Antiestrogenic activity of hydroxylated polychlorinated biphenyl congeners identified in human serum.
Several hydroxylated polychlorinated biphenyls (PCBs) identified in human serum have been synthesized and these include 2,2',3,4',5,5'-hexachloro-4-biphenylol; 2,3,3',4',5-pentachloro-4-biphenylol; 2',3,3',4',5-pentachloro-4-biphenylol; 2,2',3,3',4',5-hexachloro-4-biphenylol; 2,2',3,3',4',5,5'-heptachloro-4-biphenylol; 2,2',3,4',5,5',6-heptachloro-4-biphenylol; and 2,2',3',4,4',5,5'-heptachloro-3-biphenylol. The hydroxy-PCBs exhibited minimal binding to the rat uterine cytosolic estrogen receptor (ER) and did not induce proliferation of estrogen-responsive MCF-7 human breast cancer cells at concentrations ranging from 10(-5) to 10(-8) M. The estrogenic activity of these compounds was further investigated utilizing two estrogen-responsive in vitro bioassays, namely, (i) HeLa cells stably transfected with a Gal4:human ER chimera and a 17-mer-regulated luciferase reporter gene, and (ii) MCF-7 cells transiently transfected with a full-length human ER expression plasmid and a plasmid containing an estrogen-responsive vitellogenin A2 promoter linked to a chloramphenicol acetyl transferase (CAT) reporter gene. None of the hydroxy-PCBs significantly induced luciferase activity in the stably transfected HeLa cells or CAT activity in MCF-7 cells at concentrations as high as 10(-5) M. The antiestrogenic effects of the hydroxy-PCBs were also investigated using the same bioassays in which the cells were cotreated with 17beta-estradiol plus the hydroxy-PCBs. All of the hydroxy-PCB congeners inhibited one or more estrogenic response, and one congener, 2,2',3,4',5,5',6-heptachloro-4-biphenylol, inhibited 17beta-estradiol-induced cell proliferation and CAT activity in MCF-7 cells and luciferase activity in HeLa cells.
Moore
M
M
Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station 77843-4466, USA.
Mustain
M
M
Daniel
K
K
Chen
I
I
Safe
S
S
Zacharewski
T
T
Gillesby
B
B
Joyeux
A
A
Balaguer
P
P
D000230:Adenocarcinoma / Q000473:pathology; D000818:Animals; D001667:Binding, Competitive; D001943:Breast Neoplasms / Q000473:pathology; D015500:Chloramphenicol O-Acetyltransferase / Q000235:genetics; D004965:Estrogen Antagonists / Q000097:blood / Q000494:pharmacology*; D004967:Estrogens; D005260:Female; D006367:HeLa Cells / Q000187:drug effects; D006801:Humans; D008156:Luciferases / Q000235:genetics; D015394:Molecular Structure; D009376:Neoplasms, Hormone-Dependent / Q000473:pathology; D011078:Polychlorinated Biphenyls / Q000097:blood; D011401:Promoter Regions, Genetic / Q000187:drug effects; D051381:Rats; D011960:Receptors, Estrogen / Q000187:drug effects* / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D013329:Structure-Activity Relationship; D014162:Transfection; D014407:Tumor Cells, Cultured / Q000187:drug effects; D014599:Uterus / Q000737:chemistry; D014819:Vitellogenins / Q000235:genetics
C104006:2',3',4',5'-tetrachloro-4-biphenylol; D004965:Estrogen Antagonists; D004967:Estrogens; D011960:Receptors, Estrogen; D011993:Recombinant Fusion Proteins; D014819:Vitellogenins; D011078:Polychlorinated Biphenyls; D008156:Luciferases; D015500:Chloramphenicol O-Acetyltransferase