HYDROXYLATED POLYCHLORINATED-BIPHENYLS (PCBS) AS ESTROGENS AND ANTIESTROGENS - STRUCTURE-ACTIVITY-RELATIONSHIPS

The effects of structure on the estrogenicity and antiestrogenicity of hydroxylated polychlorinated biphenyls were investigated using the fo llowing estrogen-sensitive assays: competitive binding to the rat and mouse cytosolic estrogen receptor (ER); immature rat and mouse uterine wet weight, peroxidase and progesterone receptor (PR) levels; inducti on of luciferase activity in HeLa cells stably transfected with a Gal4 :human ER chimera and a 17mer-reguIated luciferase reporter gene; prol iferation of MCF-7 human breast cancer cells; induction of chloramphen icol acetyl transferase (CAT) activity in MCF-7 cells transiently tran sfected with a full-length human ER expression plasmid and a plasmid c ontaining an estrogen-responsive vitellogenin A2 promoter linked to a CAT reporter gene. The chemicals synthesized for this study contained a 4-hydroxy group in one ring, a 2- or 3-chloro substituent meta or or tho to the hydroxyl group, and variable substitution (2',3',4',5'-2,3, 5 2',3',4',6'-, 2',3',5',6'-tetrachloro and 2',4',6'-trichloro) in the chlorophenyl ring. The compounds included: 2,2',3',4',5'- (A), 2,2',3 ',4',6'- (B), and 2,2',3',5',6'-pentachloro- (C); 2,2',4',6'-tetrachlo ro-4-biphenylol (D); 2',3,3',4',5'- (E), 2',3,3',4',6'- (F), and 2',3, 3 ',5',6'-pentachloro (G); and 2',3,4',6'-tetrachloro-4-biphenylol (H) . With the exception of 2',3,4',6'-tetrachloro-4-biphenylol (TI), all of the compounds competitively bound to the mouse and rat ER with rela tive binding affinities [compared to 17 beta-estradiol (E2)] varying f rom 1.4 x 10(-3) to 5.3 x 10(-5). The structure-ER binding relationshi ps for the hydroxy-PCB congeners were different in the rat and mouse, and no dose-dependent estrogenic activities were observed in the mouse or rat uterus. Several hydroxy-PCB congeners exhibited antiestrogenic activity (primarily in the mouse uterus) and two compounds, 2,2',3',5 ',6- and 2,2',3',4',6'-pentachloro-4-biphenylol, inhibited E2-induced uterine wet weight, PR binding, ,5 and peroxidase activity in the mous e uterus. 2,2',3',4',5'- and 2,2',3',4',6'-Pentachloro-4-biphenylol in duced CAT activity but exhibited antiestrogenic activity in MCF-7 cell s transiently transfected with the Vit-CAT plasmid; the remaining cong eners did not induce CAT activity but exhibited antiestrogenic activit y in MCF-7 cells cotreated with 10(-9) E2 plus 10(-5) M hydroxy-PCBs. Complementary structure-estrogenicity relationships were observed util izing the HeLa cell luciferase induction and MCF-7 cell proliferation assays. The placement of the 2- or 3-chloro groups in the phenolic rin g had minimal effects on estrogenic activity, whereas 2,4,6-trichloro- and 2,3,4,6-tetrachloro substitution in the chlorophenyl ring (B, D, F, and H) were required for this response. Substitution in the phenoli c ring was also not important for structure-antiestrogenicity relation ships, and the ,3 most active compounds (A, C, E, and G) contained 2', 3',4',5'- and 2',3',5',6'-tetrachlorophenyl groups. Thus, structure-es trogenicity/ antiestrogenicity relationships for this series of hydrox y-PCBs were complex and response-specific. (C) 1997 Academic Press.