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ToxSci Advance Access originally published online on April 21, 2007
Toxicological Sciences 2007 98(1):187-197; doi:10.1093/toxsci/kfm093
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© The Author 2007. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Adult Hippocampal Neural Stem/Progenitor Cells In Vitro Are Vulnerable to the Mycotoxin Ochratoxin-A

Vasyl Sava, Adriana Velasquez, Shijie Song and Juan Sanchez-Ramos1

Department of Neurology, University of South Florida, Tampa, Florida 33612; and James Haley VA Hospital, Tampa, Florida 33612

1 To whom correspondence should be addressed at Department of Neurology, University of South Florida, 12901 Bruce B. Downs, Tampa, FL 33612. Fax: 813-974-5841. E-mail: jsramos{at}hsc.usf.edu.

Received March 2, 2007; accepted April 14, 2007


  Abstract

The common mycotoxin ochratoxin-A (OTA) accumulates in brain, causes oxidative stress, and elicits a DNA repair response that varies across brain regions and neuronal populations. Neural stem/progenitor cells (NSCs) prepared from hippocampus of adult mouse brain were tested for their vulnerability to the toxin in vitro. The following measurements were made in NSC cell cultures in both proliferation and differentiation media: (1) viability (trypan blue exclusion), (2) proliferative activity ([3H]-thymidine uptake), (3) the DNA repair response (oxyguanosine glycosylase activity), and (4) antioxidative response (superoxide dismutase). Cells that had proliferated to 90–100% confluency in the presence of epidermal growth factor and basic fibroblast growth factor were induced to differentiate by removal of the growth factors. OTA, added to the cultures in concentrations of 0.01–100 µg/ml, caused a dose- and time-dependent (6–72 h) decrease in viability of both proliferating and differentiating NSC. Proliferating NSC exhibited a greater vulnerability to the toxin than differentiated neurons despite robust DNA repair and antioxidative responses. Preconditioning of NSC with a 12-h incubation with the pro-oxidant diethyl maleate increased DNA repair activity and, subsequently, provided a moderate degree of neuroprotection. Overall, these results lead to speculation that OTA exposure may contribute to impaired hippocampal neurogenesis in vivo, resulting in depression and memory deficits, conditions reported to be linked to mycotoxin exposure in humans.

Key Words: neural stem/progenitor cells; hippocampus; ochratoxin-A; mycotoxin; oxidative stress; DNA repair; 8-oxoguanine glycosylase-1 (OGG1); superoxide dismutase (SOD); diethyl maleate (DEM).


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