Thyroid hormone-like and estrogenic activity of hydroxylated PCBs in cell culture.
The thyroid hormone-disrupting activity of hydroxylated PCBs was examined. 4-Hydroxy-2,2',3,4',5,5'-hexachlorobiphenyl (4-OH-2,2',3,4',5,5'-HxCB), 4-hydroxy-3,3',4',5-tetrachlorobiphenyl (4-OH-3,3',4',5-TCB) and 4,4'-dihydroxy-3,3',5,5'-tetrachlorobiphenyl (4,4'-diOH-3,3',5,5'-TCB), which have been detected as metabolites of PCBs in animals and humans, and six other 4-hydroxylated PCBs markedly inhibited the binding of triiodothyronine (1x10(-10)M) to thyroid hormone receptor (TR) in the concentration range of 1 x 10(-6) to 1 x 10(-4) M. However, 4-hydroxy-2',4',6'-trichlorobiphenyl (4-OH-2',4',6'-TCB), 3-hydroxy-2,2',5,5'-tetrachlorobiphenyl, 4-hydroxy-2,2',5,5'-tetrachlorobiphenyl, 4-hydroxy-2,3,3',4'-tetrachlorobiphenyl, 2,3',5,5'-tetrachlorobiphenyl and 2,3',4',5,5'-pentachlorodiphenyl did not show affinity for TR. The thyroid hormonal activity of PCBs was also examined using rat pituitary cell line GH3 cells, which grow and release growth hormone in a thyroid hormone-dependent manner. 4-OH-2,2',3,4',5,5'-HxCB, 4,4'-diOH-3,3',5,5'-TCB and 4-OH-3,3',4',5-TCB enhanced the proliferation of GH3 cells and stimulated their production of growth hormone in the concentration range of 1 x 10(-7) to 1 x 10(-4) M, while PCBs which had no affinity for thyroid hormone receptor were inactive. In contrast, only 4-OH-2',4',6'-TCB exhibited a significant estrogenic activity using estrogen-responsive reporter assay in MCF-7 cells. However, the 3,5-dichloro substitution of 4-hydroxylated PCBs markedly decreased the estrogenic activity. These results suggest that, at least for the 17 PCB congeners and hydroxylated metabolites tested, a 4-hydroxyl group in PCBs is essential for thyroid hormonal and estrogenic activities, and that 3,5-dichloro substitution favors thyroid hormonal activity, but not estrogenic activity.
Kitamura
Shigeyuki
S
Graduate School of Biomedical Sciences, Hiroshima University, Kasumi 1-2-3, Hiroshima 734-8551, Japan. skitamu@hiroshima-u.ac.jp
Jinno
Norimasa
N
Suzuki
Tomoharu
T
Sugihara
Kazumi
K
Ohta
Shigeru
S
Kuroki
Hiroaki
H
Fujimoto
Nariaki
N
D000818:Animals; D001667:Binding, Competitive; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D004785:Environmental Pollutants / Q000378:metabolism / Q000633:toxicity*; D004967:Estrogens / Q000378:metabolism / Q000633:toxicity*; D013006:Growth Hormone / Q000096:biosynthesis; D006801:Humans; D006900:Hydroxylation; D011078:Polychlorinated Biphenyls / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity*; D011869:Radioligand Assay; D051381:Rats; D011960:Receptors, Estrogen / Q000187:drug effects / Q000378:metabolism; D011988:Receptors, Thyroid Hormone / Q000187:drug effects / Q000378:metabolism; D013329:Structure-Activity Relationship; D013963:Thyroid Hormones / Q000502:physiology*
D004785:Environmental Pollutants; D004967:Estrogens; D011960:Receptors, Estrogen; D011988:Receptors, Thyroid Hormone; D013963:Thyroid Hormones; D013006:Growth Hormone; D011078:Polychlorinated Biphenyls