Evaluation of the timing and duration of low level dimethylarsinic acid exposure to its fate, metabolism, and development of neurodevelopmental and neurodegenerative biomarkers

评估低水平二甲基胂酸暴露的时间和持续时间对其命运、代谢以及神经发育和神经退行性生物标志物发育的影响

• 批准号: 10593990
• 负责人: Jeremy Davidson Bailoo
• 金额: $ 7.33万
• 依托单位: TEXAS TECH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-17 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10593990
• 关键词: Acids; Address; Adult; Affect; Arsenic; Arsenicals; Behavior Disorders; Behavioral; Biological Markers; Brain; Brain region; Cacodylic Acid; Cell physiology; Cells; Cereals; Child; Chronic; Cognitive; Cognitive deficits; Data; Development; Diagnosis; Diet; Disease; Economics; Epidemic; Evaluation; Exhibits; Exposure to; Food; Functional disorder; Future; Goals; Health; Human; In Vitro; Infant; Inflammation; Ingestion; Kidney; Knowledge; Life; Liver; Metabolic Pathway; Metabolism; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neurodevelopmental Disorder; Organ; Outcome Study; Oxidative Stress; Phenotype; Public Health; Reference Standards; Regulation; Reporting; Research; Rice; Risk; Role; Route; Skin; Source; Sulfides; System; Tissues; Toxic effect; Toxicology; United States; Work; behavioral phenotyping; bioaccumulation; brain tissue; critical period; cytotoxic; cytotoxicity; drinking water; epidemiology study; feeding; genetic risk factor; in vitro Model; in vivo; insight; metabolomics; neurotoxic; neurotoxicity; novel; postnatal; public health relevance; transcriptomics

PROJECT SUMMARY / ABSTRACT Recent epidemiological studies have highlighted that chronic exposure to Arsenic (As) is associated with neurodevelopmental disorders and neurodegenerative diseases (collectively, NDs) in humans. The primary route of As exposure in humans is via the diet: food and drinking water. While the toxicological risks of exposure to As from drinking water have been well studied, little is known about the toxicological risk of chronic exposure to As from food sources. Addressing this data gap is critical considering that 93% of As exposure occurs via the ingestion of food. Moreover, increasing evidence suggests that chronic exposure to As can affect cognitive- behavioral development—an understudied, yet significant, health- and economic- consequence. Dimethylarsinic acid (DMA(V)) is an As species that is prevalent in foods as well as a primary metabolite of inorganic As metabolism (inorganic As is also present in foods). In vitro DMA(V) exposure studies highlight cellular oxidative stress and inflammation consequences, which are shared with NDs. The timing and duration of chronic exposure to DMA(V), in relation to sensitive periods of development associated with NDs, have not been studied in vivo. To address this critical knowledge gap, we will conduct a mouse study to evaluate the relationship between chronic low-level exposure to DMA(V) and its fate, metabolism, and development of ND-related biomarkers. This evaluation will provide new data on the potential for neurotoxicity of DMA(V). To further investigate mechanisms of neurotoxicity, we will also determine the bioaccumulation of DMA(V) in whole brain, specific brain regions, kidneys and liver, as well as identify metabolites of DMA(V). Completion of this study will provide significant new knowledge about the role of organic As species, in general, and DMA(V), in particular, in human health and neurodegenerative diseases, with potential consequences for the development of public health regulations in order to mitigate health consequences.

项目总结/摘要 最近的流行病学研究强调，长期接触砷（As）与 神经发育障碍和神经退行性疾病（统称ND）。主 人类接触砷的途径是通过饮食：食物和饮用水。虽然接触的毒理学风险 对饮用水中砷的毒性研究已经很充分，但对慢性暴露的毒理学风险知之甚少 从食物来源。考虑到93%的As暴露是通过 食物的摄入。此外，越来越多的证据表明，长期接触砷会影响认知能力， 行为发展--一个未充分研究但重要的健康和经济后果。二甲胂 DMA（V）是一种常见于食品中的砷形态，也是无机砷的初级代谢产物 无机砷也存在于食物中。体外DMA（V）暴露研究强调细胞氧化 压力和炎症的后果，这是与ND共享。慢性接触的时间和持续时间 DMA（V）与ND相关的敏感发育期的关系尚未在体内研究。 为了解决这一关键的知识差距，我们将进行一项小鼠研究，以评估 长期低水平暴露于DMA（V）及其命运，代谢和ND相关生物标志物的发展。这 评估将提供关于DMA（V）神经毒性潜力的新数据。为了进一步研究 神经毒性，我们还将确定DMA（V）在全脑，特定脑区， 肾脏和肝脏，以及鉴定DMA（V）的代谢物。这项研究的完成将提供重要的新的 关于有机砷物种的作用的知识，一般来说，DMA（V），特别是在人类健康和 神经退行性疾病，对公共卫生法规的制定具有潜在影响， 以减轻健康后果。