Neurological impacts of prolonged asymptomatic exposure to the marine neurotoxin domoic acid

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.