Low concentrations of bisphenol a suppress thyroid hormone receptor transcription through a nongenomic mechanism.
Bisphenol (BPA) is one of the highest-volume chemicals produced worldwide, and human exposure to BPA is thought to be ubiquitous. Various rodent and in vitro studies have shown that thyroid hormone (TH) function can be impaired by BPA. However, it is still unknown if low concentrations of BPA can suppress the thyroid hormone receptor (TR) transcription. The present study aims to investigate the possible suppressing effects of low concentrations of BPA on TR transcription and the involved mechanism(s) in CV-1 cells derived from cercopithecus aethiops monkey kidneys. Using gene reporter assays, BPA at concentrations as low as 10(-9)M suppresses TR or steroid receptor coactivator-1(SRC-1)-enhanced TR transcription, but not reducing TR/SRC-1 interaction in mammalian two-hybrid and glutathione S-transferase pull-down studies. It has been further shown that both nuclear receptor co-repressor (N-CoR) and silencing mediator for retinoid and thyroid hormone receptors (SMRT) are recruited to the TR-β1 by BPA in the presence of physiologic concentrations of T3 or T4. However, the overexpression of β3 integrin or c-Src significantly reduces BPA-induced recruitment of N-CoR/SMRT to TR or suppression of TR transcription. Furthermore, BPA inhibits the T3/T4-mediated interassociation of the β3 integrin/c-Src/MAPK/TR-β1 pathways by the co-immunoprecipitation. These results indicate that low concentrations of BPA suppress the TR transcription by disrupting physiologic concentrations of T3/T4-mediated β3 integrin/c-Src/MAPK/TR-β1 pathways, followed by recruiting N-CoR/SMRT to TR-β1, providing a novel insight regarding the TH disruption effects of low concentration BPA.
State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Science, Chinese Academy of Sciences, 18 Shuangqing Road, Beijing 100085, PR China.
Zhi-Guo
ZG
Sheng
Yuan
Y
Tang
Yu-Xiang
YX
Liu
Ye
Y
Yuan
Bao-Quan
BQ
Zhao
Xi-Juan
XJ
Chao
Ben-Zhan
BZ
Zhu
D000818:Animals; D001559:Benzhydryl Compounds; D018929:Cell Culture Techniques; D002460:Cell Line; D002522:Chlorocebus aethiops; D004305:Dose-Response Relationship, Drug; D004785:Environmental Pollutants / Q000633:toxicity*; D017930:Genes, Reporter; D005822:Genetic Vectors; D006801:Humans; D056985:Nuclear Receptor Co-Repressor 2 / Q000378:metabolism; D056920:Nuclear Receptor Coactivator 1 / Q000378:metabolism; D010636:Phenols / Q000633:toxicity*; D010957:Plasmids; D015398:Signal Transduction / Q000187:drug effects*; D037042:Thyroid Hormone Receptors beta / Q000235:genetics* / Q000378:metabolism; D013974:Thyroxine / Q000494:pharmacology / Q000502:physiology; D014158:Transcription, Genetic / Q000187:drug effects* / Q000502:physiology; D014284:Triiodothyronine / Q000494:pharmacology / Q000502:physiology; D000098826:Bisphenol A Compounds
D001559:Benzhydryl Compounds; D004785:Environmental Pollutants; D056985:Nuclear Receptor Co-Repressor 2; D056920:Nuclear Receptor Coactivator 1; D010636:Phenols; D037042:Thyroid Hormone Receptors beta; D013974:Thyroxine; D014284:Triiodothyronine; C538859:NCOA1 protein, human; C006780:bisphenol A; D000098826:Bisphenol A Compounds