Specific Metabolic Fingerprint of a Dietary Exposure to a Very Low Dose of Endosulfan

Like other persistent organochlorine pesticides, endosulfan residues have been detected in foods including fruit, vegetables, and fish. The aim of our study was to assess the impact of a dietary exposure to low doses of endosulfan from foetal development until adult age on metabolic homeostasis in mice and to identify biomarkers of exposure using an 1H-NMR-based metabonomic approach in various tissues and biofluids. We report in both genders an increase in plasma glucose as well as changes in levels of factors involved in the regulation of liver oxidative stress, confirming the prooxidant activities of this compound. Some metabolic changes were distinct in males and females. For example in plasma, a decrease in lipid LDL and choline content was only observed in female. Lactate levels in males were significantly increased. In conclusion, our results show that metabolic changes in liver could be linked to the onset of pathologies like diabetes and insulin resistance. Moreover from our results it appears that the NMR-based metabonomic approach could be useful for the characterization in plasma of a dietary exposure to low dose of pesticide in human

Obesity promotes fumonisin B1 hepatotoxicity

Obesity, which is a worldwide public health issue, is associated with chronic inflammation that contribute to long-term complications, including insulin resistance, type 2 diabetes and non-alcoholic fatty liver disease. We hypothesized that obesity may also influence the sensitivity to food contaminants, such as fumonisin B1 (FB1), a mycotoxin produced mainly by the Fusarium verticillioides. FB1, a common contaminant of corn, is the most abundant and best characterized member of the fumonisins family. We investigated whether diet-induced obesity could modulate the sensitivity to oral FB1 exposure, with emphasis on gut health and hepatotoxicity. Thus, metabolic effects of FB1 were assessed in obese and non-obese male C57BL/6J mice. Mice received a high-fat diet (HFD) or normal chow diet (CHOW) for 15 weeks. Then, during the last three weeks, mice were exposed to these diets in combination or not with FB1 (10 mg/kg body weight/day) through drinking water. As expected, HFD feeding induced significant body weight gain, increased fasting glycemia, and hepatic steatosis. Combined exposure to HFD and FB1 resulted in body weight loss and a decrease in fasting blood glucose level. This co-exposition also induces gut dysbiosis, an increase in plasma FB1 level, a decrease in liver weight and hepatic steatosis. Moreover, plasma transaminase levels were significantly increased and associated with liver inflammation in HFD/FB1-treated mice. Liver gene expression analysis revealed that the combined exposure to HFD and FB1 was associated with reduced expression of genes involved in lipogenesis and increased expression of immune response and cell cycle-associated genes. These results suggest that, in the context of obesity, FB1 exposure promotes gut dysbiosis and severe liver inflammation. To our knowledge, this study provides the first example of obesity-induced hepatitis in response to a food contaminant.L.D. PhD was supported by the INRAE Animal Health department. This work was also supported by grants from the French National Research Agency (ANR) Fumolip (ANR-16-CE21-0003) and the Hepatomics FEDER program of Région Occitanie. We thank Prof Wentzel C. Gelderblom for generously providing the FB1 and for his interest and support in our project. B.C. laboratory is supported by a Starting Grant from the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program (grant agreement No. ERC-2018-StG- 804135), a Chaire d'Excellence from IdEx Université de Paris - ANR-18-IDEX-0001, an Innovator Award from the Kenneth Rainin Foundation, an ANR grant EMULBIONT ANR-21-CE15-0042-01 and the national program “Microbiote” from INSERM. We thank Anexplo (Genotoul, Toulouse) for their excellent work on plasma biochemistry. Neutral Lipids MS and NMR experiments were performed with instruments in the Metatoul-AXIOM platform. Sphingolipid MS analysis were performed with instruments in the RUBAM platform. The FB1 plasma levels were determined using an UPLC-MS/MS instrument part of the Ghent University MSsmall expertise centre for advanced mass spectrometry analysis of small organic molecules. We thank Elodie Rousseau-Bacquié and all members of the EZOP staff for their assistance in the animal facility. We are very grateful to Talal al Saati for histology analyses and review, and we thank all members of the US006/CREFRE staff at the histology facility and the Genom'IC platforms (INSERM U1016, Paris, France) for their expertise.Peer reviewe

Pesticides : quels impacts sur la santé ?

National audienc

Health impact of combined pesticide exposures

Occupational or environmental exposure to pesticides is a public health concern. Numerous epidemiologic studies show that occupational exposure to these substances is positively correlated with an increased risk of developing certain diseases. Epidemiologic studies among consumers of organic food products (which have greatly reduced pesticide levels) show an inverse relation with the rates of some cancers and metabolic diseases. Experimental studies provide arguments of a plausible link between pesticides and health. Pesticides are biologically active compounds that can individually exert specific effects on different targets that play a major role in cellular function and by extension in the physiological functions of the body. Consumers are exposed to low doses of mixtures of pesticides. When combined, they can interact with one another and induce synergistic effects. Their interactions are complex phenomena involving a network of targets and mechanisms at both the cell and organ levels. It is thus difficult to predict the effects of any given pesticide cocktail, given the diversity of their effects and interaction levels and of the organism's adaptability and biological responses

Compact finite difference schemes on non-uniform meshes. Application to direct numerical simulations of compressible flows

International audienceIn this paper, the development of a fourth- (respectively third-) order compact scheme for the approximation of first (respectively second) derivatives on non-uniform meshes is studied. A full inclusion of metrics in the coefficients of the compact scheme is proposed, instead of methods using Jacobian transformation. In the second part, an analysis of the numerical scheme is presented. A numerical analysis of truncation errors, a Fourier analysis completed by stability calculations in terms of both semi- and fully discrete eigenvalue problems are presented. In those eigenvalue problems, the pure convection equation for the first derivative, and the pure diffusion equation for the second derivative are considered. The last part of this paper is dedicated to an application of the numerical method to the simulation of a compressible flow requiring variable mesh size: the direct numerical simulation of compressible turbulent channel flow. Present results are compared with both experimental and other numerical (DNS) data in the literature. The effects of compressibility and acoustic waves on the turbulent flow structure are discussed

Pregnane X receptor deletion modifies recognition memory and electroencephalographic activity

Nuclear receptors (NR) are emerging as key players in the central nervous system (CNS) with reported implications in physiological and pathophysiological conditions. While other NR have been studied, it is unknown whether invalidation of the pregnane xenobiotic receptor (PXR, NR1I2) corresponds to neurological modifications in the adult brain. PXR-/- C57BL/6j and wild type mice were used to investigate: i) recognition memory, motor coordination, and anxiety-like behaviors; ii) longitudinal video-electroencephalographic (EEG) recordings and frequency wave analysis; iii) neurovascular structures by histological evaluation and expression of the cerebrovascular tight junctions ZO1 and CLDN5. Absence of PXR was associated with anxiety-like behavior and recognition memory impairment in adult mice. The latter was simultaneous to an electroencephalographic signature of lower theta frequency during sleep and abnormal delta waves. Neurophysiological changes did not correspond to significant structural changes in the adult brain, expect for a localized and minor increase in the fronto-parietal neurovascular density and reduced ZO1, but not CLDN5, expression in isolated brain capillaries. Our results converge with existing evidence supporting a link between NR expression and brain physiology. Although the exact modalities remain to be elucidated, the possibility that extra-physiological modulation of PXR may constitute a pathophysiological entry point or a molecular target for brain diseases is proposed