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

项目摘要/摘要 砷(As)是一种环境毒素，与心血管疾病的风险增加有关， 人类的糖尿病、神经缺陷和癌症。人体接触砷的主要途径是通过饮食： 食物和饮用水。虽然从饮用水中接触砷的毒理学风险一直很好 在研究中，对从食物来源接触砷的毒理学风险知之甚少。填补这一数据鸿沟 考虑到93%的砷暴露是通过摄入食物--海鲜消费--发生的，这一点至关重要 占总风险敞口的83.7%。此外，越来越多的证据表明，长期接触砷、砷 食用海鲜会影响认知行为发育--一个 对健康和经济的影响尚未得到充分研究，但意义重大。考虑到与 海鲜作为蛋白质的贫乏来源的消费，以及由此预测的消费增加， 描述摄入砷的消除、生物积累和行为后果 海鲜常见的物种是至关重要的。在海鲜中，很大一部分砷存在于 砷脂是一类化合物，包括砷脂肪酸(AS-FA)、砷碳氢化合物(AS-HC)。 和含砷脂肪醇(TMA-FOH)。人们通常认为，有机结合的As物种，如- Fas、AS-HCS和TMA-FOHs没有毒理学后果。这一假设被两个汇聚在一起的 一连串的证据。首先，无机砷经常被代谢成有毒的有机砷物种。第二，AS-FA 而AS-HCS在体外已被确定为具有细胞毒性和潜在的神经毒性。TMA-FOH已收到 缺乏关注，尽管具有相似的化学结构，因此可能具有相似的毒理学 特点。为了解决这些关键的知识差距，我们将开发方法来合成和 生物基质，如器官、尿液和粪便中TMA-FOHs的定量。我们还将描述 具有代表性的As-FA、As-HC和TMA-FOH化合物急性染毒小鼠的消除谱 浓度各不相同。这项评估将提供关于潜在毒性的重要新知识。 海鲜中常见的三种砷磷脂。为了进一步理清这一潜力，我们还将延长这次评估 作为物种长期暴露在这些环境中的小鼠。我们将评估这些物种在器官中的储存情况以及 这种暴露的与健康相关的行为后果。这项研究的完成将提供重要的 关于有机As物种，特别是毒物脂在人类健康中的作用的新知识 和疾病，对制定公共卫生法规具有潜在的后果。

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.