Disruption of thyroid hormone receptor-mediated transcription and thyroid hormone-induced Purkinje cell dendrite arborization by polybrominated diphenyl ethers.
BACKGROUND
Polybrominated diphenyl ethers (PBDEs) have been used as flame retardants and are becoming a ubiquitous environmental contaminant. Adverse effects in the developing brain are of great health concern.


OBJECTIVE
We investigated the effect of PBDEs/hydroxylated PBDEs (OH-PBDEs) on thyroid hormone (TH) receptor (TR)-mediated transcription and on TH-induced dendrite arborization of cerebellar Purkinje cells.


METHODS
We examined the effect of PBDEs/OH-PBDEs on TR action using a transient transfection-based reporter gene assay. TR-cofactor binding was studied by the mammalian two-hybrid assay, and TR-DNA [TH response element (TRE)] binding was examined by the liquid chemiluminescent DNA pull-down assay. Chimeric receptors generated from TR and glucocorticoid receptor (GR) were used to identify the functional domain of TR responsible for PBDE action. The change in dendrite arborization of the Purkinje cell in primary culture of newborn rat cerebellum was also examined.


RESULTS
Several PBDE congeners suppressed TR-mediated transcription. The magnitude of suppression correlated with that of TR-TRE dissociation. PBDEs suppressed transcription of chimeric receptors containing the TR DNA binding domain (TR-DBD). We observed no such suppression with chimeras containing GR-DBD. In the cerebellar culture, PBDE significantly suppressed TH-induced Purkinje cell dendrite arborization.


CONCLUSIONS
Several PBDE congeners may disrupt the TH system by partial dissociation of TR from TRE acting through TR-DBD and, consequently, may disrupt normal brain development.
Ibhazehiebo
Kingsley
K
Department of Integrative Physiology, Gunma University Graduate School of Medicine, Maebashi, Japan.
Iwasaki
Toshiharu
T
Kimura-Kuroda
Junko
J
Miyazaki
Wataru
W
Shimokawa
Noriaki
N
Koibuchi
Noriyuki
N
D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D005260:Female; D055768:Halogenated Diphenyl Ethers / Q000494:pharmacology*; D000882:Haplorhini; D007150:Immunohistochemistry; D011247:Pregnancy; D011689:Purkinje Cells / Q000187:drug effects* / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D011988:Receptors, Thyroid Hormone / Q000235:genetics / Q000378:metabolism*; D013963:Thyroid Hormones / Q000494:pharmacology*; D014158:Transcription, Genetic / Q000187:drug effects*
D055768:Halogenated Diphenyl Ethers; D011988:Receptors, Thyroid Hormone; D013963:Thyroid Hormones