Les interactions entre contaminants chimiques et maladies hépatiques: Activation synergique de récepteurs nucléaires par des mélanges de xénobiotiques

International audienceLes contaminants chimiques, présents dans notre environnement, sont suspectés d’avoir des propriétés de type obésogène, diabétogène ou stéatogène c’est-à-dire de contribuer au développement de troubles métaboliques en perturbant la balance énergétique des organismes. Ceci concerne les plastifiants, des composés de la famille des organoétains ou encore certaines substances organochlorées, considérées comme des polluants organiques persistants. À ce jour, les mécanismes par lesquels ces contaminants contribuent au développement des stéatoses hépatiques non alcooliques (NAFLD ) restent méconnus

Bisphénols, perturbations des voies métaboliques et rôles dans l’obésité et le diabète

De nombreuses études expérimentales, cliniques et épidémiologiques récentes montrent que l’exposition à des contaminants de notre environnement pourrait perturber les fonctions métaboliques et endocriniennes des organismes. Ceci contribuerait au développement de pathologies métaboliques telles que l’obésité et le diabète de type II. Le Bisphénol A, un contaminant œstrogéno-mimétique largement exploité dans l’industrie des emballages alimentaires plastiques, présente un impact sur le métabolisme énergétique. Depuis l’interdiction du BPA, des analogues structuraux tels que le BPS et le BPF sont utilisés. Les effets de ces derniers sont moins connus mais des études suggèrent des effets obésogènes. Cette revue est principalement axée sur les effets métaboliques du BPA ainsi que ses cibles, et sur les analogues structuraux du BPA utilisés en substituts.Numerous experimental, clinical and epidemiological studies reveal that exposure to environmental contaminants may disrupt endocrine and metabolic functions of organisms. This could contribute to the development of metabolic disorders such as obesity and type II diabetes. Bisphenol A, a widely used xenoestrogen in plastic food packaging industry, affects energy metabolism. Following BPA ban, structural analogues such as BPS and BPF are used. Their effects are less known; however, some studies reveal an obesogenic effect. This review focuses on the metabolic effects and targets of BPA as well as the structural analogues used as substitutes

Comprenhensive investigation of the transcriptome

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Endocrine disruptive compounds (EDCs) : mechanisms and effects in domestic animals

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In vitro cross-species infections using a caprine arthritis encephalitis lentivirus carrying the GFP marker gene

International audienceA caprine arthritis encephalitis virus (CAEV), carrying the green fluorescent protein (GFP) into the tat region was recently reported [.Mselli-Lakhal, L., Guiguen, F., Greenland, T., Mornex, J.F., Chebloune, Y., 2006. Gene transfer system derived from the caprine arthritis-encephalitis lentivirus. J. Virol. Meth. 136, 177-184]. This construct, called pK2EGFPH replicated to titres up to 10(5) IU/ml on infection of caprine cells, and could be concentrated to 106 IU/ml by ultracentrifugation. In the present study, the pK2EGFPH construct was characterized better and used in cross-species infection studies. The pK2EGFPH virus could transduce GFP protein expression both to goat synovial membrane cells and to an immortalized goat milk epithelial cell line. The pK2EGFPH infected cells were demonstrated to express both GFP protein and CAEV viral proteins, as demonstrated by radioimmunoprecipitation and multinucleated cell formation. However GFP expression could not be maintained over passages. This vector was used to investigate cross-species infectious potential of CAEV. The bovine cell lines MDBK and GBK were found to be sensitive to infection while the human cell lines Hela, A431 and THP-1 were not. The pK2EGFPH vector should prove useful in studies of CAEV tropism both in vitro and in vivo

Constitutive Androstane Receptor: A Peripheral and a Neurovascular Stress or Environmental Sensor

International 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

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

CAR Protects Females from Diet-Induced Steatosis and Associated Metabolic Disorders

Non-Alcoholic Fatty Liver Disease (NAFLD) is the most common cause of chronic liver disease worldwide, affecting 70–90% of obese individuals. In humans, a lower NAFLD incidence is reported in pre-menopausal women, although the mechanisms affording this protection remain under-investigated. Here, we tested the hypothesis that the constitutive androstane nuclear receptor (CAR) plays a role in the pathogenesis of experimental NAFLD. Male and female wild-type (WT) and CAR knock-out (CAR−/−) mice were subjected to a high-fat diet (HFD) for 16 weeks. We examined the metabolic phenotype of mice through body weight follow-up, glucose tolerance tests, analysis of plasmatic metabolic markers, hepatic lipid accumulation, and hepatic transcriptome. Finally, we examined the potential impact of HFD and CAR deletion on specific brain regions, focusing on glial cells. HFD-induced weight gain and hepatic steatosis are more pronounced in WT males than females. CAR−/− females present a NASH-like hepatic transcriptomic signature suggesting a potential NAFLD to NASH transition. Transcriptomic correlation analysis highlighted a possible cross-talk between CAR and ERα receptors. The peripheral effects of CAR deletion in female mice were associated with astrogliosis in the hypothalamus. These findings prove that nuclear receptor CAR may be a potential mechanism entry-point and a therapeutic target for treating NAFLD/NASH

Immortalized goat milk epithelial cell lines replicate CAEV at high level

Primary milk epithelial cells were isolated from CAEV-uninfected goats and three cell lines designated TIGMEC-1, TIGMEC-2 and TIGMEC-3 were established. The three cell lines retained their morphological characteristics of epithelial cells and expressed specific epithelial cytokeratin marker as well as the immortalizing SV40 large T antigen. The kinetics of growth of TIGMEC1, TIGMEC2 and TIGMEC3 cell lines showed a doubling time of 24-48 hours while the parental cell lines became senescent after the passage 6 in cell culture. Like the parental primary cells, the three cell lines were found to be highly sensitive to CAEV-pBSCA, an infectious molecular clone of CAEV-CO strain, and to a French isolate CAEV-3112. TIGMEC cell lines infected with CAEV-pBSCA became chronically infected producing high virus titers in absence of cytopathic effects. These cell lines may be useful for study of the possible physiological alterations in mammary epithelial cells infected with small ruminant lentiviruses and their consequences on milk quality. On an other hand, these cell lines can be used to study their role in virus transmission and pathogenesis.Des cellules épithéliales du lait immortalisées répliquent le CAEV avec une grande efficacité. Des cellules épithéliales primaires isolées à partir de chèvres non infectées par le CAEV ont été immortalisées pour dériver 3 lignées appelées TIGMEC-1, TIGMEC-2 et TIGMEC-3. Les cellules des 3 lignées ont conservé leurs caractéristiques morphologiques de cellules épithéliales et expriment la cytokératine, un marqueur spécifique des cellules épithéliales et l'antigène immortalisant T du virus SV40. La courbe de croissance des lignées TIGMEC-1, TIGMEC-2 et TIGMEC-3 montre une multiplication des cellules toutes les 24 à 48 heures alors que les cellules parentales ne se divisent plus après 6 passages en culture. Comme les cellules primaires dont elles dérivent, ces lignées se sont avérées sensibles à l'infection par le CAEV-pBSCA, un clone moléculaire infectieux de la souche CAEV-CO, et un isolat français le CAEV-3112. Les lignées TIGMEC infectées avec le CAEV-pBSCA deviennent chroniquement infectées et produisent des titres élevés de virus en l'absence d'effet cytopathogène. Ces lignées pourront être très utiles pour étudier les altérations physiologiques éventuelles liées à l'infection de cellules épithéliales par les lentivirus des petits ruminants et pouvant avoir des conséquences sur la qualité du lait. Par ailleurs, ces cellules pourraient être utilisées pour étudier le rôle des cellules épithéliales du lait dans la transmission du virus et l'induction de pathologie