title: Androgen receptor activation by polychlorinated biphenyls: epigenetic effects mediated by the histone demethylase Jarid1b.
abstract: The exposure to environmental endocrine disrupting compounds (EDC), as polychlorinated biphenyls (PCBs), widely diffused in the environment may produce epigenetic changes that affect the endocrine system. We found that PCBs activate AR transcriptional activity and that this effect is potentiated by the demethylase Jarid1b, a histone demethylase that catalyzes the removal of trimethylation of lysine 4 on histone H3 (H3K4me3), induced by PCB. The aim of the present study was to investigate the effect of the treatment of cultured cells (HEK293) with a mixture of the most diffused environmental PCBs and, also with dihydrotestosterone (DHT), on the functional interaction between AR and Jarid1b. Although the effect induced by DHT on the AR transactivation was considerably higher, the PCB mixture produced an AR-mediated transactivation in a dose-dependent manner. Cotransfection with plasmids expressing Jarid1b and various AR isoforms containing polyglutamine tracts (polyQ tracts) of different lengths showed that Jarid1b potentiates the AR transcriptional activity induced by PCBs but only with the shortest AR isoform. The potentiating effect of Jarid1b on the AR is mediated by a direct interaction of the enzyme with the AR promoter. In fact, utilizing constructs containing AR promoters with a different length and a luciferase reporter gene, we showed that the effect of PCBs, but not of DHT, needs the presence of Jarid1b and of at least two DNA binding sites for Jarid1b.
authors.affiliation: Department of Pharmacological and Biomolecular Sciences; University of Milan; Milano, Italy.
authors.forename: Lavinia
authors.initials: L
authors.lastname: Casati
authors.affiliation: Departament de Bioquímica i Biologia Molecular; Universitat de València; Valencia, Spain.
authors.forename: Ramon
authors.initials: R
authors.lastname: Sendra
authors.affiliation: Department of Pharmacological and Biomolecular Sciences; University of Milan; Milano, Italy.
authors.forename: Angelo
authors.initials: A
authors.lastname: Poletti
authors.affiliation: Department of Pharmacological and Biomolecular Sciences; University of Milan; Milano, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Negri-Cesi
authors.affiliation: Department of Pharmacological and Biomolecular Sciences; University of Milan; Milano, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Celotti
mesh_terms: D052244:Endocrine Disruptors / Q000633:toxicity*; D044127:Epigenesis, Genetic; D005260:Female; D006657:Histones / Q000378:metabolism; D006801:Humans; D056484:Jumonji Domain-Containing Histone Demethylases / Q000235:genetics / Q000378:metabolism*; D008297:Male; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D011078:Polychlorinated Biphenyls / Q000633:toxicity*; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured
chemical_list: C410798:AR protein, human; D052244:Endocrine Disruptors; D006657:Histones; D009687:Nuclear Proteins; D011944:Receptors, Androgen; D012097:Repressor Proteins; D011078:Polychlorinated Biphenyls; D056484:Jumonji Domain-Containing Histone Demethylases; C119611:KDM5B protein, human
keywords: Jarid1b; androgen receptor; endocrine disruptors; environment; epigenetic; histone modification; polychlorinated biphenyls
references.citation: Neurobiol Dis. 2009 Mar;33(3):395-404
references.pmid: 19100835
references.citation: Epigenetics. 2009 Jan;4(1):47-53
references.pmid: 19029819
references.citation: Biochem Pharmacol. 2006 Nov 30;72(11):1589-96
references.pmid: 16844098
references.citation: Toxicology. 2005 Nov 5;215(1-2):115-25
references.pmid: 16125295
references.citation: Reprod Toxicol. 2011 Nov;32(3):293-7
references.pmid: 21729750
references.citation: Reprod Toxicol. 2006 Nov;22(4):738-45
references.pmid: 16938428
references.citation: Oncogene. 2012 Jul 19;31(29):3444-56
references.pmid: 22120715
references.citation: Biol Psychiatry. 2009 Feb 1;65(3):198-203
references.pmid: 18814864
references.citation: Toxicol Appl Pharmacol. 2009 Aug 15;239(1):46-54
references.pmid: 19464308
references.citation: Mol Endocrinol. 1996 Dec;10(12):1527-35
references.pmid: 8961263
references.citation: J Steroid Biochem Mol Biol. 2004 Jan;88(1):27-36
references.pmid: 15026081
references.citation: Acta Crystallogr Sect F Struct Biol Cryst Commun. 2011 Aug 1;67(Pt 8):907-10
references.pmid: 21821892
references.citation: Cell. 2006 May 5;125(3):483-95
references.pmid: 16603237
references.citation: Psychoneuroendocrinology. 2009 Jun;34(5):752-61
references.pmid: 19167832
references.citation: Proc Natl Acad Sci U S A. 2007 Dec 4;104(49):19226-31
references.pmid: 18048344
references.citation: Epigenomics. 2012 Aug;4(4):355-7
references.pmid: 22920174
references.citation: Soc Sci Med. 2012 Jun;74(11):1738-44
references.pmid: 21962724
references.citation: Epigenomics. 2012 Feb;4(1):101-12
references.pmid: 22332662
references.citation: Biochem Biophys Res Commun. 2008 Jun 13;370(4):541-6
references.pmid: 18358233
references.citation: Toxicol Appl Pharmacol. 2002 Mar 15;179(3):185-94
references.pmid: 11906248
references.citation: Environ Toxicol. 2014 Aug;29(8):856-66
references.pmid: 22987612
references.citation: J Androl. 2012 Mar-Apr;33(2):210-5
references.pmid: 21597087
references.citation: Int J Toxicol. 2009 Jul-Aug;28(4):294-307
references.pmid: 19636072
references.citation: PLoS Genet. 2013 Apr;9(4):e1003461
references.pmid: 23637629
references.citation: Nat Cell Biol. 2007 Mar;9(3):347-53
references.pmid: 17277772
references.citation: Epigenetics. 2010 Feb 16;5(2):100-4
references.pmid: 20160483
references.citation: Biochem Biophys Res Commun. 1999 Mar 24;256(3):462-8
references.pmid: 10080920
references.citation: Toxicol Sci. 2011 May;121(1):123-31
references.pmid: 21292640
references.citation: Science. 2005 Nov 4;310(5749):819-23
references.pmid: 16272115
references.citation: Hum Mol Genet. 2004 Aug 15;13(16):1677-92
references.pmid: 15198988
references.citation: Reprod Toxicol. 2013 Jan;35:144-9
references.pmid: 23117151
references.citation: J Mol Endocrinol. 2011 Feb;46(1):R11-32
references.pmid: 21322125
references.citation: Hum Mol Genet. 1995 Apr;4(4):523-7
references.pmid: 7633399
references.citation: Arch Toxicol. 2003 Jun;77(6):335-43
references.pmid: 12799773
references.citation: J Steroid Biochem Mol Biol. 2010 Jan;118(1-2):51-8
references.pmid: 19815066
references.citation: J Mol Endocrinol. 2012 Aug 30;49(2):R61-7
references.pmid: 22798698
references.citation: Genomics. 1992 Feb;12(2):241-53
references.pmid: 1740333