Toxic Effects of TCDD on Osteogenesis through Altering IGFBP-6 Gene Expression in Osteoblasts(Molecular and Cell Biology)
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概要
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Since 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin (TCDD) has reproductive and developmental toxicity as an estrogen antagonist, we investigated the effects of TCDD on osteogenesis in rat skeleton and the human female-responsive osteoblastic osteosarcoma cell line SaOS-2. Rat fetuses were exposed to 5, 10, or 15μg/kg TCDD on gestation day (GD) 10. TCDD dose-dependently induced single or multiple rat fetal skeletal development malformations in vivo. In vitro, 10 nM TCDD significantly inhibited cell proliferation in the presence of 1μM 17-β-estradiol (E2) in SaOS-2 cells. Insulin-like growth factor binding protein 6 (IGFBP-6), as a crucial regulator in IGF system, plays an important role in osteogenesis and bone function. TCDD (15μg/kg) induced a dramatic 3-fold increase in IGFBP-6 mRNA expression in rat fetal calvaria on GD 21. On the other hand, the concurrent treatment of 10 nM TCDD and 1μM E2 resulted in a significant increase in IGFBP-6 mRNA and protein after 24h in SaOS-2 cells, but TCDD and (or) E2 had no effect on the mRNA level of cytosolic aromatic hydrocarbon receptor. The functional estrogen-responsive element (ERE) [5'-CCT TCA CCT G-3'] (-9 to +1) in the IGFBP-6 promoter region was identified in this study for the first time as the ER genomic binding site. Collectively, these results suggest that TCDD can alter the expression of IGFBP-6 gene and exerts growth-inhibitory effects on osteogenesis. In addition, TCDD exhibits an anti-estrogenic effect through its interference with the binding of activated estrogen-liganded ER to the functional ERE in IGFBP-6 gene promoter.
- 2007-11-01
著者
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Liu Hong
Department Of Cell Engineering Beijing Institute Of Biotechnology
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Zhao Yan-yan
Department Of Medical Genetics China Medical University
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SUN Zhi-Jun
Department of Medical Genetics, China Medical University
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Zhao Yu-yan
Department Of Endocrinology First Affiliated Hospital China Medical University
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Guo Lei
Department Of Artificial Organ And Transplantation Surgery Graduate School Of Medicine And Faculty O
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Guo Lei
Department Of Orthopedic Surgery First Affiliated Hospital China Medical University
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Sun Zhi-jun
Department Of Medical Genetics China Medical University
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Zhang Shi-liang
Department Of Orthopedic Surgery First Affiliated Hospital China Medical University
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Liu Hong
Department Of Anesthesiology And Pain Medicine University Of California Davis Medical Center
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Liu Hong
Department Of Medical Genetics China Medical University
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Sun Zhi-jun
中華人民共和国
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