Éditeur(s) : National Shellfisheries Association
Résumé : The subcellular fractionation of the digestive gland cells of the common cuttlefish Sepia officinalis was performed to investigate the distribution of metals between organelles and cytosol and the different cytosolic fractions separated by gel-filtration chromatography. Total metal concentrations vary over 3 orders of magnitude, ranging from dwt for Pb to dwt for Zn. With the exception of Cd, Co, and Cu, metals were mostly bound to the organelles. Whereas no specific organelle compartment was found for Mn, Ph, and Zn, Fe was mainly associated with nucleus, brown body, and "boule" fraction (i.e., 52%) and 44% of the total Ag was contained in the lysosomal and mitochondria enriched fraction. The link of metals with hydrosoluble proteins in the cytosolic fraction was investigated at 254 and 280 not. Direct relationship between cytosolic metal and metallothioneins could only be established for Ag and Cu, whereas Cd and Zn seem to mainly bind high (> 70 kDa) and low (< 4 kDa) molecular weight proteins.
The Journal of Shellfish Research (0730-8000) (National Shellfisheries Association), 2006-12 , Vol. 25 , N. 3 , P. 987-993

Droits : 2006 NSA
http://archimer.ifremer.fr/doc/2006/publication-2532.pdf
http://archimer.ifremer.fr/doc/00000/2532/

Éditeur(s) : Elsevier
Résumé : In the Gulf of Gabes (Tunisia, Eastern Mediterranean sea), the grooved carpet shell Ruditapes decussatus has been seen to contain persistent levels of gymnodimine (GYM) for several years. The present experimental work represents the first attempt to assess detoxification kinetics of fast-acting toxins (FAT) in marine molluscs fed specific diets of non-toxic algae (Isochrysis galbana). To find an optimal detoxification method, two experiments were performed in which clams were first fed the toxic dinoflagellate Karenia selliformis to artificially contaminate them with GYM, thus simulating the effect of natural toxic episodes. As a second step, the same clams were fed a non-toxic algae, I. galbana. to speed up the detoxification process. Changes in toxin content over the whole experiment were assessed by liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) analysis. The first results revealed (i) faster detoxification rates in digestive gland (DG) when clams were fed on L galbana compared with a starved control (no food) and (ii) a typical detoxification pattern, i.e. a rapid drop in toxin content within the first days followed by a secondary slower decrease. GYM levels could be reduced approximately to less than 5% within 7-8 days in clams fed I. galbana, according to the initial toxin levels of 1400 and 9400 mu g GYM/kg of DG, respectively. At the end of the second experiment, DSP mouse bioassay was negative when GYM was less than 100 mu g/kg DG. (C) 2009 Elsevier B.V. All rights reserved.
Harmful Algae (1568-9883) (Elsevier), 2010-02 , Vol. 9 , N. 2 , P. 200-207

Droits : 2010 Elsevier Ltd All rights reserved.
http://archimer.ifremer.fr/doc/2010/publication-7488.pdf
DOI:10.1016/j.hal.2009.10.002
http://archimer.ifremer.fr/doc/00000/7488/

Éditeur(s) : HAL CCSD Wiley
Résumé : International audience
Digestive tubules of Strombidae are composed by three cell types: digestive cells, vacuolated cells, and crypt cells. The last one is characterized by the presence of intracellular granules identified as spherocrystals. Such structures are known to occur in basophilic cells of gastropod digestive gland, where they are supposed to be involved in the regulation of some minerals and in detoxification. In this study, energy-dispersive X-ray analysis (EDX) and energy filtered transmission electron microscopy (EFTEM) were used to determine the elemental content of spherocrystals in two Strombidae, Strombus gigas and Strombus pugilis. In freshly collected individuals of both species, the following elements were detected: Ca, Fe, Mg, P, and Zn. Aluminum and Mn were also detected in S. gigas. Their presence in spherocrystals indicates that, in Strombidae, spherocrystals are involved in the regulation of minerals and essential trace metals. In order to answer the question ''are spherocrystals involved in nonessential trace metals scavenging?,'' artificial cadmium and lead exposure by both waterborne and dietary pathways was applied to S. pugilis. No evidence of cadmium (Cd(NO3)2) or lead (Pb(NO3)2) provided by food was found in spherocrystals. Cadmium provided in water (Cd(NO3)2 and CdCl2) causes structural modifications of the digestive gland; however, this element was not trapped in spherocrystals. These results suggest that spherocrystals are not involved in detoxification of such nonessential trace metals.
ISSN: 1059-910X

hal-00743762
https://hal.univ-antilles.fr/hal-00743762
DOI : 10.1002/jemt.21073

Éditeur(s) : HAL CCSD Federation of American Society of Experimental Biology
Résumé : International audience
Testes of most male mammals present the particularity of being externalized from the body and are consequently slightly cooler than core body temperature (4-8 degrees C below). Although, hypothermia of the testis is known to increase germ cells apoptosis, little is known about the underlying molecular mechanisms, including cold sensors, transduction pathways, and apoptosis triggers. In this study, using a functional knockout mouse model of the cold and menthol receptors, dubbed transient receptor potential melastatine 8 (TRPM8) channels, we found that TRPM8 initiated the cold-shock response by differentially modulating cold- and heat-shock proteins. Besides, apoptosis of germ cells increased in proportion to the cooling level in control mice but was independent of temperature in knockout mice. We also observed that the rate of germ cell death correlated positively with the reactive oxygen species level and negatively with the expression of the detoxifying enzymes. This result suggests that the TRPM8 sensor is a key determinant of germ cell fate under hypothermic stimulation.Borowiec, A.-S., Sion, B., Chalmel, F., Rolland, A. D., Lemonnier, L., De Clerck, T., Bokhobza, A., Derouiche, S., Dewailly, E., Slomianny, C., Mauduit, C., Benahmed, M., Roudbaraki, M., Jegou, B., Prevarskaya, N., Bidaux, G. Cold/menthol TRPM8 receptors initiate the cold-shock response and protect germ cells from cold-shock-induced oxidation.
ISSN: 0892-6638

hal-01390973
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01390973
DOI : 10.1096/fj.201600257R
PUBMED : 27317670

Éditeur(s) : HAL CCSD PeerJ
Résumé : International audience
Background: Heterocyclic aromatic amines (HAA) are environmental and food contaminants that are potentially carcinogenic for humans. 2-Amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) is one of the most abundant HAA formed in cooked meat. MeIQx is metabolized by cytochrome P450 1A2 in the human liver into detoxificated and bioactivated products. Once bioactivated, MeIQx metabolites can lead to DNA adduct formation responsible for further genome instability.Methods: Using a computational approach, we developed a numerical model for MeIQx metabolism in the liver that predicts the MeIQx biotransformation into detoxification or bioactivation pathways according to the concentration of MeIQx.Results: Our results demonstrate that 1) the detoxification pathway predominates, 2) the ratio between detoxification and bioactivation pathways is not linear and shows a maximum at 10µM of MeIQx in hepatocyte cell models, 3) CYP1A2 is a key enzyme in the system that regulates the balance between bioactivation and detoxification. Our analysis suggests that such a ratio could be considered as an indicator of MeIQx genotoxicity at a low concentration of MeIQx.Conclusions: Our model permits the investigation of the balance between bioactivation (i.e. DNA adduct formation pathway through the prediction of potential genotoxic compounds) and detoxification of MeIQx in order to predict the behaviour of this environmental contaminant in the human liver. It highlights the importance of complex regulations of enzyme competitions that should be taken into account in any further multi-organ models.
ISSN: 2167-8359

hal-01575579
https://hal.inria.fr/hal-01575579
PUBMED : 28879062
DOI : 10.7717/peerj.3703

Éditeur(s) : HAL CCSD Taylor & Francis
Résumé : International audience
INTRODUCTION: The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor historically known for regulating expression of several important drug-detoxifying proteins. Besides drug metabolism pathways, cytokines have been recently recognized as targeted by the AhR signaling cascade, which may contribute to toxicity and changes in xenobiotic detoxification caused by AhR agonists. AREAS COVERED: This article summarizes the nature of the main cytokines regulated by AhR ligands and reviews their involvement in toxic effects of AhR ligands, especially in relation with inflammation. The article also discusses the potential implications for drug detoxification pathways. EXPERT OPINION: Even if various cytokines, including inflammatory ones, have already been demonstrated to constitute robust targets for AhR, the exact role played by AhR with respect to inflammation remains to be determined. Further studies are also required to better characterize the molecular mechanisms implicated in regulation of cytokines by AhR ligands and to determine the role that may play AhR-targeted cytokines in alteration of xenobiotic detoxification. Finally, changes in cytokine receptor expression triggered by AhR ligands have additionally to be taken into account to better and more extensively comprehend the role played by AhR in the cytokine/inflammation area.
ISSN: 1742-5255

inserm-00831662
http://www.hal.inserm.fr/inserm-00831662
DOI : 10.1517/17425255.2013.738194
PUBMED : 23230817

Éditeur(s) : HAL CCSD Public Library of Science
Résumé : International audience
Pyrethroids are widely-used chemical insecticides, to which humans are commonly exposed, and known to alter functional expression of drug metabolizing enzymes. Limited data have additionally suggested that drug transporters, that constitute key-actors of the drug detoxification system, may also be targeted by pyrethroids. The present study was therefore designed to analyze the potential regulatory effects of these pesticides towards activities of main ATP-binding cassette (ABC) and solute carrier (SLC) drug transporters, using transporter-overexpressing cells. The pyrethroids allethrin and tetramethrin were found to inhibit various ABC and SLC drug transporters, including multidrug resistance-associated protein (MRP) 2, breast cancer resistance protein (BCRP), organic anion transporter polypeptide (OATP) 1B1, organic anion transporter (OAT) 3, multidrug and toxin extrusion transporter (MATE) 1, organic cation transporter (OCT) 1 and OCT2, with IC50 values however ranging from 2.6 muM (OCT1 inhibition by allethrin) to 77.6 muM (OAT3 inhibition by tetramethrin) and thus much higher than pyrethroid concentrations (in the nM range) reached in environmentally pyrethroid-exposed humans. By contrast, allethrin and tetramethrin cis-stimulated OATP2B1 activity and failed to alter activities of OATP1B3, OAT1 and MATE2-K, whereas P-glycoprotein activity was additionally moderately inhibited. Twelve other pyrethoids used at 100 muM did not block activities of the various investigated transporters, or only moderately inhibited some of them (inhibition by less than 50%). In silico analysis of structure-activity relationships next revealed that molecular parameters, including molecular weight and lipophilicity, are associated with transporter inhibition by allethrin/tetramethrin and successfully predicted transporter inhibition by the pyrethroids imiprothrin and prallethrin. Taken together, these data fully demonstrated that two pyrethoids, i.e., allethrin and tetramethrin, can act as regulators of the activity of various ABC and SLC drug transporters, but only when used at high and non-relevant concentrations, making unlikely any contribution of these transporter activity alterations to pyrethroid toxicity in environmentally exposed humans.
ISSN: 1932-6203

hal-01477206
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01477206
DOI : 10.1371/journal.pone.0169480
PUBMED : 28099443

Éditeur(s) : HAL CCSD
Résumé : International audience
Gevokizumab is a potent anti-interleukin (IL)-1 beta neutralizing monoclonal antibody (mAb), which may be used for treating inflammatory or autoimmune diseases. The present study was designed to characterize the potential effects of this mAb towards well-established IL-1 beta-mediated repression of hepatic drug detoxifying proteins, like cytochrome P450 (CYP) 3A4 and drug transporters. Primary cultured human hepatocytes were exposed to various concentrations of IL-1 beta in the absence or presence of gevokizumab (5 A mu g/mL); mRNA expression and activity of CYP3A4 and transporters were next determined. Gevokizumab was found to down-modulate, but not abolish, the repression of CYP3A4 and drug transporter mRNAs caused by IL-1 beta in human hepatocytes, through shifting up IL-1 beta half maximal inhibitory concentration (IC50) values by factors ranging from 6.8 to 10.4. The mAb concomitantly shifted IL-1 beta IC50 values towards CYP3A4 activity from 22.0 pg/mL (in the absence of gevokizumab) to 796 pg/mL (in the presence of gevokizumab) and counteracted the decrease of organic anion-transporting polypeptide activity occurring in response to 50 pg/mL IL-1 beta, but not that occurring at higher IL-1 beta concentration (1000 pg/mL). Gevokizumab attenuates, but not abolishes, IL-1 beta-mediated functional repression of CYP3A4 and drug transporters in human hepatocytes, which agrees with the fact that the mAb is considered as a modulator and not a blocker of IL-1 beta signaling. This attenuation of IL-1 beta-mediated down-regulation of hepatic detoxifying proteins by gevokizumab may have to be evaluated in terms of potential therapeutic protein drug-drug interactions when considering future development and therapeutic uses of this IL-1 beta neutralizing mAb.
ISSN: 0378-7966

hal-01616062
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01616062
DOI : 10.1007/s13318-017-0406-1

Éditeur(s) : Elsevier
Résumé : The uptake and loss kinetics of Cd were determined in two species of scallops from the European coasts, the variegated scallop Chlamys varia and the king scallop Pecten maximus, following exposures via seawater, phytoplankton and sediment using highly sensitive radiotracer techniques (Cd-109). Results indicate that, for seawater and dietary pathways, C. varia displays higher bioaccumulation capacities in terms of uptake rate from water and fraction absorbed from ingested food (assimilation efficiency) than Pecten maximus. Regarding sediment exposure, P. maximus displayed low steady-state Cd transfer factor (TFSS < 1); however, once incorporated, a very large part of Cd transferred from sediment (92%) was strongly retained within R maximus tissues. Both species showed a high retention capacity for Cd (biological half-life, T-b1/2 > 4 months), suggesting efficient mechanisms of detoxification and storage in both species. The digestive gland was found to be the main storage organ of Cd in the two scallops regardless of the exposure pathway. However, Cd was stored differently within this organ according to the species considered: 40% of the total Cd was found in the soluble cellular fraction in C. varia whereas this soluble fraction reached 80% for P. maximus. This suggests that the two species displayed different Cd detoxification/storage mechanisms. Finally, the present study has determined the relative contribution of the different exposure pathways to global Cd bioaccumulation for the two scallop species. Results clearly show that for both species, food constitutes the major accumulation pathway, contributing for >99% and 84% of the global Cd bioaccumulation in C. varia and R maximus, respectively. This work confirms the previous assumption, derived from a bibliographic overview, that dietary pathway plays a prevalent role in metal bioaccumulation in Pectinidae. (C) 2007 Elsevier B.V. All rights reserved.
Journal of Experimental Marine Biology and Ecology (0022-0981) (Elsevier), 2007-12 , Vol. 353 , N. 1 , P. 58-67

Droits : 2007 Elsevier B.V. All rights reserved.
http://archimer.ifremer.fr/doc/2007/publication-3581.pdf
DOI:10.1016/j.jembe.2007.09.001
http://archimer.ifremer.fr/doc/00000/3581/

Éditeur(s) : Pergamon-elsevier Science Ltd
Résumé : The present work aimed at better understanding metal and metalloid bioaccumulation in the edible Pacific blue shrimp Litopenaeus stylirostris, using both laboratory and field approaches. In the laboratory, the bioaccumulation kinetics of Ag, Cd, Co, Cr, and Zn have been investigated in shrimp exposed via seawater and food, using the corresponding gamma-emitting radiotracers (Ag-110m, Cd-109, Co-57, Cr-51, and Zn-65) and highly sensitive nuclear detection techniques. Results showed that hepatopancreas and intestine concentrated the metals to the highest extent among the blue shrimp organs and tissues. Moulting was found to play a non negligible detoxification role for Co, Cr and, to a lesser extent, Zn. Metal retention by L stylirostris widely varied (from a few days to several months), according to the element and exposure pathway considered (a given metal was usually less strongly retained when ingested with food than when it was taken up from the dissolved phase). In the field study, Ag, As, Cd, Co, Cr, Cu, Mn, Ni, and Zn were analysed in shrimp collected from a New Caledonian aquaculture pond. Metal concentrations in the shrimp muscles were generally relatively low and results confirmed the role played by the digestive organs and tissues in the bioaccumulation/storage/detoxification of metals in the Pacific blue shrimp. Preliminary risk considerations indicate that consumption of the shrimp farmed in New Caledonia is not of particular concern for human health. (C) 2010 Elsevier Ltd. All rights reserved.
Marine Pollution Bulletin (0025-326X) (Pergamon-elsevier Science Ltd), 2010 , Vol. 61 , N. 7-12 , P. 576-584

Droits : 2010 Elsevier Ltd All rights reserved.
http://archimer.ifremer.fr/doc/00014/12528/9869.pdf
DOI:10.1016/j.marpolbul.2010.06.035
http://archimer.ifremer.fr/doc/00014/12528/

Éditeur(s) : HAL CCSD Elsevier
Résumé : International audience
The catecholamine epinephrine is known to repress expression of hepatic drug metabolizing enzymes such as cytochromes P-450. The present study was designed to determine whether epinephrine may also target expression of main hepatic drug transporters, that play a major role in liver detoxification and are commonly coordinately regulated with drug detoxifying enzymes. Treatment of primary human hepatocytes with 10 mu M epinephrine for 24 h repressed mRNA expression of various transporters, such as the sinusoidal influx transporters NTCP, OATP1B1, OATP2B1, OAT2, OAT7 and OCT1 and the efflux transporters MRP2, MRP3 and BSEP, whereas it induced that of MDR1, but failed to alter that of BCRP. Most of these changes in transporter mRNA levels were also found in epinephrine-exposed human highly-differentiated hepatoma HepaRG cells, which additionally exhibited reduced protein expression of OATP2B1 and MRP3, increased expression of P-glycoprotein and decreased transport activity of NTCP, OATPs and OCT1. Epinephrine effects towards transporter mRNA expression in human hepatocytes were next shown to be correlated to those of the selective beta 2-adrenoreceptor (ADR) agonist fenoterol, of the adenylate cyclase activator forskolin and of the cAMP analogue 8-bromo-cAMP. In addition, the non-selective beta-ADR antagonist carazolol and the selective beta 2-ADR antagonist ICI-118,551, unlike the alpha-ADR antagonist phentolamine, suppressed epinephrine -mediated repressions of transporter mRNA expression. Taken together, these data indicate that epinephrine regulates in vitro expression of main hepatic drug transporters in a beta 2-ADR/adenylate cyclase/cAMP-dependent manner. Hepatic drug transport appears therefore as a target of the beta 2-adrenergic system, which may have to deserve attention for drugs interacting with beta 2-ADRs.
ISSN: 0928-0987

hal-01578583
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01578583
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01578583/file/Mayati%20et%20al.%20-%20%CE%B22-adrenergic%20receptor-mediated%20in%20vitro%20regulatio.pdf
DOI : 10.1016/j.ejps.2017.06.010
PUBMED : 28603032

Éditeur(s) : HAL CCSD Elsevier
Résumé : International audience
This study investigates if acclimatization to residual pesticide contamination in agricultural soils is reflected in detoxification, antioxidant enzyme activities and energy budget of earthworms. Five fields within a joint agricultural area exhibited different chemical and farming histories from conventional cultivation to organic pasture. Soil multiresidual pesticide analysis revealed up to 9 molecules including atrazine up to 2.4 ng g(-1) dry soil. Exposure history of endogeic Aporrectodea caliginosa and Allolobophora chlorotica modified their responses to pesticides. In the field, activities of soluble glutathione-S-transferases (sGST) and catalase increased with soil pesticide contamination in A. caliginosa. Pesticide stress was reflected in depletion of energy reserves in A. chlorotica. Acute exposure of pre-adapted and naïve A. caliginosa to pesticides (fungicide Opus(®), 0.1 μg active ingredient epoxiconazole g(-1) dry soil, RoundUp Flash(®), 2.5 μg active ingredient glyphosate g(-1) dry soil, and their mixture), revealed that environmental pre-exposure accelerated activation of the detoxification enzyme sGST towards epoxiconazole.
ISSN: 0269-7491

hal-01063923
https://hal.archives-ouvertes.fr/hal-01063923
DOI : 10.1016/j.envpol.2014.05.001
PUBMED : 24874794

Éditeur(s) : HAL CCSD
Résumé : The ovary is not solely the unique source of oocytes necessary for fertilization but also a crucial conductor of endocrine regulations of the reproductive system. In the fetal ovary, oocytes grouped in clusters are surrounded by somatic pre-granulosa cells, altogether delineated by a basement membrane and constituting ovarian cords. The formation of the definitive ovarian functional units requires their fragmentation into follicles formed by a single oocyte surrounded by granulosa cells and delineated by a basement membrane. This partitioning occurs within a tiny period and is dependent on the correct timing of the meiotic process, on an apoptotic wave that specifically targets oocytes and the remodelling of the basement membrane. Follicle formation is a crucial event of ovarian development because the follicle stock formed at the end of this process is non-renewable. Therefore, any disturbance of this process can lead to reproductive abnormalities in adulthood. Recent data on endocrine disruptors displaying estrogenic activity have involved the fragile estrogenic homeostasis in the process. We aimed at better understanding how the endogen estrogen 17b-estradiol (E2) contributes to follicle formation. To assess it, Sprague-Dawley rats were treated with E2 at different doses during follicle formation, /i.e./ in the 3 days following birth. We show that although this treatment impairs the development of the hepatic and ovarian detoxification systems, the female neonate is able to increase its estrogen clearance capabilities. Nevertheless, E2 treatment within this critical period triggers a dose-dependent decrease of oocyte number per ovary. Regardless of the E2 dose, puberty is advanced. All treated females are at least transiently fertile, yet these reproductive capabilities rapidly decline. A high (10 µg/day) dose of E2 leads to a secondary infertility characterized by anovulation that probably result from a dysfunction of the whole reproductive tract. By contrast, a lower (0.1 µg/day) dose of E2, that does not significantly modify neonatal oocyte survival, leads to a progressive reproductive senescence likely due to ovarian failure. Long-term troubles may originate from precocious E2 impact on the ovary since it disturbs ovarian transcriptome and produces many lesions on ovarian cell DNA.
L'ovaire est au cœur de la physiologie de la reproduction féminine. Il est à la fois à l'origine des ovocytes nécessaires à la fécondation et acteur des régulations endocrines du système reproducteur. Les ovocytes de l'ovaire fœtal sont groupés en amas bordés de cellules somatiques et d'une membrane basale, formant les cordons ovariens. Ces cordons ovariens se fragmentent pour former les follicules ovariens: un ovocyte bordé de cellules somatiques et d'une membrane basale. Cette fragmentation se déroule sur une courte période (/in utero/ chez la femme et juste après la naissance chez les rongeurs) et fait intervenir une vague de mort cellulaire programmée touchant les ovocytes pendant leur méiose et un remodelage de la membrane basale. La formation des follicules est une période cruciale du développement ovarien puisque le stock de follicules formés à l'issue de ce processus est non renouvelable. Son altération peut donc être à l'origine de troubles de la fonction de reproduction chez le futur adulte. Il existe une fragile homéostasie œstrogénique en place au moment de la formation folliculaire: chez la femme, l'ovaire se développe /in utero/, sous l'influence des œstrogènes circulants maternels et la production ovarienne fœtale. Chez les rongeurs, les follicules se forment lors de la levée de l'imprégnation hormonale maternelle au moment de la naissance. Nous avons souhaité comprendre comment le 17b-œstradiol (E2), œstrogène endogène, pouvait contribuer à la mise en place des follicules. Pour cela, des rattes Sprague-Dawley ont été traitées pendant la période de formation des follicules avec de l'E2 à différentes doses entre 0.01 et 10 µg/jour. Nos travaux démontrent que le traitement de rattes par des œstrogènes entre leur naissance et 3 jours induit une réduction dose-dépendante de leur nombre d'ovocytes. Bien que le traitement entrave le développement normal du système de détoxication hépatique et ovarien, l'animal est capable d'accroître ses capacités d'élimination des œstrogènes. Ces capacités sont toutefois insuffisantes pour bloquer les effets du traitement. Quelle que soit la dose d'E2 utilisée (0.1 ou 10 µg/jour), la puberté est plus précoce chez les femelles exposées mais toutes sont fertiles, au moins transitoirement. Cependant le traitement induit une dégradation rapide des capacités reproductives. L'E2 modifie la dynamique folliculaire chez l'adulte, longtemps après l'arrêt du traitement. Si une forte dose d'E2 réduit la survie des ovocytes lors de la formation des follicules et conduit à une infertilité secondaire due à un dysfonctionnement général du tractus reproducteur, une dose faible n'affecte pas la survie des ovocytes à court terme mais conduit à une sénescence reproductive précoce vraisemblablement d'origine ovarienne. L'origine de ces troubles pourrait résider dans les effets précoces de l'exposition à E2 : cette molécule altère le transcriptome ovarien et induit de nombreuses lésions de l'ADN des cellules ovariennes.
https://tel.archives-ouvertes.fr/tel-00953657

NNT : 2013REN1S107
tel-00953657
https://tel.archives-ouvertes.fr/tel-00953657
https://tel.archives-ouvertes.fr/tel-00953657/document
https://tel.archives-ouvertes.fr/tel-00953657/file/CHALMEY_Clementine.pdf

Éditeur(s) : HAL CCSD Public Library of Science
Résumé : International audience
Diesel exhaust particles (DEPs) are common environmental air pollutants primarily affecting the lung. DEPs or chemicals adsorbed on DEPs also exert extra-pulmonary effects, including alteration of hepatic drug detoxifying enzyme expression. The present study was designed to determine whether organic DEP extract (DEPe) may target hepatic drug transporters that contribute in a major way to drug detoxification. Using primary human hepatocytes and transporter-overexpressing cells, DEPe was first shown to strongly inhibit activities of the sinusoidal solute carrier (SLC) uptake transporters organic anion-transporting polypeptides (OATP) 1B1, 1B3 and 2B1 and of the canalicular ATP-binding cassette (ABC) efflux pump multidrug resistance-associated protein 2, with IC50 values ranging from approximately 1 to 20 μg/mL and relevant to environmental exposure situations. By contrast, 25 μg/mL DEPe failed to alter activities of the SLC transporter organic cation transporter (OCT) 1 and of the ABC efflux pumps P-glycoprotein and bile salt export pump (BSEP), whereas it only moderately inhibited those of sodium taurocholate co-transporting polypeptide and of breast cancer resistance protein (BCRP). Treatment by 25 μg/mL DEPe was next demonstrated to induce expression of BCRP at both mRNA and protein level in cultured human hepatic cells, whereas it concomitantly repressed mRNA expression of various transporters, including OATP1B3, OATP2B1, OCT1 and BSEP. Such changes in transporter expression were found to be highly correlated to those caused by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a reference activator of the aryl hydrocarbon receptor (AhR) pathway. This suggests that DEPe, which is enriched in known ligands of AhR like polycyclic aromatic hydrocarbons, alters drug transporter expression via activation of the AhR cascade. Taken together, these data established human hepatic transporters as targets of organic chemicals containing in DEPs, which may contribute to their systemic effects through impairing hepatic transport of endogenous compound or drug substrates of these transporters.
ISSN: 1932-6203

Droits : http://creativecommons.org/licenses/by/
hal-01138535
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01138535
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01138535/document
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01138535/file/Regulation%20of%20human%20hepatic%20drug.pdf
DOI : 10.1371/journal.pone.0121232

Éditeur(s) : HAL CCSD American Chemical Society
Résumé : International audience
Cyanobacterial toxins and pesticides regularly impact freshwaters. Microcystin-LR is one of the most toxic and common cyanobacterial toxins whereas glyphosate is the active ingredient of a widely use herbicide. As filter feeders, freshwater mussels are particularly exposed. Like many native bivalve species, Unio pictorum suffers from a continuous decline in Europe. In order to get a deeper insight of its response to contaminants, U. pictorum was exposed to either 10 μg L(-1) of microcystin-LR or 10 μg L(-1) of glyphosate or a mixture of both. Proteins of the digestive glands were extracted and analyzed by DIGE. Gel analysis revealed 103 spots with statistical variations, and the response seems to be less toward glyphosate than to microcystin-LR. Specific spots have variations only when exposed to the mixture, showing that there is an interaction of both contaminants in the responses triggered. The proteins of 30 spots have been identified. They belong mostly to the cytoskeleton family, but proteins of the oxidative pathway, detoxification, and energetic metabolism were affected either by glyphosate or microcystin-LR or by the mixture. These results demonstrate the importance to study contaminants at low concentrations representative of those found in the field and that multicontaminations can lead to different response pathways.
ISSN: 1535-3893

hal-00877711
https://hal.archives-ouvertes.fr/hal-00877711
DOI : 10.1021/pr4006316
PUBMED : 23972258

Éditeur(s) : HAL CCSD Wiley
Résumé : International audience
Exposure to solvents during pregnancy has long been suspected to increase the risk of congenital malformations. Glutathione S-transferases (GSTs) are enzymes essential for the detoxification of various chemicals. Our objective here was to assess whether GST polymorphisms might modify the association between maternal solvent exposure and the risk of birth defects. A prospective cohort included 3421 pregnant women in Brittany, France (2002-2006). Occupational exposure to solvents was assessed from a job-exposure matrix. Congenital malformations were diagnosed among livebirths, stillbirths, and medical pregnancy terminations. Using a nested case-control design, 32 babies with major birth defects were compared to 348 normal births for babies' cord blood genotypes (at GSTT1 and GSTM1) and maternal occupational solvent exposure. Logistic models were used to adjust for potential confounders. The risk of major defects increased significantly in women with solvent exposure (20% of controls and 34% of cases). Frequencies of the null genotype of both the GSTT1 and GSTM1 genes were similar among controls and cases. There was a significantly increased risk of birth defects in GSTM1 not-null cord-blood genotype in pregnancies exposed to solvents (odds ratio [OR], 1.0 for not-null, not-exposed; OR, 4.0 for not-null, exposed; 95% confidence interval [CI], 1.4-11.2; OR, 1.6 for null, not-exposed; 95% CI, 0.6-3.9; OR, 1.0 for null, exposed; 95% CI, 0.2-4.7; p = 0.05). This nested case-control study suggests that the child's GSTM1 genotype modifies the risk of major birth defects among offspring of solvent-exposed women. Replication and additional investigations are necessary to confirm and elucidate these findings.
ISSN: 1542-0752

hal-00875957
https://hal.archives-ouvertes.fr/hal-00875957
DOI : 10.1002/bdra.23018
PUBMED : 22570144

Éditeur(s) : HAL CCSD Wiley
Résumé : International audience
Recent reports suggest that extracellular signal-regulated kinase (ERK1) and ERK2 mitogen-activated protein kinases (MAPK) may direct specific biological functions under certain contexts. In this study, we investigated the role of early and sustained epidermal growth factor (EGF) stimulation on long-term hepatocyte differentiation and the possible role of ERK1 and ERK2 in this process. We demonstrate a long-term survival and an elevated level of differentiation up to 3 weeks. The differentiation state of hepatocytes is supported by sustained expression of aldolase B, albumin, and the detoxifying enzymes CYP1A2, 2B2, and 3A23. Similarly to freshly isolated cells, cultured hepatocytes also retain the ability to respond to 3-methylcholanthrene (3MC) and phenobarbital (PB), two known CYP inducers. In addition, we show evidence that continuous MAPK/ERK kinase (MEK) inhibition enhances the level of differentiation. Using RNA interference approaches against ERK1 and ERK2, we demonstrate that this effect requires both ERK1 and ERK2 activity, whereas the specific ERK1 knockdown promotes cell survival and the specific ERK2 knockdown regulates cell proliferation. In conclusion, we demonstrate that early and sustained EGF stimulation greatly extends long-term hepatocyte survival and differentiation, and that inhibition of the ERK1/2 MAPK pathway potentiates these pro-survival/pro-differentiation phenotypes. We clearly attest that specific ERK1 and ERK2 MAPKs determine hepatocyte survival and proliferation, respectively, whereas dual inhibition is required to stabilize a highly differentiated state.
ISSN: 0021-9541

hal-00681056
https://hal.archives-ouvertes.fr/hal-00681056
DOI : 10.1002/jcp.22742
PUBMED : 21437905

Éditeur(s) : HAL CCSD Springer Verlag
Résumé : International audience
The implication of oxidative stress as primary mechanism inducing doxorubicin (DOX) cardiotoxicity is still questionable as many in vitro studies implied supra-clinical drug doses or unreliable methodologies for reactive oxygen species (ROS) detection. The aim of this study was to clarify whether oxidative stress is involved in compliance with the conditions of clinical use of DOX, and using reliable tools for ROS detection. We examined the cytotoxic mechanisms of 2 μM DOX 1 day after the beginning of the treatment in differentiated H9c2 rat embryonic cardiac cells. Cells were exposed for 2 or 24 h with DOX to mimic a single chronic dosage or to favor accumulation, respectively. We found that apoptosis was prevalent in cells exposed for a short period with DOX: cells showed typical hallmarks as loss of anchorage ability, mitochondrial hyperpolarization followed by the collapse of mitochondrial activity, and nuclear condensation. Increasing the exposure period favored a shift to necrosis as the cells preferentially exhibited early DNA impairment and nuclear swelling. In either case, measuring the fluorescence lifetime of 1-pyrenebutyric acid or the intensities of dihydroethidium or amplex red showed a consistent pattern in ROS production which was a slight increased level far from representative of an oxidative stress. Moreover, pre-treatment with dexrazoxane provided a cytoprotective effect although it failed to detoxify ROS. Our data support that oxidative stress is unlikely to be the primary mechanism of DOX cardiac toxicity in vitro.
ISSN: 0300-8177

hal-01285736
https://hal-univ-perp.archives-ouvertes.fr/hal-01285736
DOI : 10.1007/s11010-016-2653-x

Éditeur(s) : HAL CCSD Elsevier
Résumé : International audience
The influence of redox alteration on the growth and proteomic pattern of Listeria monocytogenes was investigated. A redox shock was induced in cultures by addition of 3mM ferricyanide (FeCN) and 6mM dithiothreitol (DTT) to increase or to decrease respectively the redox potential naturally occurring at the beginning of growth. In both conditions, the reducing and oxidizing redox shock had a strong influence, decreasing the maximum growth rate by half compared to a control culture. The proteomic analysis of L. monocytogenes performed by two-dimensional difference gel electrophoresis (2D-DIGE) exhibited twenty-three proteins differentially expressed (P<0.05), among these, many were oxidoreductases, and proteins involved in cellular metabolism (glycolysis, protein synthesis), detoxification (kat) or adhesion (Lmo1634).
ISSN: 1874-3919

hal-00877138
https://hal-univ-rennes1.archives-ouvertes.fr/hal-00877138
DOI : 10.1016/j.jprot.2012.11.010
PUBMED : 23195917

Éditeur(s) : HAL CCSD Royal Society of Chemistry
Résumé : International audience
Chemical mediation regulates behavioral interactions between species and thus affects population structure,community organization and ecosystem function. Among marine taxa that have developed chemicalmediation strategies, gastropods belong to a diverse group of molluscs found worldwide, including specieswith a coiled, reduced or absent shell. Most gastropods use natural products to mediate a wide range ofbehaviors such as defense, prey location or interactions with con- and hetero-geners. Their chemicallydefended diet, such as cyanobacteria, algae, sponges, bryozoans and tunicates, provides them witha considerable opportunity either as shelter from predators, or as a means to enhance their own chemicaldefense. In addition to improving their defenses, molluscs also use prey secondary metabolites in complexchemical communication including settlement induction, prey detection and feeding preferences. Theassimilation of prey secondary metabolites further provides the opportunity for interactions withconspecifics via diet-derived chemical cues or signals. This review intends to provide an overview on thesequestration, detoxification, and biotransformation of diet-derived natural products, as well as the role ofthese compounds as chemical mediators in gastropod-prey interactions.
ISSN: 0265-0568

hal-01563402
https://hal-univ-perp.archives-ouvertes.fr/hal-01563402
DOI : 10.1039/c6np00097e