Éditeur(s) : HAL CCSD Elsevier
Résumé : International audience
Aryl hydrocarbon receptor-dependent genomic effects of environmental polycyclic aromatic hydrocarbons (PAHs) have been shown to be modulated by non-genomic protein kinase C (PKC)-related pathways. The present study was designed to determine whether PKC activation may also impair estrogenic genomic response triggered by PAHs. Treatment by the PKC activator phorbol 12-myristate 13-acetate (PMA) was found to markedly and differentially impair the up-regulation of estrogenic markers triggered by the estrogenic PAH benzanthracene (BZA) in cultured human mammary cells; BZA-mediated mRNA up-regulation of pS2 and amphiregulin was thus increased, whereas that of progesterone receptor and CXCL12 was repressed. BZA/PMA cotreatment however failed to alter BZA-mediated increase of activity of a luciferase gene reporter construct driven by an estrogen response element, thus discarding any global effect of PMA toward BZA-triggered estrogen receptor activation. Various chemicals inhibiting PKCs or extracellular signal-regulated kinase (ERK) as well as the knock-down of PKCδ expression counteracted the PMA-mediated increase of pS2 mRNA up-regulation triggered by BZA, demonstrating that it was dependent on PKCs, including PKCδ isoform, and ERKs. This non-genomic modulation of estrogenic effects of PAHs by PKC activation may have to be considered when considering the deleterious effects of these environmental contaminants towards the endocrine system.
ISSN: 0887-2333

inserm-00872862
http://www.hal.inserm.fr/inserm-00872862
DOI : 10.1016/j.tiv.2012.05.006
PUBMED : 22643241

Éditeur(s) : HAL CCSD Taylor & Francis
Résumé : International audience
INTRODUCTION: Membrane drug transporters are well recognized as important contributing factors to pharmacokinetics, notably involved in drug-drug interactions. Besides drugs, environmental chemicals, to which humans are commonly exposed, are also substrates, inhibitors or inducers of drug transporters, which may have notable consequences toward toxicokinetics, toxicity and pharmacokinetics. AREA COVERED: This review summarizes key data about the interactions of main environmental contaminants with drug transporters, including the nature of drug transporters involved in contaminant transport, or inhibited or induced by these chemicals. Implications for toxicokinetics and toxicity of pollutants and pharmacokinetics of drugs administrated to pollutant-exposed humans are also discussed. EXPERT OPINION: Although various structurally unrelated environmental chemicals have been already demonstrated to interact with drug transporters, further in vitro and in vivo studies are probably required to characterize pollutant-transporter interplays in a more extensive and accurate way. Data obtained should be next confronted with known exposure levels of humans to pollutants, with the aim to fully determine the relevance of environmental contaminant-transporter interactions in terms of toxicokinetics, toxicity and putative pollutant-drug interactions.
ISSN: 1742-5255

inserm-00872876
http://www.hal.inserm.fr/inserm-00872876
DOI : 10.1517/17425255.2012.637918
PUBMED : 22176607

Éditeur(s) : HAL CCSD Elsevier
Résumé : International audience
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.
ISSN: 0009-2797

hal-00982355
https://hal-univ-rennes1.archives-ouvertes.fr/hal-00982355
DOI : 10.1016/j.cbi.2013.12.004
PUBMED : 24361490

Éditeur(s) : HAL CCSD Elsevier
Résumé : International audience
Co-exposure to environmental polycyclic aromatic hydrocarbons (PAHs) and interleukin (IL)-1β induces expression of the tumor-promoting cytokine IL-6 in cancer cells. The present study was designed to determine whether such an IL-6 up-regulation also occurs in response to co-treatment by PAHs and tumor necrosis factor (TNF)-α, an inflammatory cytokine commonly found in tumor microenvironment. Co-exposure to the prototypical PAH benzanthracene (BZA) and TNF-α was found to markedly induce mRNA expression and secretion of IL-6 in human breast cancer cells MCF-7, whereas exposure to either BZA or TNF-α alone was without significant effect. Co-treatment by BZA and TNF-α-containing conditioned media from human inflammatory macrophages similarly up-regulated IL-6 expression in MCF-7 cells. BZA/TNF-α-mediated IL-6 induction in MCF-7 cells was counteracted by silencing aryl hydrocarbon receptor (AhR), known to mediates most of PAH effects. IL-6 up-regulation was moreover associated with NF-κB activation and was abolished by using chemical NF-κB inhibitors or knocking-down expression of the p65/RelA NF-κB subunit. Taken together, these data indicate that co-exposure to BZA/TNF-α induces IL-6 expression by AhR- and NF-κB-dependent pathways in MCF-7 cancer cells. This regulation of IL-6 by environmental PAHs, that is dependent of inflammatory cytokine microenvironment, may contribute to the well-known carcinogenic properties of these organic pollutants.
ISSN: 0009-2797

inserm-00818896
http://www.hal.inserm.fr/inserm-00818896
DOI : 10.1016/j.cbi.2013.01.005
PUBMED : 23396138