title: Inhibition of aromatase activity by methyl sulfonyl PCB metabolites in primary culture of human mammary fibroblasts.
abstract: In this study, the effects on catalytic activity and mRNA levels of aromatase in primary human mammary fibroblasts were evaluated after exposure to promoter-specific modulators of aromatase expression and methyl sulfonyl polychlorinated biphenyl metabolites (MeSO(2)-PCBs). A method for fibroblast isolation from primary breast tissue was developed and optimized, and aromatase activity and promoter-specific mRNA levels were assessed in these cells after exposure to test compounds. A 24-h exposure of fibroblasts to dexamethasone (DEX) (1-100 nM) increased aromatase activity to a maximum of 313-fold. DEX also elevated promoter I.4-specific RNA levels. A 24-h exposure of fibroblasts to 3-MeSO(2)-PCB-132, 4-MeSO(2)-PCB-132, 4-MeSO(2)-PCB-91, or 4-MeSO(2)-PCB-149 (0.1-10 microM) resulted in a concentration-dependent decrease of aromatase activity. Exposure of fibroblasts to MeSO(2)-PCBs just for the limited duration (6 h) of the catalytic assay caused a concentration-dependent inhibition of aromatase enzyme activity. mRNA levels were not altered by a 24-h MeSO(2)-PCB exposure nor was cytotoxicity observed. In aromatase-expressing human adrenocortical carcinoma H295R cells, a 24-h exposure to 3-MeSO(2)-PCB-132, 4-MeSO(2)-PCB-132, 4-MeSO(2)-PCB-91, or 4-MeSO(2)-PCB-149 (0.1-10 microM) also resulted in a concentration-dependent decrease of aromatase activity. Additionally, there were no changes in aromatase mRNA levels after 24-h exposure of H295R cells to MeSO(2)-PCBs. We conclude that in primary human mammary fibroblasts as well as in H295R cells, aromatase inhibition by MeSO(2)-PCBs is likely to be due to catalytic inhibition.
authors.affiliation: Institute for Risk Assessment Sciences, Utrecht University, 3508 TD Utrecht, The Netherlands. M.Heneweer@iras.uu.nl
authors.forename: Marjoke
authors.initials: M
authors.lastname: Heneweer
authors.forename: Martin
authors.initials: M
authors.lastname: van den Berg
authors.forename: Maarten C
authors.initials: MC
authors.lastname: de Geest
authors.forename: Paul C
authors.initials: PC
authors.lastname: de Jong
authors.forename: A
authors.initials: A
authors.lastname: Bergman
authors.forename: J Thomas
authors.initials: JT
authors.lastname: Sanderson
mesh_terms: D000293:Adolescent; D000328:Adult; D001141:Aromatase / Q000235:genetics; D047072:Aromatase Inhibitors / Q000494:pharmacology*; D001940:Breast / Q000201:enzymology*; D002478:Cells, Cultured; D003907:Dexamethasone / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005260:Female; D005347:Fibroblasts / Q000201:enzymology; D006801:Humans; D008875:Middle Aged; D011078:Polychlorinated Biphenyls / Q000378:metabolism / Q000494:pharmacology*; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000032:analysis
chemical_list: D047072:Aromatase Inhibitors; D012333:RNA, Messenger; C094859:2,2',3,3',4,6'-hexachlorobiphenyl; D003907:Dexamethasone; D011078:Polychlorinated Biphenyls; D001141:Aromatase