ToxSci Advance Access published online on April 21, 2007
Toxicological Sciences, doi:10.1093/toxsci/kfm093
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Adult Hippocampal Neural Stem-Progenitor Cells in vitro are Vulnerable to the Mycotoxin Ochratoxin-A
Department of Neurology, University of South Florida and James Haley VA Hospital, Tampa, Florida
* Correspondant J. Sanchez-Ramos, PhD, MD, Department of Neurology, University of South Florida, 12901 Bruce B. Downs, Tampa, FL 33612 jsramos{at}hsc.usf.edu 813-974-5841
Received March 2, 2007; revision received April 14, 2007; accepted April 14, 2007
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Abstract |
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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 (NSC) 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: a) viability (trypan blue exclusion), b) proliferative activity ([3H]-thymidine uptake), c) the DNA repair response (oxyguanosine glycosylase activity), and d) anti-oxidative response (superoxide dismutase). Cells that had proliferated to 90-100% confluency in the presence of epidermal growth factor (EGF) and basic fibroblast growth factor (bFGF) were induced to differentiate by removal of the growth factors.
OTA, added to the cultures in concentrations of 0.01 to 100 µg/mL, caused a dose- and time-dependent (6-72 hr) 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 anti-oxidative responses. Pre-conditioning of NSC with a 12 hr 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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