Transcriptional Profiles for Glutamate Transporters Reveal Differences Between Organophosphates but Similarities with Unrelated Neurotoxicants
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Brain Research Bulletin
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The developmental neurotoxicity of organophosphates involves mechanisms other than their shared property as cholinesterase inhibitors, among which are excitotoxicity and oxidative stress. We used PC12 cells as a neurodevelopmental model to compare the effects of chlorpyrifos and diazinon on the expression of genes encoding glutamate transporters. Chlorpyrifos had a greater effect in cells undergoing nerve growth factor-induced neurodifferentiation as compared to undifferentiated PC12 cells, with peak sensitivity at the initiation of differentiation, reflecting a global upregulation of all the glutamate transporter genes expressed in this cell line. In differentiating cells, chlorpyrifos had a significantly greater effect than did diazinon and concordance analysis indicated no resemblance in their expression patterns. At the same time, the smaller effects of diazinon were highly concordant with those of an organochlorine pesticide (dieldrin) and a metal (divalent nickel). We also performed similar evaluations for the cystine/glutamate exchanger, which provides protection against oxidative stress by moving cystine into the cell; again, chlorpyrifos had the greatest effect, in this case reducing expression in undifferentiated and differentiating cells. Our results point to excitotoxicity and oxidative stress as major contributors to the noncholinesterase mechanisms that distinguish the neurodevelopmental outcomes between different organophosphates while providing a means whereby apparently unrelated neurotoxicants may produce similar outcomes.
Slotkin, Theodore A.; Lobner, Doug; and Seidler, Frederic J., "Transcriptional Profiles for Glutamate Transporters Reveal Differences Between Organophosphates but Similarities with Unrelated Neurotoxicants" (2010). Biomedical Sciences Faculty Research and Publications. 84.
Accepted version. Brain Research Bulletin, Vol. 83, No. 1-2 (August 30, 2010): 76-83. DOI. © 2010 Elsevier. Used with permission.
NOTICE: this is the author’s version of a work that was accepted for publication in Brain Research Bulletin. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published in Brain Research Bulletin, VOL 83, ISSUE 1-2, August 2010, DOI.