Toxic Effects of TCDD on Osteogenesis through Altering IGFBP-6 Gene Expression in Osteoblasts
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- Guo Lei
- Department of Orthopedic Surgery, First Affiliated Hospital, China Medical University
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- Zhao Yu-yan
- Department of Endocrinology, First Affiliated Hospital, China Medical University
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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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- Liu Hong
- 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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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 15 μg/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 1 μM 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 (15 μg/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 1 μM E2 resulted in a significant increase in IGFBP-6 mRNA and protein after 24 h 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.
収録刊行物
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- Biological & Pharmaceutical Bulletin
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Biological & Pharmaceutical Bulletin 30 (11), 2018-2026, 2007
公益社団法人 日本薬学会
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詳細情報 詳細情報について
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- CRID
- 1390282679603566592
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- NII論文ID
- 110006473476
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- NII書誌ID
- AA10885497
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- ISSN
- 13475215
- 09186158
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- NDL書誌ID
- 8965344
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- 本文言語コード
- en
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- データソース種別
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- JaLC
- NDL
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