1,2,5,6,9,10-αHexabromocyclododecane (HBCD) impairs thyroid hormone-induced dendrite arborization of Purkinje cells and suppresses thyroid hormone receptor-mediated transcription.
1,2,5,6,9,10-αHexabromocyclododecane (HBCD) is a nonaromatic, brominated cyclic alkane used as an additive flame retardant. It bioaccumulates, persists in the environment, and has been detected in humans and wildlife. Its developmental neurotoxicity is of great concern. We investigated the effect of HBCD on thyroid hormone (TH) receptor (TR)-mediated transcription using transient transfection-based reporter gene assays and found that a low-dose (10(-10) M) HBCD suppressed TR-mediated transcription. We further examined the effect of HBCD on interaction of TR with TH response element (TRE) and found a partial dissociation of TR from TRE. HBCD did not dissociate steroid receptor coactivator-1 from TR in the presence of TH; neither did it recruit corepressors (N-CoR and SMRT) to TR in the absence of TH. Furthermore, low-dose HBCD (10(-10) M) significantly suppressed TH-induced dendrite arborization of Purkinje cells in primary cerebellar culture derived from newborn rat. These results show that low-dose HBCD can potentially disrupt TR-mediated transactivation and impairs Purkinje cell dendritogenesis, suggesting that HBCD can interfere with TH action in target organs, including the developing brain.
Ibhazehiebo
Kingsley
K
Department of Integrative Physiology, Division of Biological Regulations, Gunma University Graduate School of Medicine, Maebashi, Japan.
Iwasaki
Toshiharu
T
Shimokawa
Noriaki
N
Koibuchi
Noriyuki
N
D000818:Animals; D000831:Animals, Newborn; D013956:Antithyroid Agents; D002478:Cells, Cultured; D002999:Clone Cells; D004247:DNA / Q000096:biosynthesis / Q000235:genetics; D003712:Dendrites / Q000187:drug effects*; D005260:Female; D005411:Flame Retardants / Q000633:toxicity*; D017930:Genes, Reporter / Q000187:drug effects; D006842:Hydrocarbons, Brominated / Q000633:toxicity*; D007150:Immunohistochemistry; D049449:Luminescence; D010957:Plasmids / Q000235:genetics; D011247:Pregnancy; D011689:Purkinje Cells / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar; D011988:Receptors, Thyroid Hormone / Q000037:antagonists & inhibitors* / Q000235:genetics*; D013963:Thyroid Hormones / Q000494:pharmacology*; D013974:Thyroxine / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects; D014162:Transfection
D013956:Antithyroid Agents; D005411:Flame Retardants; D006842:Hydrocarbons, Brominated; D011988:Receptors, Thyroid Hormone; D013963:Thyroid Hormones; C089796:hexabromocyclododecane; D004247:DNA; D013974:Thyroxine