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Open Access Publications from the University of California

Scholarly Works (4 results)

  • Thesis
  • Peer Reviewed
UC Santa Cruz Electronic Theses and Dissertations (2016)

Domoic acid is an algal-derived neurotoxin that contaminates seafood during harmful algal blooms. It causes excitotoxicity in the vertebrate central nervous system by over-stimulating neurons; in high doses, this can cause seizures, brain lesions, and death. At low doses, however – those causing no outward signs of excitotoxicity – it is unclear whether domoic acid exposure could have potentially damaging neurological effects. This is especially relevant for human exposures, as we are protected from high toxin levels by seafood monitoring and regulatory efforts, but can still ingest domoic acid at concentrations below the regulatory limit (20 µg domoic acid per g wet shellfish weight). To address whether chronic exposure to these low-levels of domoic acid negatively affects neurological health and function, I: 1) examined changes in gene expression and cellular energetics in the brains of adult zebrafish chronically exposed to asymptomatic domoic acid; 2) assessed the effect of low-dose (i.e., non-cytotoxic) domoic acid exposure on the electrophysiological activity and connectivity of neural networks in organotypic mouse brain slice cultures in vitro; and 3) examined the brains of adult mice chronically exposed to asymptomatic domoic acid for signs of histopathology and disruption to a subtype of parvalbumin-positive inhibitory neurons. I found that prolonged domoic acid exposure significantly affected gene transcription and impaired mitochondrial function in zebrafish brains, and altered neuronal network activity and connectivity in mouse brain slice cultures, all in the absence of overt symptoms, gross histopathology, and neuron death/injury. Further, chronic asymptomatic domoic acid exposures that led to transient deficits in learning and memory in a mouse model did not produce measurable effects on hippocampal inflammation, cell/neuron numbers, or parvalbumin-positive staining intensity. These results indicate that chronic domoic acid exposure may have sub-clinical effects that can go undetected and may impact neurological function; further study is needed to better inform human health risk assessments.

    Cover page: Neurological impacts of prolonged asymptomatic exposure to the marine neurotoxin domoic acid
    • Article
    • Peer Reviewed
    UC Santa Cruz Previously Published Works (2018)
    Domoic acid (DA) is a neurotoxin produced during harmful algal blooms that accumulates in marine organisms that serve as food resources for humans. While acute DA neurotoxicity can cause seizures and hippocampal lesions, less is known regarding how chronic, subacute DA exposure in adulthood impacts the hippocampus. With more frequent occurrences of harmful algal blooms, it is important to understand the potential impact of repeated, low-level DA exposure on human health. To model repeated, low-dose DA exposure, adult mice received a single low-dose (0.75 ± 0.05 μg/g) of DA or vehicle weekly for 22 consecutive weeks. Quantitative immunohistochemistry was performed to assess the effects of repeated, low-level DA exposure on hippocampal cells and synapses. Vesicular glutamate transporter 1 (VGluT1) immunoreactivity within excitatory boutons in CA1 of DA-exposed mice was increased. Levels of other vesicular transporter proteins (i.e., VGluT2 and the vesicular GABA transporter (VGAT)) within boutons, and corresponding bouton densities, were not significantly altered in CA1, CA3, or dentate gyrus. There were no significant changes in neuron density or glial fibrillary acidic protein (GFAP) immunoreactivity following chronic, low-dose exposure. This suggests that repeated low doses of DA, unlike high doses of DA, do not cause neuronal loss or astrocyte activation in hippocampus in adult mice. Instead, these findings demonstrate that repeated exposure to low levels of DA leads to subtle changes in VGluT1 expression within CA1 excitatory boutons, which may alter glutamatergic transmission in CA1 and disrupt behaviors dependent on spatial memory.
      Cover page: Repeated low level domoic acid exposure increases CA1 VGluT1 levels, but not bouton density, VGluT2 or VGAT levels in the hippocampus of adult mice
      • Article
      • Peer Reviewed
      UC Santa Cruz Previously Published Works (2017)
      The consumption of one meal of seafood containing domoic acid (DA) at levels high enough to induce seizures can cause gross histopathological lesions in hippocampal regions of the brain and permanent memory loss in humans and marine mammals. Seafood regulatory limits have been set at 20mgDA/kg shellfish to protect human consumers from symptomatic acute exposure, but the effects of repetitive low-level asymptomatic exposure remain a critical knowledge gap. Recreational and Tribal-subsistence shellfish harvesters are known to regularly consume low levels of DA. The aim of this study was to determine if chronic low-level DA exposure, at doses below those that cause overt signs of neurotoxicity, has quantifiable impacts on cognitive function. To this end, female C57BL/6NJ mice were exposed to asymptomatic doses of DA (≈0.75mg/kg) or vehicle once a week for several months. Spatial learning and memory were tested in a radial water maze paradigm at one, six and 25 weeks of exposure, after a nine-week recovery period following cessation of exposure, and at three old age time points (18, 24 and 28 months old). Mice from select time points were also tested for activity levels in a novel cage environment using a photobeam activity system. Chronic low-level DA exposure caused significant spatial learning impairment and hyperactivity after 25 weeks of exposure in the absence of visible histopathological lesions in hippocampal regions of the brain. These cognitive effects were reversible after a nine-week recovery period with no toxin exposure and recovery was sustained into old age. These findings identify a new potential health risk of chronic low-level exposure in a mammalian model. Unlike the permanent cognitive impacts of acute exposure, the chronic low-level effects observed in this study were reversible suggesting that these deficits could potentially be managed through cessation of exposure if they also occur in human seafood consumers.
        Cover page: Chronic low-level exposure to the common seafood toxin domoic acid causes cognitive deficits in mice
        • Article
        • Peer Reviewed
        UC Santa Cruz Previously Published Works (2014)
        Domoic acid is an algal-derived seafood toxin that functions as a glutamate agonist and exerts excitotoxicity via overstimulation of glutamate receptors (AMPA, NMDA) in the central nervous system (CNS). At high (symptomatic) doses, domoic acid is well-known to cause seizures, brain lesions and memory loss; however, a significant knowledge gap exists regarding the health impacts of repeated low-level (asymptomatic) exposure. Here, we investigated the impacts of low-level repetitive domoic acid exposure on gene transcription and mitochondrial function in the vertebrate CNS using a zebrafish model in order to: (1) identify transcriptional biomarkers of exposure; and (2) examine potential pathophysiology that may occur in the absence of overt excitotoxic symptoms. We found that transcription of genes related to neurological function and development were significantly altered, and that asymptomatic exposure impaired mitochondrial function. Interestingly, the transcriptome response was highly variable across the exposure duration (36 weeks), with little to no overlap of specific genes across the six exposure time points (2, 6, 12, 18, 24, and 36 weeks). Moreover, there were no apparent similarities at any time point with the gene transcriptome profile exhibited by the glud1 mouse model of chronic moderate excess glutamate release. These results suggest that although the fundamental mechanisms of toxicity may be similar, gene transcriptome responses to domoic acid exposure do not extrapolate well between different exposure durations. However, the observed impairment of mitochondrial function based on respiration rates and mitochondrial protein content suggests that repetitive low-level exposure does have fundamental cellular level impacts that could contribute to chronic health consequences.
          Cover page: Chronic low-level domoic acid exposure alters gene transcription and impairs mitochondrial function in the CNS
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