Environmental Arsenic Exposure, Microbiome, and Human Health

描述(申请人提供)：土壤和水的砷(As)污染在世界范围内发生--包括在美国--源自环境和人为两种来源。自然发生的冲积性砷污染了南亚和东南亚的地下水，并对易受影响和营养不良的人群造成了大规模中毒。仅在孟加拉国，慢性砷暴露就影响了2500万人。工业砷来源--例如农业中的含砷杀虫剂--也有助于全球接触。在美国， 作为有毒物质和疾病登记局危险物质优先清单的首位，1300万美国人暴露在超过美国水质标准的水平中。长期接触会导致砷中毒，包括黑变病、角化病和心血管疾病，以及肺癌、膀胱癌、肾癌和皮肤癌。慢性砷暴露也会影响儿童的智力功能和发育。没有治疗砷中毒的有效方法，强调预防和/或新的治疗方法的重要性。预防需要有效的风险评估，这也为干预设计和治疗奠定了基础。这一建议的中心假设是，由于摄入改变了人体肠道微生物区系的结构和功能，人体肠道微生物区系的差异导致观察到的砷中毒存在/不存在的差异，因为通过地下水和大米暴露在环境中的砷水平和途径相同。为了验证这一假设，主要研究人员将追求以下具体目标：具体目标：确定外源砷对肠道微生物区系的影响，以及在没有/有砷修正的介质中使用厌氧生物反应器对由此产生的砷转化的影响；具体目标2：表征与砷转化相关的微生物基因在健康人的肠道微生物区系中的频率和多样性，以及暴露于砷中毒/没有砷中毒的人的肠道微生物区系的频率和多样性；以及具体目标3：表征有砷和无砷中毒的砷暴露个人肠道微生物区系的分类组成和功能潜力的变化。为了实现这些特定目标，他们将使用来自美国的未接触砷暴露的健康人的粪便样本，以及来自孟加拉国有(1)慢性砷暴露和砷中毒的受试者的粪便样本，(2)慢性暴露而没有砷中毒的受试者的粪便样本，或(3)没有接触砷中毒的受试者的粪便样本(对照组)。这一多学科项目为微生物组相关风险评估和进一步研究奠定了基础，这些研究将为砷中毒的新干预措施提供信息。砷中毒是一种影响全球数百万人的疾病。

DESCRIPTION (provided by applicant): Arsenic (As) contamination of soils and water occurs worldwide-including in the U.S.-originating from both environmental and anthropogenic sources. Naturally-occurring alluvial As contaminates groundwater in South and Southeast Asia, and has caused wide-scale poisoning of a susceptible and malnourished populace. Chronic As exposure affects over 25 million people in Bangladesh alone. Industrial sources of arsenic-e.g., arsenic- containing pesticides in agriculture-also contribute to global exposure. In the United States (US), As tops the hazardous substance priority list of the Agency for Toxic Substances and Disease Registries, and 13 million Americans are exposed to levels exceeding the US Water Quality Standards. Chronic exposure leads to arsenicosis, which includes melanosis, keratosis, and cardiovascular effects, as well as lung, bladder, kidney, and skin cancer. Chronic As exposure can also affect childhood intellectual function and development. There is no effective therapy for arsenicosis, emphasizing the importance of prevention and/or novel therapeutic approaches. Prevention requires effective risk-assessment, which also lays the groundwork for intervention design and treatment. The central hypothesis of this proposal is that As ingestion alters the structure and function of the human gut microbiota and that differences in the human gut microbiota contribute to the observed variation in the presence/absence of arsenicosis, given the same level and route of As environmental exposure through groundwater and rice. To test this hypothesis, the principal investigators will pursue the following specific aims: Specific Aim : To determine the effects of exogenous As on the gut microbiota and on the resulting transformation of As using anaerobic bioreactors in the absence/presence of arsenic-amended media; Specific Aim 2: To characterize the frequency and diversity of microbial genes related to As transformation in the gut microbiota of healthy humans with no As exposure, as well as of exposed individuals with/without arsenicosis; and Specific Aim 3: To characterize variations in taxonomic composition and functional potential of the gut microbiota of arsenic-exposed individuals with and without arsenicosis. To accomplish these specific aims they will make use of fecal specimens from non-exposed, healthy human individuals from the US, as well as fecal samples from subjects in Bangladesh with (1) chronic As exposure and arsenicosis, (2) chronic exposure and no arsenicosis, or (3) no exposure and no arsenicosis (control group). This multidisciplinary project lays the groundwork for microbiome-related risk assessment and further studies which will inform novel interventions for arsenicosis, a disease affecting millions worldwide.