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

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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.