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

项目摘要/摘要 最近的流行病学研究强调，长期接触砷(AS)与 人类神经发育障碍和神经退行性疾病(统称为NDS)。初级阶段 人体接触砷的途径是通过饮食：食物和饮用水。虽然暴露的毒理学风险 人们已经对饮用水的危害进行了很好的研究，但对慢性接触的毒理学风险知之甚少。 从食物来源到AS。考虑到93%的AS暴露是通过 摄取食物。此外，越来越多的证据表明，长期接触砷会影响认知能力- 行为发育--一种未被充分研究但意义重大的健康和经济后果。二甲基砷酸 酸(DMA(V))是食物中普遍存在的一种砷物种，也是无机砷的主要代谢物 新陈代谢(无机砷也存在于食物中)。体外DMA(V)暴露研究强调细胞氧化 压力和炎症后果，这是与NDS共同的。慢性暴露的时间和持续时间 与NDS相关的发育敏感期与DMA(V)有关的研究还没有在体内进行。 为了解决这一关键的知识鸿沟，我们将进行一项小鼠研究，以评估 长期低水平接触DMA(V)及其去向、代谢和ND相关生物标志物的发展这 评估将提供有关DMA(V)潜在神经毒性的新数据。进一步研究机制 在神经毒性方面，我们还将测定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 了解有机As物种的一般作用，特别是DMA(V)在人类健康和 神经退行性疾病，可能对制定公共卫生法规产生影响 以减轻健康后果。

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.