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ALS。ALS的病因仍不清楚，尽管遗传因素参与了家族形式（10%的病例）。大约20%的家族性病例在Cu/Zn超氧化物歧化酶（SOD）基因中具有突变。氧化应激也可能在散发性ALS中发挥作用，尽管在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。之前的证据最清楚地表明，接触重金属（尤其是铅）也有一定作用，尽管电磁场和化学品（包括杀虫剂和溶剂）接触也与此有关。 我们在新英格兰进行了一项ALS病例对照研究。具体目的是描述ALS与以下因素的潜在关联：（i）铅暴露;（ii）其他神经毒素暴露，如汞、溶剂和农药;（iii）生活方式因素，如吸烟和饮食;（iv）影响神经功能或铅代谢的遗传多态性。在马萨诸塞州波士顿的两家医院招募病例（N=109）。通过随机数字拨号确定的人群对照（N=256）与新英格兰内年龄、性别和居住地区的病例频率匹配。我们收集的信息，职业，住宅和娱乐接触铅使用结构化访谈。此外，我们还测量了血液和骨铅水平，后者使用体内K X射线荧光（K-XRF），并存档全血和血清样本用于基因-环境相互作用的研究。 我们已经探讨了ALS与几种生活方式因素的关系。吸烟与ALS风险增加1.7倍相关，但饮酒与ALS无关。ALS家族史也与风险增加有关。我们检查了钙、镁和抗氧化剂的饮食摄入量。总的来说，这些饮食因素与ALS风险无关，尽管镁和番茄红素有适度的保护作用。 进度： 对ALS与铅暴露关系的分析发现，ALS的风险与自我报告的铅职业暴露增加1.9倍有关，并与铅暴露的剂量反应有关。ALS风险也与血铅和骨铅水平升高相关：血铅每增加mg/dl，ALS风险增加1.9倍，对数转换髌骨电极导线每增加1单位，ALS风险增加3.6倍，对数转换胫骨电极导线每增加1单位，ALS风险增加2.3倍。这些结果扩展了以前的报告完全基于访谈数据，首次显示了ALS与铅生物标志物的关联，并表明铅暴露在ALS病因学中的潜在作用。 我们还探讨了遗传易感性对铅暴露的作用。具体来说，我们评估了ALS与δ-氨基乙酰丙酸脱氢酶（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等位基因与髌骨和胫骨中铅水平降低相关，但与血液中的铅水平无关，并且与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多态性所赋予的遗传易感性可能会影响ALS的风险，可能是通过与内部铅暴露相关的机制。

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.