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Olivier Fardel - One of the best experts on this subject based on the ideXlab platform.
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differentiation of human placental bewo cells by the Environmental Contaminant benzo a pyrene
Chemico-Biological Interactions, 2014Co-Authors: Marc Le Vee, Elise Kolasa, Elodie Jouan, Nicolas Collet, Olivier FardelAbstract:Polycyclic aromatic hydrocarbons (PAHs) such as benzo(a)pyrene (BaP) are widely-distributed Environmental Contaminants known to exert toxic effects in various tissues, including placenta. PAHs have notably been shown to inhibit proliferation of trophoblastic cells. The present study was designed to determine whether PAHs can concomitantly affect differentiated functions of trophoblastic cells. BaP was found to induce expression and secretion of β-human chorionic gonadotropin (β-hCG) in human trophoblastic BeWo cells. The PAH also increased mRNA expressions of other trophoblastic differentiation markers, including those of the steroid metabolism enzymes CYP19A1 and HSD11B2 and of the fusogenic protein syncytin-2; in parallel, it triggered syncytialisation of BeWo cells. BaP-mediated β-hCG and syncytin-2 up-regulation was prevented by co-treatment by the aryl hydrocarbon receptor (AhR) antagonist CH-223191 or by knocking-down AhR expression through siRNA transfection. However, the potent AhR agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) failed to induce expression of β-hCG and syncytin-2, indicating that activation of the AhR pathway, known to be implicated in most, if not all, effects of PAHs, was required, but not sufficient. Interestingly, the p53 signaling pathway was activated by BaP, but not by TCDD, in BeWo cells and co-treatment by the p53 inhibitor pifithrin-α or siRNAs-mediated silencing of p53 prevented up-regulation of β-hCG and syncytin-2 induced by BaP. Taken together, these data demonstrate that BaP induces differentiation of placental trophoblastic BeWo cells in an AhR- and p53-dependent manner.
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Inorganic arsenic impairs proliferation and cytokine expression in human primary T lymphocytes.
Toxicology, 2012Co-Authors: Claudie Morzadec, Olivier Fardel, Fidaa Bouezzedine, Mélinda Macoch, Laurent VernhetAbstract: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.
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MAPK- and PKC/CREB-dependent induction of interleukin-11 by the Environmental Contaminant formaldehyde in human bronchial epithelial cells.
Toxicology, 2012Co-Authors: Valérie Lecureur, Matthieu Arzel, Sarah Ameziane, Noémie Houlbert, Marc Le Vee, Stéphane Jouneau, Olivier FardelAbstract:Formaldehyde (FA) is a volatile organic compound (VOC), considered as a major indoor air pollutant and suspected to favor the development of inflammatory lung diseases. The present study was aimed at identifying cytokines/chemokines targeted by FA in human lung cells. This VOC was demonstrated to up-regulate interleukin-11 (IL-11) mRNA and secretion levels in a dose-dependent manner in cultured lung epithelial BEAS-2B cells. It concomitantly induced mRNA expression of transforming growth factor (TGF)-β1, a fibrogenic marker regulated by IL-11. FA was also found to trigger an early phosphorylation of p38 and extracellular signal-regulated kinase (ERK)1/2 mitogen-activated protein kinases (MAPKs) in BEAS-2B cells, whose inhibition by ERK and p38 MAPK chemical inhibitors (U0126 and SB203580, respectively) counteracted FA-mediated induction of IL-11. In addition, FA increased phosphorylation of cAMP response element binding protein (CREB) and the use of small-interfering RNA targeting CREB demonstrated that this transcription factor was required for the up-regulation of IL-11 by FA. Implication of protein kinase C (PKC) in FA-induced IL-11 expression was moreover demonstrated by using RO-31-8220, a PKC inhibitor. We finally showed using SB203580 and RO-31-8220 that phosphorylation of CREB and CREB-promoter activity induced by FA are under the control of both p38 MAPK and PKC. Taken together, the results showed that FA uses different pathways to induce IL-11 expression in lung BEAS-2B cells. IL-11, well-known to contribute to lung inflammatory diseases, appears thus as a molecular target of FA, which could be involved in putative deleterious inflammatory and fibrogenic pulmonary effects of this VOC.
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mapk and pkc creb dependent induction of interleukin 11 by the Environmental Contaminant formaldehyde in human bronchial epithelial cells
Toxicology, 2012Co-Authors: Valérie Lecureur, Marc Le Vee, Matthieu Arzel, Sarah Ameziane, Noémie Houlbert, Stéphane Jouneau, Olivier FardelAbstract:Formaldehyde (FA) is a volatile organic compound (VOC), considered as a major indoor air pollutant and suspected to favor the development of inflammatory lung diseases. The present study was aimed at identifying cytokines/chemokines targeted by FA in human lung cells. This VOC was demonstrated to up-regulate interleukin-11 (IL-11) mRNA and secretion levels in a dose-dependent manner in cultured lung epithelial BEAS-2B cells. It concomitantly induced mRNA expression of transforming growth factor (TGF)-β1, a fibrogenic marker regulated by IL-11. FA was also found to trigger an early phosphorylation of p38 and extracellular signal-regulated kinase (ERK)1/2 mitogen-activated protein kinases (MAPKs) in BEAS-2B cells, whose inhibition by ERK and p38 MAPK chemical inhibitors (U0126 and SB203580, respectively) counteracted FA-mediated induction of IL-11. In addition, FA increased phosphorylation of cAMP response element binding protein (CREB) and the use of small-interfering RNA targeting CREB demonstrated that this transcription factor was required for the up-regulation of IL-11 by FA. Implication of protein kinase C (PKC) in FA-induced IL-11 expression was moreover demonstrated by using RO-31-8220, a PKC inhibitor. We finally showed using SB203580 and RO-31-8220 that phosphorylation of CREB and CREB-promoter activity induced by FA are under the control of both p38 MAPK and PKC. Taken together, the results showed that FA uses different pathways to induce IL-11 expression in lung BEAS-2B cells. IL-11, well-known to contribute to lung inflammatory diseases, appears thus as a molecular target of FA, which could be involved in putative deleterious inflammatory and fibrogenic pulmonary effects of this VOC.
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transcriptional signature of human macrophages exposed to the Environmental Contaminant benzo a pyrene
Toxicological Sciences, 2010Co-Authors: Lydie Sparfel, Marielaure Pinelmarie, Magali Boize, Serge Koscielny, Sophie Desmots, Alexandre R R Pery, Olivier FardelAbstract:Polycyclic aromatic hydrocarbons (PAHs) are widely distributed immunotoxic and carcinogenic Environmental Contaminants, known to affect macrophages. In order to identify their molecular targets in such cells, we have analyzed gene expression profile of primary human macrophages treated by the prototypical PAH benzo(a)pyrene (BaP), using pangenomic oligonucleotides microarrays. Exposure of macrophages to BaP for 8 and 24 h resulted in 96 and 1100 genes, differentially expressed by at least a twofold change factor, respectively. Some of these targets, including the chemokine receptor CXCR5, the G protein-coupled receptor 35 (GPR35), and the Ras regulator RASAL1, have not been previously shown to be affected by PAHs, in contrast to others, such as interleukin-1beta and the aryl hydrocarbon receptor (AhR) repressor. These BaP-mediated gene regulations were fully validated by reverse transcription-quantitative polymerase chain reaction assays for some selected genes. Their bioinformatic analysis indicated that biological functions linked to immunity, inflammation, and cell death were among the most affected by BaP in human macrophages and that the AhR and p53 signaling pathways were the most significant canonical pathways activated by the PAH. AhR and p53 implications were moreover fully confirmed by the prevention of BaP-related upregulation of some selected target genes by AhR silencing or the use of pifithrin-alpha, an inhibitor of PAH bioactivation-related DNA damage/p53 pathways. Overall, these data, through identifying genes and signaling pathways targeted by PAHs in human macrophages, may contribute to better understand the molecular basis of the immunotoxicity of these Environmental Contaminants.
Valérie Lecureur - One of the best experts on this subject based on the ideXlab platform.
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MAPK- and PKC/CREB-dependent induction of interleukin-11 by the Environmental Contaminant formaldehyde in human bronchial epithelial cells.
Toxicology, 2012Co-Authors: Valérie Lecureur, Matthieu Arzel, Sarah Ameziane, Noémie Houlbert, Marc Le Vee, Stéphane Jouneau, Olivier FardelAbstract:Formaldehyde (FA) is a volatile organic compound (VOC), considered as a major indoor air pollutant and suspected to favor the development of inflammatory lung diseases. The present study was aimed at identifying cytokines/chemokines targeted by FA in human lung cells. This VOC was demonstrated to up-regulate interleukin-11 (IL-11) mRNA and secretion levels in a dose-dependent manner in cultured lung epithelial BEAS-2B cells. It concomitantly induced mRNA expression of transforming growth factor (TGF)-β1, a fibrogenic marker regulated by IL-11. FA was also found to trigger an early phosphorylation of p38 and extracellular signal-regulated kinase (ERK)1/2 mitogen-activated protein kinases (MAPKs) in BEAS-2B cells, whose inhibition by ERK and p38 MAPK chemical inhibitors (U0126 and SB203580, respectively) counteracted FA-mediated induction of IL-11. In addition, FA increased phosphorylation of cAMP response element binding protein (CREB) and the use of small-interfering RNA targeting CREB demonstrated that this transcription factor was required for the up-regulation of IL-11 by FA. Implication of protein kinase C (PKC) in FA-induced IL-11 expression was moreover demonstrated by using RO-31-8220, a PKC inhibitor. We finally showed using SB203580 and RO-31-8220 that phosphorylation of CREB and CREB-promoter activity induced by FA are under the control of both p38 MAPK and PKC. Taken together, the results showed that FA uses different pathways to induce IL-11 expression in lung BEAS-2B cells. IL-11, well-known to contribute to lung inflammatory diseases, appears thus as a molecular target of FA, which could be involved in putative deleterious inflammatory and fibrogenic pulmonary effects of this VOC.
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mapk and pkc creb dependent induction of interleukin 11 by the Environmental Contaminant formaldehyde in human bronchial epithelial cells
Toxicology, 2012Co-Authors: Valérie Lecureur, Marc Le Vee, Matthieu Arzel, Sarah Ameziane, Noémie Houlbert, Stéphane Jouneau, Olivier FardelAbstract:Formaldehyde (FA) is a volatile organic compound (VOC), considered as a major indoor air pollutant and suspected to favor the development of inflammatory lung diseases. The present study was aimed at identifying cytokines/chemokines targeted by FA in human lung cells. This VOC was demonstrated to up-regulate interleukin-11 (IL-11) mRNA and secretion levels in a dose-dependent manner in cultured lung epithelial BEAS-2B cells. It concomitantly induced mRNA expression of transforming growth factor (TGF)-β1, a fibrogenic marker regulated by IL-11. FA was also found to trigger an early phosphorylation of p38 and extracellular signal-regulated kinase (ERK)1/2 mitogen-activated protein kinases (MAPKs) in BEAS-2B cells, whose inhibition by ERK and p38 MAPK chemical inhibitors (U0126 and SB203580, respectively) counteracted FA-mediated induction of IL-11. In addition, FA increased phosphorylation of cAMP response element binding protein (CREB) and the use of small-interfering RNA targeting CREB demonstrated that this transcription factor was required for the up-regulation of IL-11 by FA. Implication of protein kinase C (PKC) in FA-induced IL-11 expression was moreover demonstrated by using RO-31-8220, a PKC inhibitor. We finally showed using SB203580 and RO-31-8220 that phosphorylation of CREB and CREB-promoter activity induced by FA are under the control of both p38 MAPK and PKC. Taken together, the results showed that FA uses different pathways to induce IL-11 expression in lung BEAS-2B cells. IL-11, well-known to contribute to lung inflammatory diseases, appears thus as a molecular target of FA, which could be involved in putative deleterious inflammatory and fibrogenic pulmonary effects of this VOC.
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inhibition of human mesenchymal stem cell derived adipogenesis by the Environmental Contaminant benzo a pyrene
Toxicology in Vitro, 2009Co-Authors: Normand Podechard, Olivier Fardel, Michel Corolleur, Marc Bernard, Valérie LecureurAbstract:Polycyclic aromatic hydrocarbons (PAHs) such as benzo(a)pyrene (BP) are Environmental Contaminants exerting various toxic effects. PAHs have notably been found to inhibit adipogenesis in rodent species. To determine whether a similar process concerns human cells, we have analyzed the effects of BP towards differentiation of human cultured mesenchymal stem cells (MSC) into adipocytes, triggered by a pro-adipogenic culture medium. BP was found to markedly prevent formation of lipid vesicles, cellular lipid accumulation and up-regulation of adipogenic markers such as fatty acid binding protein-4 and glyceraldehyde-3-phosphate dehydrogenase, which represent major hallmarks of human MSC-derived adipocytes. The aryl hydrocarbon receptor (AhR), known to mediate most of the toxic effects of PAHs, was demonstrated to be present and functional in human MSC. 2,3,7,8-tetrachlorodibenzo-p-dioxin, an AhR agonist like BP, was found to inhibit lipid accumulation in human MSC cultured with adipogenic medium, in contrast to the PAH benzo(e)pyrene, known to not, or only poorly, interact with AhR. Moreover, BP inhibitory effect toward lipid accumulation in MSC exposed to adipogenic medium was fully counteracted by co-treatment with the AhR antagonist alpha-naphtoflavone. Taken together, these data indicate that Environmental PAHs like BP can likely inhibit human adipogenesis in an AhR-dependent manner.
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Interleukin-8 induction by the Environmental Contaminant benzo(a)pyrene is aryl hydrocarbon receptor-dependent and leads to lung inflammation.
Toxicology Letters, 2008Co-Authors: Normand Podechard, Valérie Lecureur, E. Le Ferrec, Isabelle Guenon, Lydie Sparfel, David Gilot, John R. Gordon, Vincent Lagente, Olivier FardelAbstract:Benzo(a)pyrene (BP) is an Environmental Contaminant known to favor airway inflammation likely through up-regulation of pro-inflammatory cytokines. The present study was designed to characterize its effects toward interleukin-8 (IL-8), a well-established pulmonary inflammatory cytokine. In primary human macrophages, BP was shown to induce IL-8 expression at both mRNA and secretion levels in a dose-dependent manner. Such an up-regulation was likely linked to aryl hydrocarbon receptor (AhR)-activation since BP-mediated IL-8 induction was reduced after AhR expression knock-down through RNA interference. Moreover, electrophoretic mobility shift assays (EMSAs) and chromatin immunoprecipitation experiments showed BP-triggered binding of AhR to a consensus xenobiotic responsive element (XRE) found in the human IL-8 promoter. Finally, BP administration to mice led to over-expression of keratinocyte chemoattractant (KC), the murine functional homologue of IL-8, in lung. It also triggered the recruitment of neutrophils in bronchoalveolar lavage (BAL) fluids, which was however fully abolished in the presence of a chemical antagonist of the KC/IL-8 receptors CXCR1/CXCR2, thus supporting the functional and crucial involvement of KC in BP-induced lung inflammation. Overall, these data highlight an AhR-dependent regulation of IL-8 in response to BP that likely contributes to the airway inflammatory effects of this Environmental chemical.
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aryl hydrocarbon receptor and calcium dependent induction of the chemokine ccl1 by the Environmental Contaminant benzo a pyrene
Journal of Biological Chemistry, 2006Co-Authors: Monique Ndiaye, Valérie Lecureur, David Gilot, Eric Le Ferrec, Dominique Lagadicgossmann, Sebastien Corre, Patricia Monteiro, Claudine Rauch, Mariedominique Galibert, Olivier FardelAbstract:Polycyclic aromatic hydrocarbons (PAHs) are widely distributed immunotoxic Environmental Contaminants well known to regulate expression of pro-inflammatory cytokines such as interleukine-1beta and tumor necrosis factor-alpha. In the present study, we demonstrated that the chemokine CCL1, notably involved in cardiovascular diseases and inflammatory or allergic processes, constitutes a new molecular target for PAHs. Indeed, exposure to PAHs such as benzo[a]pyrene (BP) markedly increased mRNA expression and secretion of CCL1 in primary human macrophage cultures. Moreover, intranasal administration of BP to mice enhanced mRNA levels of TCA3, the mouse orthologue of CCL1, in lung. CCL1 induction in cultured human macrophages was fully prevented by targeting the aryl hydrocarbon receptor (AhR) through chemical inhibition or small interfering RNA-mediated down-modulation of its expression. In addition, BP and the potent AhR agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin were found to enhance activity of a CCL1 promoter sequence containing a consensus xenobiotic-responsive element known to specifically interact with AhR. Moreover, 2,3,7,8-tetrachlorodibenzo-p-dioxin triggered AhR binding to this CCL1 promoter element as revealed by chromatin immunoprecipitation experiments and electrophoretic mobility shift assays. In an attempt to further characterize the mechanism of CCL1 induction, we demonstrated that BP was able to induce an early and transient increase of intracellular calcium concentration in human macrophages. Inhibition of this calcium increase, using the calcium chelator 1,2-bis(o-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid tetra(acetoxymethyl) ester or the calcium store-operated channel inhibitor 2-aminoethoxydiphenyl borate, fully blocked CCL1 up-regulation. Taken together, these results bring the first demonstration that PAHs induce expression of the chemokine CCL1 in an AhR- and calcium-dependent manner.
Kristen M Rappazzo - One of the best experts on this subject based on the ideXlab platform.
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science linking Environmental Contaminant exposures with fertility and reproductive health impacts in the adult female
Fertility and Sterility, 2008Co-Authors: Pauline Mendola, Lynne C Messer, Kristen M RappazzoAbstract:Study Objective To broadly review the recent literature linking Environmental factors and adult female reproductive health for the UCSF–CHE Summit on Environmental Challenges to Reproductive Health and Fertility. Design Reviewed articles indexed in PubMed from 1999–2007 addressing environment and puberty, menstrual and ovarian function, fertility, and menopause. Result(s) The strongest evidence of Environmental Contaminant exposures interfering with healthy reproductive function in adult females is for heavy metals, particularly lead. Compounds that can influence hormone function, including pesticides and persistent pollutants, are also associated with risk. The pattern of effects for these endocrine-active compounds is often complex, with no clear dose response, but alterations in function and poor reproductive health outcomes are observed. From a clinical perspective, most modifiable risk appears to be associated with exposures in unique populations (contaminated fish consumers) or occupational groups (farmworkers). Many compounds have demonstrated increased risks for reproductive health impairment in women, but the literature is largely cross-sectional in nature and too sparse or inconclusive to support causal inference. Conclusion(s) Reproductive function in adult females is impaired by lead exposure. Pesticides and persistent pollutants can alter hormone function resulting in adverse reproductive health effects. Coordinated research is needed to address Contaminant effects across the life span.
Lynne C Messer - One of the best experts on this subject based on the ideXlab platform.
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science linking Environmental Contaminant exposures with fertility and reproductive health impacts in the adult female
Fertility and Sterility, 2008Co-Authors: Pauline Mendola, Lynne C Messer, Kristen M RappazzoAbstract:Study Objective To broadly review the recent literature linking Environmental factors and adult female reproductive health for the UCSF–CHE Summit on Environmental Challenges to Reproductive Health and Fertility. Design Reviewed articles indexed in PubMed from 1999–2007 addressing environment and puberty, menstrual and ovarian function, fertility, and menopause. Result(s) The strongest evidence of Environmental Contaminant exposures interfering with healthy reproductive function in adult females is for heavy metals, particularly lead. Compounds that can influence hormone function, including pesticides and persistent pollutants, are also associated with risk. The pattern of effects for these endocrine-active compounds is often complex, with no clear dose response, but alterations in function and poor reproductive health outcomes are observed. From a clinical perspective, most modifiable risk appears to be associated with exposures in unique populations (contaminated fish consumers) or occupational groups (farmworkers). Many compounds have demonstrated increased risks for reproductive health impairment in women, but the literature is largely cross-sectional in nature and too sparse or inconclusive to support causal inference. Conclusion(s) Reproductive function in adult females is impaired by lead exposure. Pesticides and persistent pollutants can alter hormone function resulting in adverse reproductive health effects. Coordinated research is needed to address Contaminant effects across the life span.
Lydie Sparfel - One of the best experts on this subject based on the ideXlab platform.
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transcriptional signature of human macrophages exposed to the Environmental Contaminant benzo a pyrene
Toxicological Sciences, 2010Co-Authors: Lydie Sparfel, Marielaure Pinelmarie, Magali Boize, Serge Koscielny, Sophie Desmots, Alexandre R R Pery, Olivier FardelAbstract:Polycyclic aromatic hydrocarbons (PAHs) are widely distributed immunotoxic and carcinogenic Environmental Contaminants, known to affect macrophages. In order to identify their molecular targets in such cells, we have analyzed gene expression profile of primary human macrophages treated by the prototypical PAH benzo(a)pyrene (BaP), using pangenomic oligonucleotides microarrays. Exposure of macrophages to BaP for 8 and 24 h resulted in 96 and 1100 genes, differentially expressed by at least a twofold change factor, respectively. Some of these targets, including the chemokine receptor CXCR5, the G protein-coupled receptor 35 (GPR35), and the Ras regulator RASAL1, have not been previously shown to be affected by PAHs, in contrast to others, such as interleukin-1beta and the aryl hydrocarbon receptor (AhR) repressor. These BaP-mediated gene regulations were fully validated by reverse transcription-quantitative polymerase chain reaction assays for some selected genes. Their bioinformatic analysis indicated that biological functions linked to immunity, inflammation, and cell death were among the most affected by BaP in human macrophages and that the AhR and p53 signaling pathways were the most significant canonical pathways activated by the PAH. AhR and p53 implications were moreover fully confirmed by the prevention of BaP-related upregulation of some selected target genes by AhR silencing or the use of pifithrin-alpha, an inhibitor of PAH bioactivation-related DNA damage/p53 pathways. Overall, these data, through identifying genes and signaling pathways targeted by PAHs in human macrophages, may contribute to better understand the molecular basis of the immunotoxicity of these Environmental Contaminants.
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Identification of genes regulated by the Environmental Contaminant benzo(a)pyrene in primary human macrophages
2009Co-Authors: Lydie Sparfel, Magali Boize, Serge Koscielny, Sophie Desmots, Alexandre R R Pery, Marie-laure Pinel-marie, Olivier FardelAbstract:Polycyclic aromatic hydrocarbons (PAHs), such as benzo(a)pyrene (BP) are ubiquitous Environmental Contaminants generated by a variety of industrial processes. They exert a wide range of toxic effects including inflammation and carcinogenesis which have been linked, at least in part, to activation of the aryl hydrocarbon receptor (AhR), a ligand-activated basic helix-loop-helix transcriptional factor and to the formation of DNA adducts. Moreover, we have demonstrated that exposure to BP inhibits the differentiation of human monocytes into macrophages and that mature differentiated macrophagic cells also constitute targets for BP. However, the molecular basis of this PAH-induced immunotoxicity is poorly understood. In this way, a precise identification by microarrays of genes regulated by aromatic hydrocarbons is likely interesting to perform in order to characterize molecular targets of PAHs. Moreover, whereas several microarray-based gene expression studies have been conducted to investigate the mechanism of PAH toxicity in various cell strains or tissues of human or rodent origin, only few of these studies have been conducted in human normal cells and especially no study has been done in human macrophagic cells. By using microarray (pangenomic chips 44K Agilent), we have identified a set of genes that are regulated by BP in primary human macrophages. We then attempted to confirm array findings for the leading differentially expressed genes, using real-time quantitative polymerase chain reaction (RT-qPCR). Preliminary data indicate the identification of genes directly regulated by the AhR and also of genes whose regulation are rather linked to the formation of DNA adducts. Such genes may represent potential biomarkers of PAHs-exposure or effects in normal human cells, which could be useful in molecular epidemiology and risk evaluation.
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Interleukin-8 induction by the Environmental Contaminant benzo(a)pyrene is aryl hydrocarbon receptor-dependent and leads to lung inflammation.
Toxicology Letters, 2008Co-Authors: Normand Podechard, Valérie Lecureur, E. Le Ferrec, Isabelle Guenon, Lydie Sparfel, David Gilot, John R. Gordon, Vincent Lagente, Olivier FardelAbstract:Benzo(a)pyrene (BP) is an Environmental Contaminant known to favor airway inflammation likely through up-regulation of pro-inflammatory cytokines. The present study was designed to characterize its effects toward interleukin-8 (IL-8), a well-established pulmonary inflammatory cytokine. In primary human macrophages, BP was shown to induce IL-8 expression at both mRNA and secretion levels in a dose-dependent manner. Such an up-regulation was likely linked to aryl hydrocarbon receptor (AhR)-activation since BP-mediated IL-8 induction was reduced after AhR expression knock-down through RNA interference. Moreover, electrophoretic mobility shift assays (EMSAs) and chromatin immunoprecipitation experiments showed BP-triggered binding of AhR to a consensus xenobiotic responsive element (XRE) found in the human IL-8 promoter. Finally, BP administration to mice led to over-expression of keratinocyte chemoattractant (KC), the murine functional homologue of IL-8, in lung. It also triggered the recruitment of neutrophils in bronchoalveolar lavage (BAL) fluids, which was however fully abolished in the presence of a chemical antagonist of the KC/IL-8 receptors CXCR1/CXCR2, thus supporting the functional and crucial involvement of KC in BP-induced lung inflammation. Overall, these data highlight an AhR-dependent regulation of IL-8 in response to BP that likely contributes to the airway inflammatory effects of this Environmental chemical.