ENDOCRINE TOXICITY OF LOW LEVEL LEAD

身材矮小是儿童铅中毒的典型症状之一(铅) 中毒，几乎没有得到当代的考虑。 全国健康与营养体检调查结果分析 (NHANES II)1976-1980年2695名6个月至7岁儿童的数据 年显示出显著的，独立的，负相关 血铅(PBB)与身高、体重和胸围的关系。 将营养缺乏联系起来的典型解释 而处于社会经济风险的儿童中高铅暴露并不是 经过统计验证。有几个看似合理的生物学证据 铅抑制生长的机制，有强有力的证据 神经内分泌毒性。两例患者的临床内分泌研究 铅中毒的儿童表现为甲状腺受损 促甲状腺激素(TSH)对促甲状腺激素释放的反应 激素(TRH)，与成年铅工人的报告相似。 这促使了对可能机制的初步体外研究。 有毒性。大鼠脑垂体细胞在0.1- 100uM铅对TRH诱导的TSH有剂量依赖性抑制作用 放手。钙在土壤中分布的动力学分析 铅孵育后的脑垂体前叶切片显示 铅/钙的相互作用。拟议研究的具体目标是： 1)确定低水平多溴联苯对2-5岁儿童的内分泌毒性 年龄25-55ug/d1，横断面和纵向 以及对甲状腺基础反应和刺激反应的研究 促甲状腺激素(TSH)转化为TRH，生长激素(GH)和 基础TSH、GH、催乳素、FSH、LHT3、T4、游离T4、皮质醇 ACTH及其与内分泌功能和生长发育的相关性 铅的急性和慢性身体负荷指标。2)测试，在 铅对幼年和成熟大鼠脑垂体细胞的影响 激素测定对TRH、GnRH和GHRH的反应 释放和形态。3)研究铅的作用机制 通过研究可能抑制TRH诱导的TSH在促甲状腺激素细胞中的释放 在未成熟大鼠中，铅对：A)~3H-TRH结合的影响 膜受体、b)电压与受体介导的钙离子 通道，c)细胞内钙的分布，以及d) 钙调素等细胞内钙受体的激活 和蛋白激酶C。

Short stature, one of the classic stigmata of childhood lead (Pb) poisoning, has received almost no contemporary consideration. Analysis of the National Health and Nutrition Examination Survey (NHANES II) of 1976-1980 data on 2695 children ages 6 months - 7 years showed a significant, independent, negative correlation of blood lead (PbB) with height, weight and chest circumference. The typical explanation which associates nutritional deficiency and high lead exposure in children at socioeconomic risk, was not statistically verified. There are several plausible biologic mechanisms for growth retardation by lead, with strong evidence for neuroendocrine toxicity. Clinical endocrine studies of two children with lead toxicity demonstrated an impaired thyroid stimulation hormone (TSH) response to thyrotropin releasing hormone (TRH), similar to that reported in adult lead workers. This prompted preliminary in vitro studies of possible mechanisms of toxicity. Rat pituitary cells incubated in the presence of 0.1- 100uM Pb++ showed a dose related inhibition of TRH-induced TSH release. Additional kinetic analysis of calcium distribution in anterior pituitary slices after incubation with Pb++ implicates a Pb/Ca interaction. The specific aims of the proposed study are: 1) Define the endocrine toxicity of low level PbB in children 2-5 years old with PbB 25-55 ug/d1 by cross sectional and longitudinal and studies of the basal and stimulated responses of thyroid stimulating hormone (TSH) to TRH, and growth hormone (GH) and basal TSH, GH, prolactin, FSH and LH T3, T4, free T4, Cortisol and ACTH and correlate endocrine function and growth with indices of acute and chronic body burden of lead. 2) Test, in pituitary cells of immature and mature rats, the effect of lead on the response to TRH, GnRH and GHRH as measured by hormone release and morphology. 3) Examine the mechanisms by which Pb might inhibit TRH induced TSH release by studying, in thyrotrophs of immature rats, the effect of Pb on: a) 3H-TRH binding to membrane receptors, b) voltage and receptor-mediated calcium channels, c) intracellular distribution of calcium, and d) the activation of intracellular calcium receptors such as calmodulin and protein kinase C.