ANTIESTROGENIC ACTIVITY OF HYDROXYLATED POLYCHLORINATED BIPHENYL CONGENERS IDENTIFIED IN HUMAN SERUM

Several hydroxylated polychlorinated biphenyls (PCBs) identified in hu man serum have been synthesized and these include 2,2',3,4',5,5'-hexac hloro-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 hyd roxy-PCBs exhibited minimal binding to the rat uterine cytosolic estro gen receptor (ER) and did not induce proliferation of estrogen-respons ive MCF-7 human breast cancer cells at concentrations ranging from 10( -5) to 10(-8) M. The estrogenic activity of these compounds was furthe r investigated utilizing two estrogen-responsive in vitro bioassays, n amely, (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 promo ter linked to a chloramphenicol acetyl transferase (CAT) reporter gene . None of the hydroxy-PCBs significantly induced luciferase activity i n 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 17 beta-estradiol plus the hydroxy-PCBs. All of the hydroxy-PCB congeners inhibited one or more estrogenic res ponse, and one congener, 2,2',3,4',5,5',6-heptachloro-4-biphenylo inhi bited 17 beta-estradiol-induced cell proliferation and CAT activity in MCF-7 cells and luciferase activity in HeLa cells. (C) 1997 Academic Press