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Open AccessFeature PaperArticle

Detecting Neurodevelopmental Toxicity of Domoic Acid and Ochratoxin A Using Rat Fetal Neural Stem Cells

Regulatory Toxicology Research Division, Health Products and Food Branch, Tunney’s Pasture, Health Canada, 251 Sir Frederick Banting Driveway, Ottawa, ON K1A 0K9, Canada
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Mar. Drugs 2019, 17(10), 566; https://doi.org/10.3390/md17100566
Received: 11 September 2019 / Revised: 1 October 2019 / Accepted: 2 October 2019 / Published: 4 October 2019
(This article belongs to the Special Issue Genetics of Marine Organisms Associated with Human Health)
Currently, animal experiments in rodents are the gold standard for developmental neurotoxicity (DNT) investigations; however, testing guidelines for these experiments are insufficient in terms of animal use, time, and costs. Thus, alternative reliable approaches are needed for predicting DNT. We chose rat neural stem cells (rNSC) as a model system, and used a well-known neurotoxin, domoic acid (DA), as a model test chemical to validate the assay. This assay was used to investigate the potential neurotoxic effects of Ochratoxin A (OTA), of which the main target organ is the kidney. However, limited information is available regarding its neurotoxic effects. The effects of DA and OTA on the cytotoxicity and on the degree of differentiation of rat rNSC into astrocytes, neurons, and oligodendrocytes were monitored using cell-specific immunofluorescence staining for undifferentiated rNSC (nestin), neurospheres (nestin and A2B5), neurons (MAP2 clone M13, MAP2 clone AP18, and Doublecortin), astrocytes (GFAP), and oligodendrocytes (A2B5 and mGalc). In the absence of any chemical exposure, approximately 46% of rNSC differentiated into astrocytes and neurons, while 40.0% of the rNSC differentiated into oligodendrocytes. Both non-cytotoxic and cytotoxic concentrations of DA and OTA reduced the differentiation of rNSC into astrocytes, neurons, and oligodendrocytes. Furthermore, a non-cytotoxic nanomolar (0.05 µM) concentration of DA and 0.2 µM of OTA reduced the percentage differentiation of rNSC into astrocytes and neurons. Morphometric analysis showed that the highest concentrations (10 μM) of DA reduced axonal length. These indicate that low, non-cytotoxic concentrations of DA and OTA can interfere with the differentiation of rNSC.
Keywords: stem cell differentiation; cytotoxicity; neurotoxicity; domoic acid; ochratoxin A; oligodendrocytes; astrocytes; neurons stem cell differentiation; cytotoxicity; neurotoxicity; domoic acid; ochratoxin A; oligodendrocytes; astrocytes; neurons
MDPI and ACS Style

Gill, S.; Kumara, V.M.R. Detecting Neurodevelopmental Toxicity of Domoic Acid and Ochratoxin A Using Rat Fetal Neural Stem Cells. Mar. Drugs 2019, 17, 566.

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