Thursday, November 21, 2024
11/21/2024
7. Project Summary Millions of people throughout the world are exposed to arsenic, through their drinking water and food, at concentrations above the current US EPA standard. Epidemiological studies demonstrate that exposure is associated with changes locomotor activity, muscular strength, and neuropathy of the peripheral nervous system. One important functions of motor neurons in the peripheral nervous system is to synthesize and secrete the neurotransmitter acetylcholine to regulate skeletal muscle contraction. Studies have assessed changes in brain acetylcholine levels in response to arsenic exposure, but its levels in motor neurons have not been investigated. We conducted preliminary studies exposing human induced pluripotent stem (iPS) cells to arsenic for up to 28 days during their differentiation into mature motor neurons. Exposure to arsenic reduced transcript levels of stage specific motor neuron markers, reduced neurite length, but increased the number of neurites. Additional data from these studies suggest that neurotransmitter vesicular transport is impaired. The work in this proposal will ascertain the mechanisms by which arsenic can impair motor neuron formation and can alter cholinergic neurotransmitter production and function. In the first aim, we will pulse expose iPS cells to human-relevant concentrations of arsenic during their differentiation into cholinergic motor neurons, with the goal of assessing the dose-response, time course, and stage specificity of arsenic. In the second aim, we will explore changes in neurotransmitter uptake and release is a mechanism responsible for the aberrant differentiation. These studies will further our understanding of how arsenic impairs cellular differentiation and may suggest a mechanism for the neuropathy and muscle weakness noted in human epidemiological studies.
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