Lead-induced developmental perturbations in hippocampal Sp1 DNA-binding are prevented by zinc supplementation: in vivo evidence for Pb and Zn competition
Lead-induced developmental perturbations in hippocampal Sp1 DNA-binding are prevented by zinc supplementation: in vivo evidence for Pb and Zn competition
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DOI：
10.1016/s0736-5748(02)00137-5
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发表时间：
2003-02-01
影响因子：
1.8
通讯作者：
Zawia, NH
中科院分区：
文献类型：
--
作者：
Basha, MR;Wei, W;Zawia, NH
锌指蛋白（ZFP）转录因子对发育中的大脑基因表达调控至关重要。我们之前报道过铅暴露会干扰小脑中ZFP的dna结合，如Sp1和Egr-1，它们在中枢神经系统的发育中起关键作用。在本研究中，我们重点研究了新生儿铅暴露动物海马Sp1 dna结合和mRNA表达。Sp1靶基因（NMDAR1）的表达模式也被监测。为了研究铅和锌在体内和体外的竞争关系，我们给动物补充锌，并检测了这两种金属对海马Sp1 dna结合和重组Sp1蛋白（rhSp1） dna结合的影响。组织金属分析表明，锌的存在只影响铅在脑中的分布，而不影响其在血液中的分布。Sp1 dna结合的发育特征在PND 15上出现峰值，随后下降到成虫水平。与早期的研究一致，铅暴露使PND 5的Sp1 dna结合过早达到峰值，随后又恢复到成人水平。Sp1 mRNA的基础和pb诱导的发育模式与其dna结合谱不同。然而，NMDAR1基因的表达模式与Sp1 dna结合有关。补充锌对铅诱导的Sp1 dna结合变化具有保护作用。此外，Pb和Zn在体外直接干扰rhSp1的dna结合。这些数据表明，铅和锌在体内和体外都可以在Sp1的锌指结构域竞争，从而影响Sp1的dna结合、随后的基因表达和大脑发育。(C) 2002年由Elsevier Science Ltd代表ISDN出版。
Zinc finger protein (ZFP) transcription factors are essential for regulation of gene expression in the developing brain. We previously reported that Pb exposure perturbed the DNA-binding of ZFP such as Sp1 and Egr-1 in the cerebellum, which play critical role in CNS development. In this study, we focused on hippocampal Sp1 DNA-binding and mRNA expression in neonatal Pb-exposed animals. The expression pattern of an Sp1 target (NMDAR1) gene was also monitored. To study in vivo and in vitro competition between Pb and Zn, we supplemented animals with Zn, and examined the effects of both metals on hippocampal Sp1 DNA-binding and the DNA-binding of a recombinant Sp1 protein (rhSp1). Tissue metal analysis revealed that only the disposition of Pb in the brain but not its distribution in the blood was influenced by the presence of Zn. The developmental profile of Sp1 DNA-binding exhibited a peak on PND 15 which subsequently declined to adult levels. Consistent with earlier studies, Pb exposure produced premature peaks of Sp1 DNA-binding on PND 5 which later returned to adult levels. The basal and Pb-induced developmental patterns of Sp1 mRNA departed from its DNA-binding profiles. However, the expression patterns of the NMDAR1 gene were relative to Sp1 DNA-binding. Supplementation with zinc provided a protective effect on Pb-induced changes in Sp1 DNA-binding. Moreover, Pb and Zn directly interfered with the DNA-binding of rhSp1 in vitro. These data suggest that Pb and Zn can compete both in vivo and in vitro at the zinc finger domain of Sp1 with a consequential effect on Sp1 DNA-binding, subsequent gene expression and brain development. (C) 2002 Published by Elsevier Science Ltd on behalf of ISDN.