Molecular mechanisms of lead neurotoxicity
Molecular mechanisms of lead neurotoxicity
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DOI：
10.1023/a:1022596115897
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发表时间：
1999-04-01
影响因子：
4.4
通讯作者：
Goldstein, G
中科院分区：
文献类型：
--
作者：
Bressler, J;Kim, K;Goldstein, G
流行病学研究表明，通过智商测试和其他心理测试评估，血液和骨骼中的铅含量之间存在密切关系。在美国，大约十分之一的儿童血铅水平高于10微克/分升，这已被确定为关注水平。对出生后暴露于铅的实验动物的研究表明，在类似的血铅水平下，学习障碍。由于学习需要重塑大脑中的突触，铅可能会特别影响突触传递。虽然铅的分子靶点尚不清楚，但多年来积累的大量证据表明，铅会破坏由钙调节的过程。我们的实验室一直在研究铅对蛋白激酶C的影响，蛋白激酶C是一个同工酶家族，其中一些同工酶的活性需要钙。我们和其他人已经表明，皮摩尔浓度的铅可以取代微摩尔浓度的钙在蛋白激酶C酶测定。此外，铅激活完整细胞中的蛋白激酶C，并通过依赖于蛋白激酶C的机制诱导新基因的表达。我们认为，铅引起的学习障碍是由于蛋白激酶C调节的事件，最有可能发生在突触。
Epidemiological studies have shown a strong relationship between the level of lead in blood and bone as assessed by performance on IQ tests and other psychometric tests. Approximately 1 out of 10 children in the United States have blood lead levels above 10 mu g/dl, which has been established as the level of concern. Studies on experimental animals exposed to lead after birth have shown learning deficits at similar blood lead levels. Since learning requires the remodeling of synapses in the brain, lead may specifically affect synaptic transmission. Although the molecular targets for lead are unknown, a vast amount of evidence accumulated over many years has shown that lead disrupts processes that are regulated by calcium. Our laboratory has been studying the effect of lead on protein kinase C, a family of isozymes some of which require calcium for activity. We and others have shown that picomolar concentrations of lead can replace micromolar concentrations of calcium in a protein kinase C enzyme assay. Furthermore, lead activates protein kinase C in intact cells and induces the expression of new genes by a mechanism dependent on protein kinase C. We propose that the learning deficits caused by lead are due to events regulated by protein kinase C that most likely occur at the synapse.