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Chronic, low-level oral exposure to marine toxin, domoic acid, alters whole brain morphometry in nonhuman primates.

ABSTRACT: Domoic acid (DA) is an excitatory neurotoxin produced by marine algae and responsible for Amnesiac Shellfish Poisoning in humans. Current regulatory limits (˜0.075-0.1?mg/kg/day) protect against acute toxicity, but recent studies suggest that the chronic consumption of DA below the regulatory limit may produce subtle neurotoxicity in adults, including decrements in memory. As DA-algal blooms are increasing in both severity and frequency, we sought to better understand the effects of chronic DA exposure on reproductive and neurobehavioral endpoints in a preclinical nonhuman primate model. To this end, we initiated a long-term study using adult, female Macaca fascicularis monkeys exposed to daily, oral doses of 0.075 or 0.15?mg/kg of DA for a range of 321-381, and 346-554 days, respectively. This time period included a pre-pregnancy, pregnancy, and postpartum period. Throughout these times, trained data collectors observed intentional tremors in some exposed animals during biweekly clinical examinations. The present study explores the basis of this neurobehavioral finding with in vivo imaging techniques, including diffusion tensor magnetic resonance imaging and spectroscopy. Diffusion tensor analyses revealed that, while DA exposed macaques did not significantly differ from controls, increases in DA-related tremors were negatively correlated with fractional anisotropy, a measure of structural integrity, in the internal capsule, fornix, pons, and corpus callosum. Brain concentrations of lactate, a neurochemical closely linked with astrocytes, were also weakly, but positively associated with tremors. These findings are the first documented results suggesting that chronic oral exposure to DA at concentrations near the current human regulatory limit are related to structural and chemical changes in the adult primate brain.

SUBMITTER: Petroff R

PROVIDER: S-EPMC6527455 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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Chronic, low-level oral exposure to marine toxin, domoic acid, alters whole brain morphometry in nonhuman primates.

Petroff Rebekah R Richards Todd T Crouthamel Brenda B McKain Noelle N Stanley Courtney C Grant Kimberly S KS Shum Sara S Jing Jing J Isoherranen Nina N Burbacher Thomas M TM

Neurotoxicology 20190228

Domoic acid (DA) is an excitatory neurotoxin produced by marine algae and responsible for Amnesiac Shellfish Poisoning in humans. Current regulatory limits (˜0.075-0.1 mg/kg/day) protect against acute toxicity, but recent studies suggest that the chronic consumption of DA below the regulatory limit may produce subtle neurotoxicity in adults, including decrements in memory. As DA-algal blooms are increasing in both severity and frequency, we sought to better understand the effects of chronic DA e ...[more]

PMID: 30826346

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Project description:We recently developed the radiotracer 4-[(3-iodophenyl)amino]-7-(2-[2-{2-(2-[2-{2-((18)F-fluoroethoxy)-ethoxy}-ethoxy]-ethoxy)-ethoxy}-ethoxy]-quinazoline-6-yl-acrylamide) ((18)F-PEG(6)-IPQA) for noninvasive detection of active mutant epidermal growth factor receptor kinase-expressing non-small cell lung cancer xenografts in rodents. In this study, we determined the pharmacokinetics, biodistribution, metabolism, and radiation dosimetry of (18)F-PEG(6)-IPQA in nonhuman primates.Six rhesus macaques were injected intravenously with 141 ± 59.2 MBq of (18)F-PEG(6)-IPQA, and dynamic PET/CT images covering the thoracoabdominal area were acquired for 30 min, followed by whole-body static images at 60, 90, 120, and 180 min. Blood samples were obtained from each animal at several time points after radiotracer administration. Radiolabeled metabolites in blood and urine were analyzed using high-performance liquid chromatography. The (18)F-PEG(6)-IPQA pharmacokinetic and radiation dosimetry estimates were determined using volume-of-interest analysis of PET/CT image datasets and blood and urine time-activity data.(18)F-PEG(6)-IPQA exhibited rapid redistribution and was excreted via the hepatobiliary and urinary systems. (18)F-PEG(6) was the major radioactive metabolite. The critical organ was the gallbladder, with an average radiation-absorbed dose of 0.394 mSv/MBq. The other key organs with high radiation doses were the kidneys (0.0830 mSv/MBq), upper large intestine wall (0.0267 mSv/MBq), small intestine (0.0816 mSv/MBq), and liver (0.0429 mSv/MBq). Lung tissue exhibited low uptake of (18)F-PEG(6)-IPQA due to the low affinity of this radiotracer to wild-type epidermal growth factor receptor kinase. The effective dose was 0.0165 mSv/MBq. No evidence of acute cardiotoxicity or of acute or delayed systemic toxicity was observed. On the basis of our estimates, diagnostic dosages of (18)F-PEG(6)-IPQA up to 128 MBq (3.47 mCi) per injection should be safe for administration in the initial cohort of human patients in phase I clinical PET studies.The whole-body and individual organ radiation dosimetry characteristics and pharmacologic safety of diagnostic dosages of (18)F-PEG(6)-IPQA in nonhuman primates indicate that this radiotracer should be acceptable for PET/CT studies in human patients.

Dataset Information

Chronic, low-level oral exposure to marine toxin, domoic acid, alters whole brain morphometry in nonhuman primates.

Publications

Chronic, low-level oral exposure to marine toxin, domoic acid, alters whole brain morphometry in nonhuman primates.

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