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

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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.