroids) levels. Theirdévelopment and functioning are finely regulated. Among the regulators, steroids play an important role by performing feedback loops. EDs mimickingsteroids are therefore potentially able to impact these regulations. The objective of this work was to evaluate the effects of xenoestrogens on theimplementation of cerebral actors involved in the HPG axis in the European sea bass (Dicentrarchus labrax). We first described the ontogeny of thekisspeptin, GnRH and gonadotropin systems during larval development. We have highlighted a differential regulation of these actors suggesting a roleduring this developmental process. In addition, we show that 17α-ethinylestradiol (EE2) is able to disrupt the ontogeny of GnRH2 and GnRH3 systemsduring the early stages of larval development.These data provide a basis for evaluation of the EDs effects on the ontogeny of neuroendocrine systems.; Les perturbateurs endocriniens (PE) sont une préoccupation majeure de par leurs effets sur les grandes fonctions physiologiques des organismes etparticulièrement sur la fonction de reproduction. Chez les vertébrés, la reproduction est sous le contrôle d’un axe neuroendocrinien nommé axegonadotrope. Celui-ci comprend différents acteurs cérébraux (gonadolibérines et kisspeptines), hypophysaires (gonadotropines) et gonadiques(stéroïdes sexuels) dont la mise en place et le fonctionnement sont régulés finement. Parmi les mécanismes de régulation, les stéroïdes vont jouer unrôle important en effectuant des boucles de rétrocontrôle. Les PE mimant ces stéroïdes sont donc potentiellement capables d’impacter ces régulations.L’objectif de ce travail était d’évaluer les effets d’un xénooestrogène sur les mises en place des acteurs cérébraux impliqués dans l’axe gonadotrope chezle bar européen (Dicentrarchus labrax). Nous avons d’abord décrit l’ontogénèse des systèmes à kisspeptine, à gonadolibérine et à gonadotropine aucours du développement larvaire. Nous avons mis en évidence une régulation différentielle de ces acteurs suggérant un rôle durant ce processusdéveloppemental. De plus, nous montrons que le 17α-éthinylestradiol (EE2) est capable de perturber l'ontogenèse des systèmes à GnRH2 et à GnRH3au cours des stades précoces du développement larvaire.Ces données constituent une base permettant l’évaluation des effets des PE sur l’ontogénèse des systèmes neuroendocriniens.

55th Congress of the European-Societies-of-Toxicology (EUROTOX) - Toxicology - Science Providing Solutions, Helsinki, FINLAND, SEP 08-11, 2019; International audience

Purpose: Recently a National Toxicology Program has issued their technical reports (NTP TR 595 [1] and NTP TR 596 [2]). They found that high exposure to radio frequency radiation (RFR) used by cell phones was associated with clear evidence of tumors in the hearts of male rats. In this context and given the large number of mobile phone users worldwide, the present study was focused on the effect of RFR of mobile phone on the heart rate variability (HRV). The aim of the present study was to analyze, in healthy subjects at rest, the influence of exposure to GSM 900MHz on HRV parameters. Participants and Methods: Twenty-six young healthy volunteers participated in the experiment. The volunteers were selected following a routine clinical examination. Inclusion criteria included regular sleep habits, no medication, no chronic disease or disability, no recent acute illness, no smoking, and no neurological or psychiatric illness. Participants having a history of cardiovascular disease were excluded. Volunteers participated into two ECG recording sessions. For each session, the participants were exposed for 26 min to sham or real GSM RF exposure. Exposure to RF EMF was performed by a commercial dual-band GSM mobile phone (Nokia 6650). The HRV was evaluated by both time domain and frequency domain analysis. Standard deviation of all R–R intervals (SDNN) and root-mean-square of successive differences (RMSSD) were measured in the time domain analysis of HRV. For frequency domain parameters, spectral analysis was performed by using fast-Fourier transform method. We analyzed the very low-frequency component (VLF), the low-frequency component (LF), and the high-frequency component (HF). The LF and HF powers were also converted into normalized units (LFnu, HFnu). Sympathovagal balance was expressed as the LF/HF ratio. Results: Analysis of time domain HRV parameters showed that SDNN was significantly higher during the exposure session when compared to the control session. Analysis of frequency domain HRV parameters demonstrated that absolute values of LF power and total power were significantly increased during exposure (p = 0.0463 and p = 0.0427 respectively). However, VLF, HF, LF n.u, HF n.u and LF/HF ration were not affected. In conclusion, it seems that most HRV parameters were not affected by GSM signal in our study. The weak effect observed on frequency domain HRV LF or total power is likely to represent a random occurrence rather than a real effect.

International audience

Background: Long-term exposure to air pollution has been consistently associated with adverse health effects and reduced life expectancy. Air pollution is a mixture of multiple pollutants originating from a large variety of sources and includes various substances classified as carcinogenic or probably carcinogenic to humans. Identifying the long-term effects of these airborne pollutants requires the computation of the spatio-temporal variability of concentration to estimate the exposure of the population. Aim : To provide an accurate assessment of long-term air pollution exposure (including airborne PM10, PM2.5, NO2, O3, BaP, PCB, PCDD/F and cadmium (cd) exposure in the whole France and in a case-control study nested in the French national prospective women’s cohort (E3N). Methods: Hourly airborne pollutant concentrations over the study period (1990-2010) were computed using a chemistry- transport model (CHIMERE) with a spatial resolution of 7x7km2. Cohort’s subjects were manually geocoded and annual concentrations were attributed to each subject’s address (n=19669). Results: Simulation scenarios of air pollutant concentrations show the variability of the pollutant sources over time with general decreasing levels of pollutant concentrations in air. At the E3N subject’s address, we observed a decline of concentration for all pollutants (PM10:-41%; PM2.5:-45%; NO2:-34%; PCB:-74%; PCDD/F:-87%, Cd:-68%; BaP:-45%) except for O3 (-0.04%). The percentage of subject exposed to an annual concentration exceeding WHO recommendation (PM10: 20 μg/m3; PM2.5: 10 μg/m3) decrease form 74% to 8% for PM10 and from 99% to 64% for PM2.5. We also observed strong territorial inequalities with differences in atmospheric concentrations that could be greater than a factor of five between regions. Conclusions: Findings from this study will be essential to increase the accuracy of the assessment of long-term airborne pollution exposure and will improve the results of epidemiological studies. The spatial resolution of concentrations will be improved by using complementary models such as land use regression.

Exposure to pesticides is characterized by the multiplicity of exposure routes (food, water, soil, air) related to their presence in all environmental media. First, for a fine characterization of the environmental exposure, it is necessary to gather within the same analysis system a dataset integrating the population behavior and the local contamination of the environmental media at fine resolutions and on large territories. This integration requires a sufficient toolchain to produce or process these data in a rigorous manner, characterize the entire continuum from the source of contamination, transport, and transfer of contaminants in environmental media, and estimate external and internal exposure doses for the general population. The aim of this work is to establish an integrated methodology for the mapping of exposure indicators at fine spatial and temporal resolutions (1 km² and week) directly comparable with individual biomonitoring measurements from French cohorts. To illustrate the approach, we consider the levels of chlorpyrifos among pregnant women in the Picardy region (France). Results provide insights into the identification of areas of potential overexposure and analysis of environmental determinants, elements useful for public health decision to reduce exposure and thus health and environmental impacts. However, the exposure characterization involves uncertainties regarding modeling assumptions and data measurements. Moreover, the efficiency of exposure modeling can be limited by calculation times. To optimize numerical resolution and reduce uncertainties related to knowledge limits and data representativeness, modeling assumptions and tools need to be reconsidered to improve the methodology and allow future developments.

International audience; Pharmaceuticals such as antidepressants are constantly released into the aquatic environment. Consequently, fluoxetine (FLX) and venlafaxine (VEN), the active molecules of Prozac© and Effexor©, are detected up to several µg.L−1 in freshwater and marine coastal waters. Both compounds act on the serotoninergic system, which may result in behavioural impairment, especially in juvenile animals presumed to be more susceptible to low concentrations than adults. The objective of this study was to determine whether environmental concentrations of FLX alone or combined with VEN modulate innate burying behaviour in two juvenile marine invertebrates, i.e. Sepia officinalis and Carcinus maenas. Juvenile cuttlefish were exposed from hatching to 30 days post-hatching to either FLX alone (i.e. 5 ng.L−1) or in mixture with VEN (i.e. either 2.5 ng.L−1 or 5 ng.L−1 of each antidepressant). Juvenile crabs (

With the extensive use of mobile phones several studies have been realized to understand the effects of radiofrequency exposure on brain activity. Results show changes in the alpha band spectral power. To better understand the cortical structures involved in these changes after exposure at 900 MHz, we carried out electroencephalography and magnetoencephalography recordings followed by the anatomical magnetic resonance imaging. Healthy volunteers were selected according to strict inclusion criteria. Preliminary results on MEG sensor space showed a modification of the alpha band right after exposure. Data analyses of MEG recordings on sensor space and source space are still under process and ready results will be presented at the conference.

We characterized exposure to RF-EMF in 357 different unique microenvironments in five European countries, using two personal exposimeters, as well as a vest with integrated sensors. We found substantial exposure differences between large cities, medium-sized townsand small villages, and found consistently higher total exposures in central, busy places with many people (business, shopping districts) than in quieter, residential areas.

We developed a new RF-EMF meter with sensors distributed over the front and back side of a vest, performed measurements in different microenvironments in five countries and compared results with commercially available exposimeters that are frequently used in epidemiological studies.

The evolution of communication technology brings great benefits to our daily life. Besides, this rapid expansion has raised concerns about their possible impact on public health. In this study, we found that repeated exposure to a low intensity 900 MHz radiofrequency induced changes in body temperature of mice. However, TRPM8 receptors don’t seem to be involved in mediating the effect of radiofrequency.

The aim of this study was to examine whether the combined exposure to solar ultraviolet (UV) radiation and radiofrequency (RF) exposure have any effect on cytokine (IL-1α, IL-6, IL-8) and MMP-1enzyme secretion on in vitro reconstructed human skin model. The full thickness skin models were exposed to UV radiation (2 SED, 4 SED) and radiofrequency (Wi-Fi, UMTS). The IL-1α, IL-6, IL-8 and MMP-1concentrations were measured 24 hours after UV and RF exposures from the culture media by the ELISA method. This experiment was done for the project named “Cellular response to co-exposure of radiofrequency (RF) and solar ultraviolet (UV) radiation in human in vitro skin model (SKIN-RF)”.