Éditeur(s) : HAL CCSD
47. European Congress of Toxicology (EUROTOX 2011)
Paris, France

ineris-00970856
https://hal-ineris.archives-ouvertes.fr/ineris-00970856
INERIS : EN-2011-261

Éditeur(s) : HAL CCSD Elsevier Masson
Résumé : National audience
The immune system contributes to maintaining the integrity of the organism. It can be the target of many xenobiotics, and immunotoxicology attempts to analyze the immunological alterations caused by exposure to these xenobiotics. Several environmental pollutants are strongly suspected of acting on the immune system to cause a decrease in the organism protective functions. Thus, polycyclic aromatic hydrocarbons, well known for their carcinogenic effects, have also been shown to induce immunosuppressive effects, pro-inflammatory actions and some hypersensitivity reactions, involved in the development of various pathologies. These different immunotoxic effects have mainly been identified by experimental studies on animals and our knowledge of the effects on humans remains incomplete. To better understand the immunotoxic effects of exposure to environmental pollutants and their consequences for human health, it is appropriate to strengthen immunotoxicology studies on humans.
Le système immunitaire contribue à la surveillance et au maintien de l’intégrité de l’organisme. Il peut être la cible de nombreux xénobiotiques, et l’immunotoxicologie s’attache à étudier les différentes atteintes immunologiques induites par l’exposition à ces xénobiotiques. De nombreux polluants environnementaux sont fortement suspectés d’agir sur le système immunitaire pour entraîner une diminution des fonctions de protection de l’organisme. Ainsi, les hydrocarbures aromatiques polycycliques, bien connus pour leurs effets cancérogènes, se sont révélés également capables d’induire des effets immunosuppresseurs, d’entraîner des actions pro-inflammatoires et de majorer certaines réactions d’hypersensibilité, impliqués dans le développement de diverses pathologies. Ces différents effets immunotoxiques ont surtout été identifiés par des études expérimentales chez l’animal et la transposition de ces effets à l’homme reste incomplète. Pour mieux appréhender les effets immunotoxiques de l’exposition aux polluants environnementaux et leurs conséquences sur la santé humaine, il convient donc de renforcer les études en immunotoxicologie chez l’homme.
ISSN: 1775-8785

hal-01467562
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01467562
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01467562/document
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01467562/file/Effets%20immunotoxiques%20des%20polluants%20environnementaux_accepted.pdf
DOI : 10.1016/j.admp.2016.09.003

Éditeur(s) : HAL CCSD Elsevier
Résumé : International audience
Predictive toxicology aims at developing methodologies to relate the results obtained from in vitro experiments to in vivo exposure. In the case of polycyclic aromatic hydrocarbons (PAHs), a substantial amount of knowledge on effects and modes of action has been recently obtained from in vitro studies of gene expression. In the current study, we built a physiologically based toxicokinetic (PBTK) model to relate in vivo and in vitro gene expression in case of exposure to benzo(a)pyrene (BaP), a referent PAH. This model was calibrated with two toxicokinetic datasets obtained on rats exposed either through intratracheal instillation or through intravenous administration and on an in vitro degradation study. A good agreement was obtained between the model's predictions and the concentrations measured in target organs, such as liver and lungs. Our model was able to relate correctly the gene expression for two genes targeted by PAHs, measured in vitro on primary human macrophages and in vivo in rat macrophages after exposure to BaP. Combining in vitro studies and PBTK modeling is promising for PAH risk assessment, especially for mixtures which are more efficiently studied in vitro than in vivo.
Toxicology Letters

hal-00873317
https://hal.archives-ouvertes.fr/hal-00873317
https://hal.archives-ouvertes.fr/hal-00873317/document
DOI : 10.1016/j.toxlet.2010.11.017
PUBMED : 21134426

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
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
Polycyclic aromatic hydrocarbons (PAHs), such as benzo[a]pyrene (B[a]P), are widely distributed environmental contaminants exerting toxic effects such as genotoxicity and carcinogenicity, mainly associated with aryl hydrocarbon receptor (AhR) activation and the subsequent induction of cytochromes P-450 (CYP) 1-metabolizing enzymes. We previously reported an up-regulation of AhR expression and activity in primary cultures of human T lymphocyte by a physiological activation. Despite the suggested link between exposure to PAHs and the risk of lymphoma, the potential of activated human T lymphocytes to metabolize AhR exogenous ligands such as B[a]P, and produce DNA damage has not been investigated. In the present study, we characterized the genotoxic response of primary activated T lymphocytes to B[a] P. We demonstrated that, following T lymphocyte activation, B[a]P treatment triggers a marked increase in CYP1 expression and activity generating, upon metabolic activation, DNA adducts and double-strand breaks (DSBs) after a 48-h treatment. At this time point, B[a]P also induces a DNA damage response with ataxia telangiectasia mutated kinase activation, thus producing a p53-dependent response and T lymphocyte survival. B[a]P activates DSB repair by mobilizing homologous recombination machinery but also induces gene mutations in activated human T lymphocytes which could consequently drive a cancer process. In conclusion, primary cultures of activated human T lymphocytes represent a good model for studying genotoxic effects of environmental contaminants such as PAHs, and predicting human health issues.
ISSN: 0006-2952

hal-01560145
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01560145
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01560145/document
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01560145/file/Liamin%20et%20al.%20-%20Benzo%5Ba%5Dpyrene-induced%20DNA%20damage%20associated%20with%20.pdf
DOI : 10.1016/j.bcp.2017.04.025

Éditeur(s) : HAL CCSD Wiley-VCH Verlag
Résumé : International audience
The aryl hydrocarbon receptor (AhR) is a ligand-dependent transcription factor that mediates immunosuppression caused by a variety of environmental contaminants, such as polycyclic aromatic hydrocarbons or dioxins. Recent evidence suggests that AhR plays an important role in T-cell-mediated immune responses by affecting the polarization and differentiation of activated T cells. However, the regulation of AhR expression in activated T cells remains poorly characterized. In the present study, we used purified human T cells stimulated with anti-CD3 and anti-CD28 Abs to investigate the effect of T-cell activation on AhR mRNA and protein expression. The expression of AhR mRNA increased significantly and rapidly after T-cell activation, identifying AhR as an immediate-early activation gene. AhR upregulation occurred in all of the T-cell subtypes, and is associated with its nuclear translocation and induction of the cytochromes P-450 1A1 and 1B1 mRNA expression in the absence of exogenous signals. In addition, the use of an AhR antagonist or siRNA-mediated AhR knockdown significantly inhibited IL-22 expression, suggesting that expression and functional activation of AhR is necessary for the secretion of IL-22 by activated T cells. In conclusion, our data support the idea that AhR is a major player in T-cell physiology.
ISSN: 0014-2980

hal-01063944
https://hal.archives-ouvertes.fr/hal-01063944
DOI : 10.1002/eji.201343920
PUBMED : 24549985

Éditeur(s) : HAL CCSD Nature Publishing Group
Résumé : International audience
Exposure to environmental polycyclic aromatic hydrocarbons (PAHs), such as benzo(a) pyrene (B(a) P), has been linked to several health-threatening risks. PAHs were also shown to hinder adrenergic receptor (ADR) responses. As we previously demonstrated that Ba) P can directly interact with the beta 2ADR, we investigated here whether B(a) P could decrease beta 2ADR responsiveness by triggering receptor desensitization phenomena. We firstly showed that exposure to B(a) P reduced beta 2ADRmediated epinephrine-induced induction of NR4A gene mRNAs and of intracellular cAMP. Analysis of beta 2ADR protein expression demonstrated that B(a) P rapidly decreased membrane expression of beta 2ADR with a subsequent degradation of receptor protein. B(a) P exposure concomitantly rapidly increased the beta 2ADR mRNA levels. The use of the beta-blockers, propranolol and ICI 118.551, demonstrated the involvement of beta 2ADR itself in this increase. However, sustained exposure to Ba) P induced a diminution of beta 2ADR mRNA steady-state as a result of the acceleration of its degradation. Together, these results show that, beside the well-known activation of the aryl hydrocarbon receptor, PAH deleterious effects may involve the dysfunction of adrenergic responses through, in part, the desensitization of beta 2ADR. This may be taken in consideration when beta 2-agonists/antagonists are administered in patients exposed to important concentrations of PAHs, e.g. in cigarette smokers.
ISSN: 2045-2322

hal-01560151
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01560151
DOI : 10.1038/s41598-017-03646-4
PUBMED : 28607424