Arsenic Methylation, One-Carbon Metabolism, and Diabetes Incidence

项目摘要/摘要 全球超过1.4亿人暴露在超过世卫组织10𝜇g/L标准的水砷中 有5亿人患有2型糖尿病(T2D)。目前的知识差距是对 可改变的风险因素之间的相互作用，例如营养状况和环境暴露，例如， 与糖尿病的结果有关。我们的目标是调查营养状况对两种疾病之间关系的影响 甲基化和糖尿病风险。一旦摄入，无机砷(IAS)就会通过一碳代谢而甲基化 (OCM)形成单甲基(MMA)和二甲基砷(DMA)；DMA的完全甲基化促进尿液 消除AS(UAS)并降低许多AS相关健康后果的风险，例如皮肤癌、膀胱癌 还有肺。然而，较高的尿DMA%(uDMA%)和相应的较低的UMMA%相关 在美国、墨西哥和台湾的人群中，糖尿病和糖尿病相关后果的风险增加。 这些发现极具争议性，因为它们与其他与AS相关的结果相矛盾。OCM，它 促进AS甲基化的甲基供体的产生，依赖于叶酸和胆碱等营养物质。 我们假设AS甲基化和糖尿病之间的联系被OCM营养素混淆了。这是 由我们在孟加拉国的初步分析支持，在孟加拉国，Umma%和Body之间存在反向关联 通过调整血浆胆碱，女性的体重指数有所下降。类似地，在子集(N=59)中 在美国印第安人(AI)社区中的强心家庭研究(SHFS)，较低的 调整OCM相关营养素后，Umma%和较高腰围完全减弱。 为了正式研究这一假设，我们将利用SHFS的数据，这是Well的一个强有力的队列 其特征是暴露、发生糖尿病和最新测量的OCM营养数据。房屋及规划地政局招募了3,838名 参与者年龄14-93岁(中位数33岁)，来自亚利桑那州、俄克拉何马州和北部/南部的12个部落/社区 在1998-1999年或2001-2003年两次访问达科他州，并对他们进行了长达11年的跟踪调查。OCM营养素，以及 许多其他代谢物目前正在使用气相色谱飞行时间(GCTOF)质谱仪进行分析 光谱仪(MS)平台。使用四极飞行时间(QTOF)分析了脂代谢组学 利用这些平台测定的代谢物和营养物质包括S-腺苷蛋氨酸、S- 腺苷同型半胱氨酸(SAH)、半胱氨酸、谷氨酸和胆碱代谢物。无针对性的分析也将 以探索性的方式进行。尽管有人推测OCM营养素可能会混淆 AS甲基化与糖尿病发病的关系，这一假说从来没有正式和 使用全面的OCM营养素小组进行前瞻性评估。这项研究将为我们深入了解 OCM营养素在AS甲基化和糖尿病发病率之间观察到的关联中可能发挥的作用 允许采取干预措施，通过有针对性的暴露、补救和改变饮食来解决毒性问题 增强OCM营养素。

PROJECT SUMMARY/ABSTRACT Over 140 million individuals worldwide are exposed to water arsenic (As) above the WHO standard of 10 𝜇g/L and 500 million people live with Type 2 diabetes (T2D). A current gap in knowledge is a thorough understanding of the interplay between modifiable risk factors, e.g. nutritional status and environmental exposures such as As, with diabetes outcomes. Our goal is to investigate the influence of nutritional status on the association between As methylation and diabetes risk. Once ingested, inorganic As (iAs) is methylated via one-carbon-metabolism (OCM) to form mono-methyl (MMA) and dimethyl (DMA) arsenicals; full methylation to DMA facilitates urinary As (uAs) elimination and reduces risk for numerous As-related health outcomes, e.g. cancers of the skin, bladder and lung. Higher urinary DMA% (uDMA%), and corresponding lower uMMA%, however, have been associated with increased risk for diabetes and diabetes-related outcomes in populations from the US, Mexico, and Taiwan. These findings are highly controversial as they contradict those for other As-related outcomes. OCM, which facilitates the production of the methyl donor for As methylation, depends on nutrients such as folate and choline. We hypothesize the association between As methylation and diabetes is confounded by OCM nutrients. This is supported by our preliminary analyses in Bangladesh, where an inverse association between uMMA% and body mass index among females was attenuated with adjustment for plasma choline. Similarly, in a subset (N=59) of the Strong Heart Family Study (SHFS) in American Indian (AI) communities, the association between lower uMMA% and higher waist circumference was completely attenuated after adjustment for OCM-related nutrients. To formally investigate this hypothesis, we will leverage data from the SHFS, a robust cohort with well characterized As exposure, incident diabetes and newly measured OCM nutrient data. The SHFS recruited 3,838 participants aged 14-93 (median 33) years from 12 tribes/communities in Arizona, Oklahoma, and North/South Dakota during two visits in 1998–1999 or 2001–2003 and followed them for up to 11 years. OCM nutrients, and many other metabolites, are currently being analyzed using a gas chromatography time of flight (GCTOF) mass spectrometer (MS) platform. Lipid metabolomics has been analyzed using a quadrupole time of flight (QTOF) MS. Metabolites and nutrients measured using these platforms include S-adenosylmethionine (SAM), S- adenosylhomocysteine (SAH), cysteine, glutamate, and choline metabolites. Untargeted analyses will also be conducted in an exploratory manner. Although it has been speculated that OCM nutrients may confound the relationship between As methylation and diabetes incidence, this hypothesis has never been formally and prospectively assessed using a comprehensive panel of OCM nutrients. This study will provide insight into the role OCM nutrients may play in the observed association between As methylation and diabetes incidence to allow for interventions that address As toxicity via targeted exposure remediation and dietary changes that enhance OCM nutrients.