title: An alkylphenol mix promotes seminoma derived cell proliferation through an ERalpha36-mediated mechanism.
abstract: Long chain alkylphenols are man-made compounds still present in industrial and agricultural processes. Their main use is domestic and they are widespread in household products, cleansers and cosmetics, leading to a global environmental and human contamination. These molecules are known to exert estrogen-like activities through binding to classical estrogen receptors. In vitro, they can also interact with the G-protein coupled estrogen receptor. Testicular germ cell tumor etiology and progression are proposed to be stimulated by lifelong estrogeno-mimetic exposure. We studied the transduction signaling pathways through which an alkyphenol mixture triggers testicular cancer cell proliferation in vitro and in vivo. Proliferation assays were monitored after exposure to a realistic mixture of 4-tert-octylphenol and 4-nonylphenol of either TCam-2 seminoma derived cells, NT2/D1 embryonal carcinoma cells or testis tumor in xenografted nude mice. Specific pharmacological inhibitors and gene-silencing strategies were used in TCam-2 cells in order to demonstrate that the alkylphenol mix triggers CREB-phosphorylation through a rapid, ERα36-PI3kinase non genomic pathway. Microarray analysis of the mixture target genes revealed that this pathway can modulate the expression of the DNA-methyltransferase-3 (Dnmt3) gene family which is involved in DNA methylation control. Our results highlight a key role for ERα36 in alkylphenol non genomic signaling in testicular germ cell tumors. Hence, ERα36-dependent control of the epigenetic status opens the way for the understanding of the link between endocrine disruptor exposure and the burden of hormone sensitive cancers.
authors.affiliation: CNRS-Université de Lorraine, UMR 7039, Centre de Recherches en Automatique de Nancy, Vandoeuvre lès Nancy, France.
authors.forename: Hussein
authors.initials: H
authors.lastname: Ajj
authors.forename: Amand
authors.initials: A
authors.lastname: Chesnel
authors.forename: Sophie
authors.initials: S
authors.lastname: Pinel
authors.forename: François
authors.initials: F
authors.lastname: Plenat
authors.forename: Stephane
authors.initials: S
authors.lastname: Flament
authors.forename: Helene
authors.initials: H
authors.lastname: Dumond
mesh_terms: D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D002274:Carcinogens, Environmental / Q000494:pharmacology*; D002277:Carcinoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000378:metabolism; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics / Q000378:metabolism; D000090205:DNA Methyltransferase 3A; D044127:Epigenesis, Genetic / Q000187:drug effects; D047628:Estrogen Receptor alpha / Q000235:genetics* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D010636:Phenols / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D018239:Seminoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction; D013736:Testicular Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000077191:Wortmannin
chemical_list: D000730:Androstadienes; D002274:Carcinogens, Environmental; D017362:Cyclic AMP Response Element-Binding Protein; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A; D047628:Estrogen Receptor alpha; D010636:Phenols; D019869:Phosphatidylinositol 3-Kinases; D020033:Protein Isoforms; D000077191:Wortmannin; C492004:Creb1 protein, mouse; C000717967:DNMT3A protein, human; C041594:4-nonylphenol; C105260:4-tert-octylphenol