White Matter Tractography and Neurohistopathology after Chronic, Low-Level Exposure to Domoic Acid in a Nonhuman Primate Model

Domoic acid (DA), a potent glutamate agonist, is produced by marine algae and can bioconcentrate in finfish and shellfish. Current regulatory limits constrain environmental exposures to this toxin to 20 ppm in shellfish tissue (~0.075-0.1 mg/kg), but changing environmental conditions are leading to more frequent and longer lasting DA algal blooms. Further, recent studies suggest that chronic DA exposure, at levels below this limit, is associated with deficits in memory in adults. To understand how low-level, chronic exposure to this toxin impacts the limbic system of the brain, the present study used magnetic resonance imaging (MRI) and histopathology to assess changes in the hippocampus, thalamus, fornix, fimbria, and internal capsule in a nonhuman primate model. Twenty-eight adult, female Macaca fascicularis were orally exposed to 0.075 and 0.15 mg/kg/day for up to two years. A subset of these females (n=12) underwent a single, sedated MRI scan in vivo, to assess volumetric and tractography changes in the hippocampus, thalamus, and connecting white matter tracts, and all animals were necropsied to evaluate the cellularity and morphology of the neurons, astrocytes, and microglia in these regions. MRI and histopathology evaluations did not suggest signs of overt neuropathology, but revealed that some animals, especially in the 0.15 mg/kg/day DA exposure group, expressed focal microglia reactions within both white and gray matter structures of the limbic system. These results suggest that chronic exposure to levels of DA near the human regulatory limit does not lead to acute neuropathic effects but may induce microglial responses and promote neuroinflammatory pathways in a nonhuman primate model of contemporary human exposure to DA. Observers were experimentally blinded to the exposure conditions of the macaques and employed positive reinforcement techniques to train animals to drink out of a syringe to allow for controlled dosing of DA or vehicle control. Following training, animals underwent a baseline period of assessment designed to asses clinical signs of toxicity prior to starting daily oral exposure of 0 (n=10), 0.075 (n=11), or 0.15 (n=11) mg/kg of DA (BioVectra, Charlottetown, PE, Canada) in 5% sucrose water. Animals continued to be assessed 3-5x per week throughout a 2-month pre-breeding period, a 1-8-month breeding period, a 6-month pregnancy, and a 2-12-month postpartum period. For all but 2 animals (A15234 and A15244), dosing continued until necropsy. Animals A15234 and A15244 had wash-out periods of 221 and 231 days, respectively, prior to necropsy. In all animals, behavioral assessment continued at least 3x/week until necropsy.