Inhibition of aromatase activity by methyl sulfonyl PCB metabolites in primary culture of human mammary fibroblasts.
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.
Heneweer
Marjoke
M
Institute for Risk Assessment Sciences, Utrecht University, 3508 TD Utrecht, The Netherlands. M.Heneweer@iras.uu.nl
van den Berg
Martin
M
de Geest
Maarten C
MC
de Jong
Paul C
PC
Bergman
A
A
Sanderson
J Thomas
JT
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
D047072:Aromatase Inhibitors; D012333:RNA, Messenger; C094859:2,2',3,3',4,6'-hexachlorobiphenyl; D003907:Dexamethasone; D011078:Polychlorinated Biphenyls; D001141:Aromatase