Arsenic Methylation, One-Carbon Metabolism, and Diabetes Incidence

项目概要/摘要 全世界有超过1.4亿人暴露于高于世卫组织标准10微克/升的水砷（As）中 5亿人患有2型糖尿病（T2 D）。当前的知识缺口是对 可改变的风险因素之间的相互作用，如营养状况和环境暴露，如砷， 糖尿病的结果。我们的目标是研究营养状况对 甲基化和糖尿病风险。一旦摄入，无机As（iAs）通过一碳代谢被甲基化 (OCM)形成单甲基（MMA）和二甲基（DMA）砷化物;完全甲基化为DMA有助于尿 消除As（uAs）并降低许多As相关健康结果的风险，例如皮肤癌、膀胱癌 和肺然而，较高的尿DMA%（uDMA%）和相应的较低的uMMA%与 在美国、墨西哥和中国台湾的人群中，糖尿病和糖尿病相关结局的风险增加。 这些发现是非常有争议的，因为它们与其他As相关结果相矛盾。OCM，其中 促进甲基供体的产生，用于As甲基化，取决于营养物质如叶酸和胆碱。 我们假设As甲基化和糖尿病之间的关联被OCM营养素混淆。这是 我们在孟加拉国的初步分析支持，在那里，uMMA%和身体之间的负相关 雌性动物的体重指数随着血浆胆碱的调整而减弱。同样，在一个子集（N=59）中， 在美国印第安人（AI）社区的强心家庭研究（SHFS）中， uMMA%和更高的腰围在调整OCM相关营养素后完全减弱。 为了正式研究这一假设，我们将利用来自SHFS的数据，这是一个稳健的队列， 特征为暴露、新发糖尿病和新测量的OCM营养数据。SHFS招募了3，838人 来自亚利桑那州、俄克拉荷马州和北/南12个部落/社区的14-93岁（中位数33）的参与者 达科他州在1998-1999年或2001-2003年的两次访问中，并跟踪他们长达11年。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）质量 质谱仪（MS）平台。使用四极杆飞行时间（QTOF）分析脂质代谢组学 女士使用这些平台测量的代谢物和营养物包括S-腺苷甲硫氨酸（SAM）、S-腺苷甲硫氨酸（SAM）、S-腺苷甲硫氨酸（SAM）和S-腺苷甲硫氨酸（SAM）。 腺苷高半胱氨酸（SAH）、半胱氨酸、谷氨酸和胆碱代谢物。非目标分析也将 以探索性的方式进行。尽管有人推测OCM营养素可能会混淆 关于As甲基化与糖尿病发病率之间的关系，这一假说从未被正式证实， 使用OCM营养素的综合面板进行前瞻性评估。这项研究将提供深入了解 OCM营养素可能在观察到的As甲基化和糖尿病发病率之间的关联中发挥作用， 允许通过有针对性的暴露补救措施和饮食改变来解决砷毒性的干预措施， 增强OCM营养。

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.