Lead And Other Neurotoxins As Risk Factors For Amyotroph

肌萎缩侧索硬化症(ALS)是一种影响脑干和脊髓运动神经元的神经退行性疾病。在美国，每1000人中就有1人死于肌萎缩侧索硬化症。ALS的病因尚不清楚，尽管遗传因素与家族性形式有关(10%的病例)。大约20%的家族性病例存在铜/锌超氧化物歧化酶(SOD)基因突变。氧化应激也可能在散发性肌萎缩侧索硬化症中发挥作用，尽管这种疾病中很少发现SOD突变。环境暴露也被认为是ALS的潜在原因。以前的证据最清楚地表明了接触重金属，特别是铅的作用，尽管电磁场和包括杀虫剂和溶剂在内的化学暴露也有牵连。 我们在新英格兰进行了一项ALS的病例对照研究。具体目的是确定ALS与(I)铅暴露的潜在联系；(Ii)暴露于其他神经毒素，如汞、溶剂和杀虫剂；(Iii)吸烟和饮食等生活方式因素；以及(Iv)影响神经功能或铅代谢的基因多态。病例(N=109)在马萨诸塞州波士顿的两家医院招募。通过随机数字拨号确定的人群对照(N=256)与新英格兰地区内年龄、性别和居住地区的病例频率相匹配。我们通过结构化访谈收集了有关铅的职业、居住和娱乐暴露的信息。此外，我们测量了血液和骨铅水平，后者使用活体K-X-射线荧光(K-XRF)，并存档了全血和血清样本，用于研究基因与环境的相互作用。 我们探讨了肌萎缩侧索硬化症与多种生活方式因素的关系。吸烟与肌萎缩侧索硬化症风险增加1.7倍相关，但饮酒与肌萎缩侧索硬化症无关。肌萎缩侧索硬化症家族史也与风险增加相关。我们检查了饮食中钙、镁和抗氧化剂的摄入量。总体而言，这些饮食因素与肌萎缩侧索硬化症的风险无关，尽管建议对镁和番茄红素有适度的保护作用。 进度： 对肌萎缩侧索硬化症与铅暴露关系的分析发现，肌萎缩侧索硬化症的风险与自我报告的职业铅暴露增加1.9倍有关，并具有终生铅暴露天数的剂量反应。ALS的风险也与血铅和骨铅水平的升高有关：血铅每增加1.9 mg/dl，经对数转化的膝盖骨铅每单位增加3.6倍，经对数转化的胫骨铅每单位增加2.3倍。这些结果扩展了之前完全基于访谈数据的报道，首次显示了ALS与铅生物标志物的关联，并暗示了铅暴露在ALS病因中的潜在作用。 我们还探索了遗传易感性在铅暴露中的作用。具体地说，我们评估了ALS与β-氨基酮丙酸脱水酶(ALAD)和维生素D受体(VDR)基因多态性的关系，这两个基因都与铅易感性有关。ALAD 2等位基因与膝盖骨和胫骨的铅水平降低有关，但与血液中的铅水平无关，并与ALS风险增加1.9倍相关。相反，VDR B等位基因与铅水平或ALS风险无关。这些新的发现表明，ALAD基因多态带来的遗传易感性可能会影响ALS风险，可能是通过与体内铅暴露有关的机制。

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease affecting the motor neurons of the brain stem and spinal cord. In the United States, 1 of every 1000 deaths is due to ALS. The etiology of ALS remains unclear, although genetic factors are involved in the familial form (10% of cases). Approximately 20% of familial cases have mutations in the gene for Cu/Zn superoxide dismutase (SOD). Oxidative stress may also play a role in sporadic ALS, although SOD mutations are rarely found in this form of the disease. Environmental exposures have also been considered as potential causes of ALS. Previous evidence most clearly suggested a role for exposure to heavy metals, particularly lead, although electromagnetic fields and chemical exposures including pesticides and solvents have also been implicated. We conducted a case-control study of ALS in New England. Specific aims were to characterize potential associations of ALS with (i) lead exposure; (ii) exposure to other neurotoxins, eg, mercury, solvents and pesticides; (iii) lifestyle factors such as cigarette smoking and diet; and (iv) genetic polymorphisms affecting neurologic function or lead metabolism. Cases (N=109) were recruited at two hospitals in Boston, MA. Population controls (N=256) identified by random digit dialing were frequency matched to cases by age, sex, and region of residence within New England. We collected information on occupational, residential, and recreational exposure to lead using a structured interview. In addition, we measured blood and bone lead levels, the latter using in vivo K x-ray fluorescence (K-XRF), and archived whole blood and serum samples for studies of gene-environment interaction. We have explored the relationship of ALS to several lifestyle factors. Cigarette smoking was associated with 1.7-fold increase in ALS risk, but alcohol use had no relationship to ALS. Family history of ALS was also associated with increased risk. We examined dietary intake of calcium, magnesium, and antioxidants. Overall, these dietary factors were not related to ALS risk, although modestly protective associations were suggested for magnesium and lycopene. Progress: Analyses of the relationship of ALS to lead exposure found that risk of ALS was associated with a 1.9-fold increase in self-reported occupational exposure to lead, with a dose-response for lifetime days of lead exposure. Risk of ALS was also associated with elevations in both blood and bone lead levels: it was increased 1.9-fold for each mg/dl increase in blood lead, 3.6-fold for each unit increase in log-transformed patella lead, and 2.3-fold for each unit increase in log-transformed tibia lead. These results extend previous reports based entirely on interview data, showing for the first time an association of ALS with lead biomarkers, and suggest a potential role for lead exposure in the etiology of ALS. We have also explored the role of genetic susceptibility to lead exposure. Specifically, we evaluated the relationship of ALS to polymorphisms in the genes for delta-aminolevulinic acid dehydratase (ALAD) and the vitamin D receptor (VDR), which have both been implicated in lead susceptibility. The ALAD 2 allele was associated with decreased lead levels in both patella and tibia, although not in blood, and with 1.9-fold increase in ALS risk. In contrast, the VDR B allele was not associated with lead levels or ALS risk. These novel findings suggest that genetic susceptibility conferred by polymorphisms in ALAD may affect ALS risk, possibly through a mechanism related to internal lead exposure.