ENDOCRINE TOXICITY OF LOW LEVEL LEAD

低水平铅的内分泌毒性

• 批准号: 3251781
• 负责人: CAROL R ANGLE
• 金额: $ 7.82万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1987
• 资助国家: 美国
• 起止时间: 1987-08-01 至 1990-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3251781
• 关键词: X ray; atomic absorption spectrometry; blood chemistry; body physical characteristic; chelation therapy; child physical development; densitometry; electrodes; endocrine disorder; environmental toxicology; epidemiology; follicle stimulating hormone; gel electrophoresis; gonadotropin releasing factor; growth hormone releasing hormone; high performance liquid chromatography; histochemistry /cytochemistry; hormone regulation /control mechanism; human subject; hypothalamic pituitary axis; lead poisoning; longitudinal human study; neuroendocrine system; physical chemical interaction; pituitary dwarfism; postnatal growth disorder; preschool child (1-5); protein kinase C; radioimmunoassay; scintillation counter; somatotropin; thyrotropin; thyrotropin releasing hormone

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.

身材矮小是儿童铅中毒的典型症状之一 中毒，几乎没有得到当代的考虑。 全国健康与营养调查分析 1976-1980年2 695名6个月至7岁儿童的数据（NHANES II） 年显示出显着的，独立的，负相关的 血铅（PbB）与身高、体重、胸围的关系。 典型的解释是， 以及处于社会经济风险中的儿童的高铅暴露， 统计验证。 有几种合理的生物学 有强有力的证据表明， 神经内分泌毒性 两个临床内分泌研究 铅中毒儿童甲状腺功能受损 促甲状腺激素释放刺激激素（TSH）反应 激素（TRH），类似于成人铅工人报告。 这促使对可能的机制进行初步的体外研究 毒性。 大鼠垂体细胞在0.1- 100 μ M Pb ~（++）呈剂量依赖性抑制TRH诱导的TSH release. 钙分布的附加动力学分析 垂体前叶切片与Pb++孵育后， Pb/Ca交互作用 拟议研究的具体目标是： 1)定义低水平PbB对2-5岁儿童的内分泌毒性 25-55微克/日1的儿童 以及对甲状腺的基础和刺激反应的研究 促甲状腺激素（TSH），促甲状腺激素释放激素（TRH），生长激素（GH）， 基础TSH、GH、催乳素、FSH和LH T3、T4、游离T4、皮质醇 促肾上腺皮质激素和相关的内分泌功能和生长与 急性和慢性铅负荷指数。 2)测试，在 铅对未成熟和成熟大鼠垂体细胞的影响 通过激素测量对TRH、GnRH和GHRH的反应 释放和形态。 3)研究Pb 通过研究，在促甲状腺细胞中， 未成年大鼠，铅的影响：a）3 H-TRH结合， 膜受体，B）电压和受体介导的钙 通道，c）钙的细胞内分布，和d） 细胞内钙受体如钙调蛋白的激活 和蛋白激酶C。