Synthesis, quantification and in vivo assessment of arsenolipids prevalent in seafoods

项目总结/摘要 砷（As）是一种环境毒素，与心血管疾病风险增加有因果关系， 糖尿病、神经缺陷和癌症。人类接触砷的主要途径是通过饮食： 食物和饮用水。虽然饮用水中砷暴露的毒理学风险一直很好 研究，很少有人知道的毒理学风险暴露于砷从食物来源。弥补这一数据差距 考虑到93%的砷暴露是通过摄入食物--食用海鲜--发生的， 占到了83.7%此外，越来越多的证据表明，长期接触砷， 可能会影响认知行为的发展， 研究不足，但重要的健康和经济后果。考虑到相关的健康益处， 作为蛋白质的精益来源的海产品消费，以及随之而来的预期消费量增加， 描述消除，生物积累和行为后果的摄入砷 海产品常见的物种至关重要。在海产品中，大部分As以 砷脂，一类化合物，包括砷脂肪酸（As-FA）、砷烃（As-HC） 和含砷脂肪醇（TMA-FOH）。通常认为，有机结合的As物种，如As- FA、As-HC和TMA-FOH无毒理学后果。这一假设被两个收敛的 证据线。首先，无机砷往往被代谢为有毒的有机砷物种。第二，作为FA 并且As-HC已经在体外被确定为具有细胞毒性和潜在的神经毒性。TMA-FOH已收到 尽管具有相似的化学结构，因此可能具有相似的毒理学，但很少受到关注 特色为了解决这些关键的知识差距，我们将开发综合方法， 生物基质中TMA-FOH的定量，例如器官、尿液和粪便。我们还将描述 急性暴露于代表性As-FA、As-HC和TMA-FOH化合物的小鼠的消除曲线， 不同浓度。该评价将提供有关潜在毒性的重要新知识， 海鲜中三种常见的砷脂。为了进一步理清这一潜力，我们还将扩展这一评估 长期接触砷的小鼠。我们将评估这些物种在器官中的储存情况， 这种暴露的健康相关行为后果。这项研究的完成将提供重要的 关于有机砷物种的作用的新知识，一般来说，特别是砷脂在人类健康中的作用 和疾病，对公共卫生法规的发展有潜在的影响。

PROJECT SUMMARY / ABSTRACT Arsenic (As) is an environmental toxin that is causally associated with increased risk of cardiovascular disease, diabetes, neurological deficits and cancers in humans. The primary route of As exposure in humans is via 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 exposure to As from food sources. Addressing this data gap is critical considering that 93% of As exposure occurs via the ingestion of food—with seafood consumption accounting for 83.7% of that exposure. Moreover, increasing evidence suggests that chronic exposure to As, as would be expected from the consumption of seafood, can affect cognitive-behavioral development—an understudied, yet significant, health- and economic- consequence. Given the associated health benefits with the consumption of seafood as a lean source of protein, and consequential predicted increase in consumption, delineating the elimination, bioaccumulation and behavioral consequences of the ingestion of As species common to seafood is of paramount importance. In seafoods, a large fraction of As occurs as arsenolipids, a class of compounds which includes arseno-fatty acids (As-FA), arseno-hydrocarbons (As-HC) and arseno-fatty alcohols (TMA-FOH). It is commonly assumed that organically-bound As species, such as As- FAs, As-HCs, and TMA-FOHs, have no toxicological consequence. This assumption is refuted by two converging lines of evidence. First, inorganic As is often metabolized to organic As species which are toxic. Second, As-FAs and As-HCs have been determined in vitro to be cytotoxic and potentially neurotoxic. TMA-FOHs have received scant attention, despite having a similar chemical structure and thus potentially similar toxicological characteristics. To address these critical knowledge gaps, we will develop methods for the synthesis and quantification of TMA-FOHs in biological matrices, such as organs, urine and feces. We will also characterize the elimination profile of mice acutely exposed to representative As-FA, As-HC and TMA-FOH compounds at varying concentrations. This evaluation will provide significant new knowledge about the potential for toxicity of three common arsenolipids in seafood. To further disentangle this potential, we will also extend this evaluation to mice exposed chronically to these As species. We will evaluate storage of these species in organs as well as the health-related behavioral consequences of such exposure. Completion of this study will provide significant new knowledge about the role of organic As species, in general, and arsenolipids, in particular, in human health and disease, with potential consequences for the development of public health regulations.