Does Age Increase Sensitivity to the Neuropathological Effects of the HAB Toxin Domoic Acid?

The neurotoxin domoic acid (DA) is produced by diatoms of the genus Pseudonitzschia during harmful algal blooms (HABS). DA enters the food chain through its accumulation in filter feeding shellfish and fish that are then eaten by larger vertebrates, including humans. DA neurotoxicity is due to its activity as a potent glutamate receptor agonist in the CNS. Although regulatory monitoring of fisheries limits the risk for acute DA toxicity in humans, there is growing evidence for neurotoxic effects associated with chronic low-level DA exposure. Consumption surveys of participants in the recreational razor clam fishery along the Washington Coast indicate that a fraction of Pacific Northwest coastal populations are chronically exposed to low levels of DA. The elderly were overrepresented in the fraction of the population chronically exposed to DA. Thus, with changing ocean conditions likely to increase the frequency and severity of HAB events, it is important to not only better understand the risks of chronic low-level DA exposure, but also identify the potential increased susceptibility to DA toxicity in at-risk populations. We are using a laboratory model of chronic DA exposure in mice to assess the the interaction between age and toxicity. Our results demonstrate reversible DA-induced learning deficits in adult mice are associated with mitochondrial dysfunction in the brain after several months of weekly exposure to levels far below those that result in visible signs of neuroexcitotoxicity. Mitochondrial defects also follow 1 week of daily exposure to subconvulsive DA levels supporting subtle physiological and behavioral responses to repetitive low-level exposure to DA. To assess the interaction of age with DA toxicity we are comparing onset of subconvulsive and convulsive effects across a range of single DA exposures (1-2.5 mk/kg) in young (7-9 month old) and aged (26-28 month old) C57Bl/6 mice. Early results suggest increased sensitivity to DA toxicity in the aged mice. These results highlight the importance of considering repetitive exposures and the potential for increased susceptibility to DA toxicity in physiologically compromised people when assessing the potential impacts of DA on human health. Supported by Oceans and Human Health grants NIH R01 ES030319 and NSF OCE-1839041.