A Novel Antibody-Based Biomarker for Chronic Algal Toxin Exposure and Sub-Acute Neurotoxicity

Abstract

The neurotoxic amino acid, domoic acid (DA), is naturally produced by marine phytoplankton and presents a significant threat to the health of marine mammals, seabirds and humans via transfer of the toxin through the foodweb. In humans, acute exposure causes a neurotoxic illness known as amnesic shellfish poisoning characterized by seizures, memory loss, coma and death. Regular monitoring for high DA levels in edible shellfish tissues has been effective in protecting human consumers from acute DA exposure. However, chronic low-level DA exposure remains a concern, particularly in coastal and tribal communities that subsistence harvest shellfish known to contain low levels of the toxin. Domoic acid exposure via consumption of planktivorous fish also has a profound health impact on California sea lions (Zalophus californianus) affecting hundreds of animals yearly. Due to increasing algal toxin exposure threats globally, there is a critical need for reliable diagnostic tests for assessing chronic DA exposure in humans and wildlife. Here we report the discovery of a novel DA-specific antibody response that is a signature of chronic low-level exposure identified initially in a zebrafish exposure model and confirmed in naturally exposed wild sea lions. Additionally, we found that chronic exposure in zebrafish caused increased neurologic sensitivity to DA, revealing that repetitive exposure to DA well below the threshold for acute behavioral toxicity has underlying neurotoxic consequences. The discovery that chronic exposure to low levels of a small, water-soluble single amino acid triggers a detectable antibody response is surprising and has profound implications for the development of diagnostic tests for exposure to other pervasive environmental toxins.

Diversity and toxicity of the diatom Pseudo-nitzschia Peragallo in the Gulf of Maine, Northwestern Atlantic Ocean

“…Shellfish in the GOM frequently accumulate high levels of PSP toxins that require regulation, however the effects of concurrent exposure to neurotoxic PSP and ASP toxins have not yet been investigated. In contrast to the ASP symptoms associated with acute DA exposure, chronic (long-term, low-level) exposure to DA has been found to cause a unique toxicosis in naturally exposed sea lions (Goldstein et al, 2008), and induced an antibody response and increased neurologic sensitivity to the toxin in subsequent exposures in a vertebrate model (Lefebvre et al, 2012). As such, chronic low-level exposure to DA, and the synergistic or additive effects with exposure to co-occurring ASP and PSP toxins, requires further investigation to better assess human and wildlife health risks and the implications for the management of nearshore and offshore shellfish resources.…”

Characterization of Renal Toxicity in Mice Administered the Marine Biotoxin Domoic Acid

“…[7][8][9][10][11][12][13][14] Although the overt gastrointestinal and neurologic manifestations have defined the disease, emerging evidence from animal and human studies support previously unrecognized threats and novel toxicologic syndromes caused by subclinical toxicity from acute and chronic DA exposures, which may ultimately challenge the adequacy of the current acceptable limit. [15][16][17][18] DA is a potent activator of kainate receptors (KRs) as well as a subpopulation of a-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid receptors (AMPARs). 19 The toxic response produced by DA is a coordinated effort, which involves initial activation of KR and AMPAR by DA and secondary activation of N-methyl-D-aspartate receptors (NMDARs) by glutamate, and it is associated with an influx of Ca 2+ across the plasma membrane, inflammation, neuronal cell injury and death, and neurobehavioral alterations.…”

Assessment of sodium channel mutations in Makah tribal members of the U.S. Pacific Northwest as a potential mechanism of resistance to paralytic shellfish poisoning

“…In laboratory studies, an antibody response has been reported in zebrafish exposed to sub-lethal concentrations of another common seafood toxin, domoic acid (Lefebvre et al, 2012). The antibody response was indicative of chronic low-level exposure and increased neurologic sensitivity to domoic acid.…”