Éditeur(s) : HAL CCSD
Résumé : Inorganic arsenic is an environmental human carcinogen, but is also studied these days because of its potential effectiveness in curing chronic inflammatory disease. Indeed, this metalloid possesses immunosuppressive properties which can dysregulate physiological mechanisms involved in immune defense, or reduce inflammation associated with those inflammatory diseases. Inorganic arsenic is known mainly to alter functions of T cells and macrophages. However, it is unknown whether arsenic targets dendritic cells (DCs). Yet, this antigen presenting cells plays a major role in the immunosurveillance, and is involved in the physiopathology of chronic inflammatory diseases. So, the aim of my thesis work was to study the effects of inorganic arsenic on in vitro differenciation and maturation of dendritic cells from human monocytes. Our results mainly shows that concentrations corresponding to those measured in environmentally exposed people, inhibits DCs secretion of proinflammatory cytokines, which plays a major role in activation and polarization of T cells. Particularly, arsenic strongly impairs expression and secretion of interleukine 12 (IL-12) by an underlying molecular mechanism involving Nrf2. Finally, this work shows that inorganic arsenic has immunosuppressive properties on the physiology in vitro of human dendritic cells. Immunotoxicity may then contribute to the metalloid toxicity in environmentally exposed people. This element could be taken into account when determining arsenic effects in curing some chronic inflammatory diseases.
L’arsenic inorganique est un contaminant environnemental, cancérogène pour l’homme, mais également un métalloïde étudié, aujourd’hui, dans le traitement de maladies inflammatoires chroniques. Il possède des propriétés immunosuppressives pouvant déréguler les mécanismes physiologiques de défense ou bloquer l’exacerbation de réponses inflammatoires chroniques. L’arsenic inorganique altère principalement les fonctions des lymphocytes T et des macrophages. En revanche, l’impact du métalloïde sur la physiologie des cellules dendritiques (DCs) est peu connu. Pourtant, ces cellules présentatrices d’antigène jouent un rôle fondamental dans les processus d’immunosurveillance et sont très impliquées dans la physiopathologie des maladies inflammatoires chroniques. Dans ce contexte, les objectifs de mon travail de thèse étaient d’étudier les effets de l’arsenic inorganique sur la différenciation et la maturation in vitro de DCs générées à partir de monocytes humains. Nos résultats démontrent principalement que des concentrations de métalloïde, compatibles avec les taux plasmatiques d’arsenic mesurés chez les individus exposés, répriment la capacité des DCs à sécréter différentes cytokines pro-inflammatoires jouant un rôle essentiel dans l’activation et la polarisation des lymphocytes T. En particulier, l’arsenic inhibe l’expression et la sécrétion de l’interleukine-12 par un mécanisme moléculaire impliquant le facteur de transcription Nrf2. Au total, ces travaux de thèse démontrent que l’arsenic inorganique possède des propriétés immunosuppressives sur la physiologie in vitro des DCs humaines. Cette immunotoxicité pourrait contribuer à la toxicité du métalloïde chez l’homme exposé par voie environnementale, et être prise en compte pour déterminer les effets de l’arsenic dans le traitement de certaines maladies inflammatoires chroniques
https://tel.archives-ouvertes.fr/tel-01135887

NNT : 2013REN1B013
tel-01135887
https://tel.archives-ouvertes.fr/tel-01135887
https://tel.archives-ouvertes.fr/tel-01135887/document
https://tel.archives-ouvertes.fr/tel-01135887/file/pdf2star-1392896105-Th--se-M--linda-Macoch2.pdf

Résumé : Arsenic levels of in the marine environment are high in comparison with other contaminants. Over the past twenty years, a large number of arsenic organic compounds have been identified in the water, sediments and living species. This document constitutes a synthesis of current knowledge on arsenic sources, and contamination levels, on its biogeochemical cycle as well as its toxic effects on human and marine fauna. This paper highlights in particular the effects of phosynthesis on arsenic speciation and its distribution throughout the marine environment. Problems of toxicity in the case of certain phyto- and zooplankton species are identified. Bioaccumulation in seaweeds, molluscs and fishes is documented as well, with special attention to the species encountered in the French coastal waters.
Les niveaux de présence de l'arsenic en milieu marin sont élevés comparativement à d'autres contaminants. Depuis une vingtaine d'années, de nombreux composés organiques de l'arsenic ont été identifiés dans l'eau, les sédiments et les espèces vivantes. Le présent document constitue une synthèse des connaissances sur les sources et les niveaux de contamination, le cycle biogéochimique, les effets toxiques pour l'homme et les espèces marines. L'accent est mis notamment sur les effets de la photosynthèse sur la spéciation de cet élément et sur sa distribution dans le milieu. Les problèmes de toxicité pour certaines espèces phyto- et zooplanctonniques sont identifiés. La bioaccumulation chez les algues, les mollusques et les poissons est bien documentée, avec une attention particulière pour les espèces présentes dans les eaux côtières françaises.

Droits : info:eu-repo/semantics/openAccess
http://archimer.ifremer.fr/doc/1993/rapport-1448.pdf
http://archimer.ifremer.fr/doc/00000/1448/

Éditeur(s) : HAL CCSD Elsevier
Résumé : International audience
Experimental studies have demonstrated that the antileukemic trivalent inorganic arsenic prevents the development of severe pro-inflammatory diseases mediated by excessive Th1 and Th17 cell responses. Differentiation of Th1 and Th17 subsets is mainly regulated by interleukins (ILs) secreted from dendritic cells (DCs) and the ability of inorganic arsenic to impair interferon-γ and IL-17 secretion by interfering with the physiology of DCs is unknown. In the present study, we demonstrate that high concentrations of sodium arsenite (As(III), 1-2 μM) clinically achievable in plasma of arsenic-treated patients, block differentiation of human peripheral blood monocytes into immature DCs (iDCs) by inducing their necrosis. Differentiation of monocytes in the presence of non-cytotoxic concentrations of As(III) (0.1 to 0.5 μM) only slightly impacts endocytotic activity of iDCs or expression of co-stimulatory molecules in cells activated with lipopolysaccharide. However, this differentiation in the presence of As(III) strongly represses secretion of IL-12p70 and IL-23, two major regulators of Th1 and Th17 activities, from iDCs stimulated with different toll-like receptor (TLR) agonists in metalloid-free medium. Such As(III)-exposed DCs also exhibit reduced mRNA levels of IL12A and/or IL12B genes when activated with TLR agonists. Finally, differentiation of monocytes with non-cytotoxic concentrations of As(III) subsequently reduces the ability of activated DCs to stimulate the release of interferon-γ and IL-17 from Th cells. In conclusion, our results demonstrate that clinically relevant concentrations of inorganic arsenic markedly impair in vitro differentiation and functions of DCs, which may contribute to the putative beneficial effects of the metalloid towards inflammatory autoimmune diseases.
ISSN: 0041-008X

inserm-00813758
http://www.hal.inserm.fr/inserm-00813758
DOI : 10.1016/j.taap.2012.11.008
PUBMED : 23164666

Résumé : Le présent rapport constitue une première présentation des résultats de l'Etude pilote des apports en contaminants par la Seine. Il est consacré aux métaux et à l'arsenic et traite de leurs niveaux de concentration, de leurs variations saisonnières et des flux à l'estuaire. Il comporte des fiches-annexes qui contiennent les méthodes de prélèvement, de filtration et de dosage ainsi que des résumés des résultats. A partir des conclusions, des recommandations sont faites quant aux méthodes à privilégier pour tirer les meilleurs enseignements du suivi des contaminants métalliques et de l'arsenic à la limite amont de l'estuaire de la Seine. Les données contenues dans ce rapport ont été produites par la Cellule de lutte contre la pollution (Service de navigation de la Seine), le laboratoire Chimie des contaminants et modélisation (IFREMER) et le Laboratoire municipal et régional de Rouen.

Droits : 1992 Ifremer
http://archimer.ifremer.fr/doc/00131/24272/22270.pdf
http://archimer.ifremer.fr/doc/00131/24272/

Éditeur(s) : HAL CCSD Elsevier
Résumé : International audience
The transcription factor nuclear factor-erythroid 2-related-2 (Nrf2) controls cellular redox homeostasis and displays immunomodulatory properties. Nrf2 alters cytokine expression in murine T cells, but its effects in human T lymphocytes are unknown. This study investigated the expression and activity of Nrf2 in human activated CD4(+) T helper lymphocytes (Th cells) that mediate the adaptive immune response. Th cells were isolated from peripheral blood mononuclear cells and activated with antibodies against CD3 and CD28, mimicking physiologic Th cell stimulation by dendritic cells. Nrf2 is hardly detectable in unstimulated Th cells. Activation of Th cells rapidly and strongly increases the levels of Nrf2 protein by increasing NRF2 gene transcription. Th cell activation also enhances mRNA and protein levels of Nrf2 target genes encoding antioxidant enzymes. Blocking Nrf2 expression using chemical inhibitors or siRNAs prevents these gene inductions. Pretreatment with inorganic arsenic, a Nrf2 inducer that does not alter NRF2 gene expression, increases protein level and transcriptional activity of Nrf2 induced by Th cell stimulation. Inorganic arsenic enhances nuclear translocation of Nrf2, its interaction with the coactivator protein p300, and its DNA binding activity. Inhibition of Nrf2 expression abrogates the effects of inorganic arsenic on mRNA levels of antioxidant genes, but does not alter the expression of IL-2, TNF-α, interferon-γ, or IL-17 in Th cells activated in the absence or presence of the metalloid. In conclusion, this study demonstrates for the first time that stimulation of human Th cells increases transcription of the NRF2 gene and activity of the Nrf2 protein. However, modulation of Nrf2 levels does not modify the secretion of inflammatory cytokines from these T lymphocytes.
ISSN: 0891-5849

hal-01018643
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01018643
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01018643/document
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01018643/file/Nrf2_expression_and_activity_in_human_T_lymphocytes_accepted.pdf
DOI : 10.1016/j.freeradbiomed.2014.03.006

Éditeur(s) : HAL CCSD Elsevier
Résumé : International audience
Inorganic arsenic is a toxic environmental contaminant to which humans are mainly exposed through drinking water. This metalloid impairs functions of several key immune cells. Particularly, it reduces IL-2 secretion and proliferation of blood peripheral mononuclear cells stimulated by lectins that, however, do not mimic physiological T cell activation. The present study used isolated human T cells activated, in a more physiological manner, through stimulation with CD3/CD28 antibodies, to carefully analyze the impact of arsenic on T cell proliferation and cytokine expression. We demonstrate that non cytotoxic concentrations of sodium arsenite (As(III), 0.25-2μM) significantly reduce T cell proliferation by increasing the percentage of non dividing cells blocked in G1 phase and by preventing cyclin D3 and CDC25A expression. They also markedly, although not totally, reduces IL-2 expression at both mRNA and protein levels; however, metalloid-dependent inhibition of T cells could not be reversed by addition of recombinant IL-2. In addition, As(III) markedly reduces secretion of interferon-γ without impairing that of IL-4 and IL-13; it also decreases interferon-γ mRNA levels but increases those of IL-13. Finally, simultaneously to its immune effects, As(III) rapidly and potently increases expression of the redox-sensitive genes HMOX1, NQO1 and GCLM in activated T cells without altering the levels of reactive oxygen species. In conclusion, our results demonstrate that As(III) inhibits T cell proliferation, independently of IL-2, and alters the Th balance of cytokines secreted by co-stimulated T cells which thus constitute direct targets of this major environmental contaminant.
ISSN: 0300-483X

inserm-00872848
http://www.hal.inserm.fr/inserm-00872848
DOI : 10.1016/j.tox.2012.05.025
PUBMED : 22683347

Éditeur(s) : Elsevier
Résumé : Regardless of the degree of closure of a recirculation system, effluents are produced and replacement water is needed, which limits the possibility of locating a seawater production system away from the shoreline. At the Palavas Ifremer station, in the south of France, a High Rate Algal Pond (HRAP) was operated during several years to treat the effluent from a recirculating aquaculture system before reusing it. The effect of the HRAP-treated water on the recirculation system and on the fish was investigated and the optimal algae growing conditions were defined. The experiments were carried out in three rearing systems: one flow through, one recirculating and one recirculating with a HRAP. The water flow rate, temperature, pH and salinity conditions were similar in all systems. The effect of reusing the HRAP-treated water is very limited (1) on the functioning of the recirculation system and (2) on fish performance, but it allows a significant reduction of the dissolved inorganic nitrogen and phosphorus concentration in the rearing water. HRAP treatment reduced metal accumulation in muscle and liver of RAS fish, except for chromium and arsenic. All biomarkers presented no significant difference between systems, except for Superoxide Dismutase (SOD) and EROD, which showed a higher concentration in RAS and in both recirculating system respectively. (c) 2005 Elsevier B.V. All rights reserved.
Aquaculture (0044-8486) (Elsevier), 2006-03 , Vol. 252 , N. 1 , P. 92-101

Droits : 2005 Elsevier
http://archimer.ifremer.fr/doc/2006/publication-2306.pdf
DOI:10.1016/j.aquaculture.2005.11.053
http://archimer.ifremer.fr/doc/00000/2306/

Éditeur(s) : HAL CCSD Elsevier
Résumé : International audience
Trivalent inorganic arsenic [As(III)] is an efficient anticancer agent used to treat patients suffering from acute promyelocytic leukemia. Recently, experimental studies have clearly demonstrated that this metalloid can also cure lymphoproliferative and/or pro-inflammatory syndromes in different murine models of chronic immune-mediated diseases. T helper (Th) 1 and Th17 lymphocytes play a central role in development of these diseases, in mice and humans, especially by secreting the potent pro-inflammatory cytokine interferon-γ and IL-17A, respectively. As(III) impairs basic functions of human T cells but its ability to modulate secretion of pro-inflammatory cytokines by differentiated Th lymphocytes is unknown. In the present study, we demonstrate that As(III), used at concentrations clinically achievable in plasma of patients, has no effect on the secretion of interferon-γ from Th1 cells but almost totally blocks the expression and the release of IL-17A from human Th17 lymphocytes co-stimulated for five days with anti-CD3 and anti-CD28 antibodies, in the presence of differentiating cytokines. In addition, As(III) specifically reduces mRNA levels of the retinoic-related orphan receptor (ROR)C gene which encodes RORγt, a key transcription factor controlling optimal IL-17 expression in fully differentiated Th17 cells. The metalloid also blocks initial expression of IL-17 gene induced by the co-stimulation, probably in part by impairing activation of the JNK/c-Jun pathway. In conclusion, our results demonstrate that As(III) represses expression of the major pro-inflammatory cytokine IL-17A produced by human Th17 lymphocytes, thus strengthening the idea that As(III) may be useful to treat inflammatory immune-mediated diseases in humans.
ISSN: 0041-008X

inserm-00872871
http://www.hal.inserm.fr/inserm-00872871
DOI : 10.1016/j.taap.2012.05.004
PUBMED : 22617429

Éditeur(s) : HAL CCSD Elsevier
Résumé : International audience
Cold seeps, located on sea floors and frequently fueled with methane, have been much studied for the formation of carbonate nodules, crusts or masses resulting from the activity og communities of anaerobic bacteria. In this paper, we examine the impact of cold seepage on their caging sediments, as far as their geochemical composition and microfaunal content are concerned. To this end, two fossil cold seeps of the Jurassic Beauvoisin site (Vocontian Trough, SE-France) are studied, focusing on the redox-sensitive and/or sulfide-forming trace metals. We observe that: 1) the carbonate edifices of the cold seeps are enriched in specific elements, namely, Sr, Mo As and Sb, compared to their caging marlstones, and 2) the benthic foraminifer populations were present close to the edifices. The Sr enrichment is ascribed to a contamination of the seeping fluids at the contact with underlying evaporites; the Mo-As-Sb enrichment may have several, non-exclusive, origins. We retain two scenarios; in the first one, the enrichment is due to the ascending fluids that could collect these elements when passing through thick shaly formations; in the second scenario, Mo, As and Sb were supplied to the sites of carbonate precipitation together with Fe- and Mn-oxy-hydroxides (the so-called particulate shuttle process). We favor the second scenario (possibly coupled to the first one) because the rather uncommon Mo-As-Sb association is also observed for reducing sediments deposited under the influence of Fe-Mn-shuttling.
ISSN: 0009-2541

hal-00806655
https://hal.archives-ouvertes.fr/hal-00806655
DOI : 10.1016/j.chemgeo.2012.12.012

Éditeur(s) : Elsevier
Résumé : Uptake of waterborne Cd, Co, Mn and Zn was determined in laboratory experiments using radiotracer techniques (Cd-109, Co-57, Mn-54 and Zn-65). Labelled Zn was mainly accumulated in the digestive gland (65%) and Co in kidneys (81%); Cd and Mn were similarly distributed in digestive gland and gills. In a complementary field study, Ag, As, Cd, Co, Cr, Cu, Fe, Mn, Ni, and Zn were analysed in scallops collected at two stations showing different contamination levels. Digestive gland and kidneys displayed the highest concentrations. Ag, As, Cd, and Fe differed in soft tissues from the two stations, suggesting that Comptopallium radula could be a valuable local biomonitor species for these elements. Low Mn and Zn concentrations found in kidneys suggest that their content in calcium-phosphate concretions differs from the other pectinids. Preliminary risk considerations suggest that As would be the only element potentially leading to exposure of concern for seafood consumers. (c) 2007 Elsevier Ltd. All rights reserved.
Environmental Pollution (0269-7491) (Elsevier), 2008-04 , Vol. 152 , N. 3 , P. 543-552

Droits : 2007 Elsevier Ltd All rights reserved.
http://archimer.ifremer.fr/doc/2008/publication-6953.pdf
DOI:10.1016/j.envpol.2007.07.009
http://archimer.ifremer.fr/doc/00000/6953/

Résumé : Aujourd’hui, il est indispensable de découvrir de nouveaux agents thérapeutiques pour faire face à l’expansion des infections fongiques humaines. D’un autre côté, certains arbres amazoniens ont acquis des moyens pour se protéger contre la dégradation fongique. Ces composés d’origine végétale pourraient donc être des candidats potentiels au développement de composés antifongiques. Il est ainsi exposé dans ce travail la sélection bio-inspirée et la récolte d’espèces d’arbres amazoniens résistants à la dégradation fongique ; à partir desquelles il est proposé d’isoler, d’identifier et de valoriser les métabolites responsables de la durabilité naturelle et d’étudier leurs propriétés sur des champignons pathogènes humains. Cette étude a conduit à l’isolement de molécules inédites apportant un complément d’information chimiotaxonomique pour les espèces étudiées. De plus, il a pu être mis en avant deux molécules pouvant devenir des composés pertinents pour le développement de traitements antimycotiques.
It is now essential to discover new therapeutic agents against the increase of human fungal infections. On the other hand, some Amazonian trees have succeeded to develop a chemical defense arsenal to protect themselves against fungal degradation. These compounds of plant origin could become potential candidates for the development of antifungal compounds for the treatment of human fungal diseases. Therefore, this manuscript describes the bio-inspired selection and collection of Amazonian tree species capable of specializing a highly fungiresistant wood; from which it is proposed to isolate, identify and valorize the secondary metabolites responsible for the natural durability, and study their properties on human pathogenic fungi. Ultimately, this study led to the isolation of new compounds and providing additional important chemotaxonomic information for the species studied. In addition, it as been established that two compounds could be relevant for the development of antimitotic therapies.

http://www.theses.fr/2011AGUY0467/document