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Phorbol ester-modulation of estrogenic genomic effects triggered by the environmental contaminant benzanthracene.

Abstract : 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.
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Submitted on : Monday, October 14, 2013 - 3:08:03 PM
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Elise Kolasa, Patrick Balaguer, Noémie Houlbert, Olivier Fardel. Phorbol ester-modulation of estrogenic genomic effects triggered by the environmental contaminant benzanthracene.. Toxicology in Vitro, Elsevier, 2012, 26 (6), pp.807-16. ⟨10.1016/j.tiv.2012.05.006⟩. ⟨inserm-00872862⟩



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