Identification of the functional domain of thyroid hormone receptor responsible for polychlorinated biphenyl-mediated suppression of its action in vitro.
BACKGROUND
Polychlorinated biphenyls (PCBs), polychlorinated dibenzo-p-dioxins, and poly-chlorinated dibenzofurans adversely affect the health of humans and various animals. Such effects might be partially exerted through the thyroid hormone (TH) system. We previously reported that one of the hydroxylated PCB congeners suppresses TH receptor (TR)-mediated transcription by dissociating TR from the TH response element (TRE). However, the binding site of PCB within TR has not yet been identified.


OBJECTIVE
We aimed to identify the functional TR domain responsible for the PCB-mediated suppression of TR action by comparing the magnitude of suppression using several representative PCB/dioxin congeners.


METHODS
We generated chimeric receptors by combining TR and glucocorticoid receptor (GR) and determined receptor-mediated transcription using transient transfection-based reporter gene assays, and TR-TRE binding using electrophoretic mobility shift assays.


RESULTS
Although several PCB congeners, including the hydroxylated forms, suppressed TR-mediated transcription to various degrees, 2,3,7,8-tetrachlorodibenzo-p-dioxin did not alter TR action, but 2,3,4,7,8-pentachlorodibenzofuran weakly suppressed it. The magnitude of suppression correlated with that of TR-TRE dissociation. The suppression by PCB congeners was evident from experiments using chimeric receptors containing a TR DNA-binding domain (DBD) but not a GR-DBD.


CONCLUSIONS
Several nondioxin-like PCB congeners and hydroxylated PCB compounds suppress TR action by dissociating TR from TRE through interaction with TR-DBD.
Miyazaki
Wataru
W
Department of Integrative Physiology, Gunma University Graduate School of Medicine, Maebashi, Japan.
Iwasaki
Toshiharu
T
Takeshita
Akira
A
Tohyama
Chiharu
C
Koibuchi
Noriyuki
N
D001572:Benzofurans / Q000378:metabolism / Q000633:toxicity*; D002460:Cell Line; D066298:In Vitro Techniques; D000072317:Polychlorinated Dibenzodioxins / Q000378:metabolism / Q000633:toxicity*; D011988:Receptors, Thyroid Hormone / Q000187:drug effects* / Q000378:metabolism
D001572:Benzofurans; D000072317:Polychlorinated Dibenzodioxins; D011988:Receptors, Thyroid Hormone; C038890:2,3,4,7,8-pentachlorodibenzofuran
J Comp Neurol. 2000 Nov 20;427(3):428-39
11054704
Regul Toxicol Pharmacol. 2007 Jul;48(2):148-70
17475378
J Formos Med Assoc. 1992 Jul;91(7):704-7
1360299
Endocr Rev. 1993 Feb;14(1):94-106
8491157
Neurotoxicology. 1997;18(2):415-24
9291491
Crit Rev Toxicol. 1998 Nov;28(6):511-69
9861526
Chemosphere. 1998 Oct-Nov;37(9-12):1789-93
9828307
Neurotoxicology. 2006 Mar;27(2):176-83
16300829
Toxicol Sci. 2002 Aug;68(2):361-71
12151632
Environ Health Perspect. 2007 Nov;115(11):1623-30
18007995
Toxicol Appl Pharmacol. 1996 Jan;136(1):29-48
8560478
Environ Health Perspect. 1999 Apr;107(4):273-8
10090705
N Engl J Med. 1996 Sep 12;335(11):783-9
8703183
Neurotoxicol Teratol. 1990 May-Jun;12(3):239-48
2115098
Toxicol Appl Pharmacol. 2000 Dec 1;169(2):159-67
11097868
Environ Health Perspect. 1989 Jul;82:323-36
2551666
Endocrinology. 1977 Jul;101(1):292-6
862558
Environ Health Perspect. 2007 Apr;115(4):556-63
17450224
Endocr Rev. 1997 Aug;18(4):462-75
9267760
Biochem Biophys Res Commun. 2002 Dec 6;299(3):384-8
12445811
J Pediatr. 1991 Jul;119(1 Pt 1):58-63
1906100
Cell Biol Toxicol. 1991 Jan;7(1):67-94
2054688
Toxicol Appl Pharmacol. 1987 Jun 30;89(2):165-74
3111013
J Pharmacol Exp Ther. 1995 May;273(2):977-85
7752103
Brain Res Dev Brain Res. 2005 Feb 8;154(2):259-63
15707680
Dose Response. 2006 May 01;3(3):273-305
18648619
Int J Biochem Cell Biol. 2005 Jul;37(7):1368-74
15833269
Toxicol Appl Pharmacol. 2003 Apr 1;188(1):6-13
12668117
Neurotoxicol Teratol. 1996 May-Jun;18(3):305-13
8725643
J Biol Chem. 2001 Sep 7;276(36):33375-83
11443112
Endocrinology. 2000 Jan;141(1):181-9
10614638
Toxicol Ind Health. 1996 May-Aug;12(3-4):435-45
8843560
Toxicol Sci. 2006 Oct;93(2):223-41
16829543
Trends Endocrinol Metab. 2000 May-Jun;11(4):123-8
10754532
Environ Res. 2001 May;86(1):2-11
11386736
Proc Natl Acad Sci U S A. 1989 May;86(10):3494-8
2726731
Neurotoxicol Teratol. 1990 Jul-Aug;12(4):319-26
2118230
Toxicology. 1996 Jan 8;106(1-3):105-14
8571380
Toxicol Ind Health. 1998 Jan-Apr;14(1-2):85-101
9460171
Child Dev. 1985 Aug;56(4):853-60
3930167
Crit Rev Toxicol. 1994;24(2):87-149
8037844
Eur J Pharmacol. 1995 May 26;293(1):77-85
7672011
Toxicol Appl Pharmacol. 1986 Jun 15;84(1):45-55
3715868
J Biol Chem. 2004 Apr 30;279(18):18195-202
14985366
Environ Health Prev Med. 2008 May;13(3):169-80
19568902
Endocrinology. 2003 May;144(5):2075-83
12697716
Toxicology. 2005 Mar 30;208(3):377-87
15695023
J Biol Chem. 1996 Nov 1;271(44):27919-26
8910392
Endocrinology. 1999 Mar;140(3):1356-64
10067863
Toxicol Ind Health. 1998 Jan-Apr;14(1-2):59-84
9460170
Neurotoxicol Teratol. 2000 Jul-Aug;22(4):511-9
10974589
Pediatr Res. 1994 Oct;36(4):468-73
7816522
Toxicol Appl Pharmacol. 1993 Nov;123(1):97-106
8236268
J Endocrinol Invest. 2003 Oct;26(10):972-8
14759069
Toxicology. 1987 Jun;44(3):297-307
3554617
Neurotoxicol Teratol. 1999 May-Jun;21(3):231-9
10386826
Toxicol Appl Pharmacol. 1995 Jun;132(2):237-44
7540335
Environ Health Perspect. 2000 Jun;108 Suppl 3:433-8
10852841
Toxicol Appl Pharmacol. 1986 Sep 30;85(3):301-12
3094194
Neurotoxicology. 1997;18(3):727-43
9339820
Toxicol Sci. 2005 May;85(1):607-14
15716479
Toxicology. 2002 Feb 28;171(2-3):73-82
11836014