Invited Perspective: The Relevance of Animal Models of Domoic Acid Neurotoxicity to Human Health

On 18 August 1961, the Santa Cruz Sentinel reported¹ that thousands of “crazed seabirds” were diving into lamp posts, buildings, cars, and streets to their death on the shores of North Monterey Bay, California. The birds appeared to be confused and disoriented, exhibited seizure activity, and flew at terrified residents. Eight people were bitten, but none suffered a related illness. Alfred Hitchcock contacted the newspaper for details. As the story is told, the Hollywood movie producer used the incident as research material for the classic 1963 thriller The Birds. About 30 years later it was established that the culprit of this extreme event was an algal bloom of Pseudo-nitzchia, select species of which produce domoic acid (DA).² DA is a potent neurotoxin that bioaccumulates in filter-feeding shellfish and subsequently enters the food web. DA has been responsible for multiple mass illness and mortality events of shore birds³ and marine^4–6 and coastal-dwelling mammals,⁷ particularly on the U.S. Pacific Coast. These events provided opportunities to capture the naturally occurring physical, physiological, neurologic, cardiac, and behavioral impacts of DA exposure, as well as advance understanding of delayed effects, reexposures, and rehabilitation possibilities.^8,9 Laboratory studies of zebrafish, shellfish, marine mammals, and mice further expanded the capacity for hypothesis testing relevant to protecting public health.^10–12 Nonhuman primate studies, such as that presented by Petroff et al.⁸ in this issue of Environmental Health Perspectives, represent a unique opportunity to improve understanding of an important contemporary issue: the neural mechanisms underlying chronic exposure to presumably safe levels of DA.

The potential risk of domoic acid to human health was first discovered in Montreal, Canada, in 1987. People who consumed mussels harvested from the Prince Edward Island region with high levels of DA suffered the acute onset of severe gastrointestinal and neurologic symptoms, which in some cases included seizures, coma, and even death.^13,14 Many survivors were left with a permanent anterograde memory disorder, amnesic shellfish poisoning (ASP). Autopsy findings of patients with ASP and early nonhuman primate studies identified damage to the hippocampus as central to seizures and memory problems associated with DA neurotoxicity.^14,15 In the aftermath of this outbreak, extensive research using shellfish, rodent, and nonhuman primate models helped establish current regulatory limits of 20 ppm, ostensibly preventing new cases of ASP.^16–19

However, the evidence collected over the past decade—which came from epidemiological cohort studies of at-risk Native American communities,^20–22 surveys of recreational and subsistence razor clam harvesters,²³ and risk assessments,²⁴ combined with zebrafish²⁵ and rodent,^26,27 models—indicates that repeated, chronic exposure to DA at presumably safe levels ($<20\text{\hspace{0.17em}ppm}$) may have neurotoxic effects impacting many people. Studies of coastal Native American communities with repetitive, low-level exposure for up to 8 y identified the hallmark memory problems associated with ASP in attenuated form.^20,21 Similarly, problems with spatial memory were found in mice exposed to low levels of DA in the absence of other neurologic symptoms.¹⁰ A key finding of this mouse study was the reversibility of the spatial memory problems with exposure cessation, signaling optimism for chronically exposed people.

Petroff et al.⁸ conducted many studies in their effort to identify the neural mechanisms of repeated dietary exposure to lower levels of DA upon brain systems, behavior, and adaptation in adult female Macaca fascicularis monkeys. The investigators did not find the expected hippocampal excitability in the low-dose monkeys compared with controls. They also did not find differences in hippocampal and thalamic volume connectivity based upon in-life magnetic resonance imaging. What they did find was a “subtle shift” in the molecular profile of the hippocampus, as well as in the microglia phenotype of the thalamus. With appropriate caution, the investigators interpreted this as an adaptive or compensatory response to lower-level DA exposures over time. This could potentially explain the relatively small effect size of memory decline in similarly exposed people. Moreover, it highlights the critical role of the thalamus in the physiological adaptation and recovery of cognitive functions after disruption that have been similarly reported after mild traumatic brain injury.²⁷ The authors also considered the extent to which these adaptations increase vulnerability to subsequent brain insults, including aging, thus also contributing to the evolving science of brain reserve capacity.²⁸

The DA story started with birds and a movie. Along the way, investigative efforts using rodents, fish, marine mammals, wildlife, nonhuman primates, and cohorts of at-risk people complemented, challenged, and advanced science toward the goal of protecting public health. These integrated efforts need to continue toward identifying a simple, reliable biomarker for human exposure assessment; establishing human thresholds for neurotoxicity across the life span; reevaluating current DA regulatory levels for vulnerable populations; further examining the reversibility of chronic exposures; elucidating the interactions of repetitive low-level DA exposure with aging, other exposures, or illnesses; and identifying robust models of community engagement and education.

Refers to https://doi.org.10.1289/EHP10923