Chronic low-level exposure to the common seafood toxin domoic acid causes cognitive deficits in mice

Abstract

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 20 mg DA/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 (≈ 0.75 mg/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.

Repeated Dietary Exposure to Low Levels of Domoic Acid and Problems with Everyday Memory: Research to Public Health Outreach

“…In both studies, the effect size of the memory decrement was small, and overall memory scores remained within normal limits. The findings were consistent with a controlled laboratory study in which weekly exposures to DA at subclinical levels for several weeks resulted in significant learning and memory deficits in mice [ 24 ]. While statistically significant and of academic interest, questions remain about the actual clinical significance of the mild memory decrement found in NAs who routinely consume a lot of RCs.…”

“…Within the context of the other findings, it also raises the possibility that some EM problems arise and persist for up to 10 to 14 days after exposure, then abate, though never fully to baseline level. The potential for reversibility of DA-related memory deficits in mice was previously demonstrated by Lefebvre et al [ 24 ]. Additionally, previously reported data referencing non-human primate and human models by Kumar et al [ 27 ], suggests a tolerable daily intake (TDI) of 0.075 ppm for gastrointestinal (GI) disturbances in humans.…”

Toxicokinetics and Physiologically Based Pharmacokinetic Modeling of the Shellfish Toxin Domoic Acid in Nonhuman Primates

“…The PBPK models also predicted a much longer duration of exposure in the brain following oral dosing than what is observed after intravenous dosing. This may be important for chronic toxicity of asymptomatic exposures to DA, that lead to the reported sensitization to DA and to epigenetic changes (Hiolski et al, 2014;Lefebvre et al, 2017). However, the current model does not incorporate possible transporter contributions to brain distribution of DA, which requires further study.…”

“…However, information to establish a chronic TDI for DA is currently not available (Pulido, 2008). Several studies in model species have suggested that chronic low-level DA exposure at asymptomatic doses results in adverse effects, including epigenetic changes and sensitization of animals to the toxicity of DA (Hiolski et al, 2014;Lefebvre et al, 2017). Yet, the underlying mechanisms of these changes and DA toxicokinetics at asymptomatic doses have not been characterized.…”

Investigation of Algal Biotoxin Removal during SWRO Desalination through a Materials Flow Analysis

“…Developmental and neurological effects of chronic (low-level) DA exposure on infants and young children are a concern, as DA has been shown to cross the placenta, enter the blood brain barrier of infants, and collect in amniotic fluid in mammals [81][82][83][84][85]. Chronic DA exposure has also been linked to cognitive impairment in mice [86]. More reliable chronic DA exposure epidemiological studies on humans, however, have been rarely reported.…”