Transcriptional profiles for glutamate transporters reveal differences between organophosphates but similarities with unrelated neurotoxicants.
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
TA
Department of Pharmacology & Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA. t.slotkin@duke.edu
Lobner
Doug
D
Seidler
Frederic J
FJ
D027322:Amino Acid Transport System X-AG / Q000235:genetics / Q000378:metabolism*; D000704:Analysis of Variance; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D004390:Chlorpyrifos / Q000494:pharmacology; D002800:Cholinesterase Inhibitors / Q000494:pharmacology; D003553:Cystine / Q000378:metabolism; D003976:Diazinon / Q000494:pharmacology; D020869:Gene Expression Profiling / Q000379:methods; D005786:Gene Expression Regulation / Q000187:drug effects*; D018698:Glutamic Acid / Q000378:metabolism; D020714:Maximum Tolerated Dose; D020932:Nerve Growth Factor / Q000494:pharmacology; D009498:Neurotoxins / Q000494:pharmacology*; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D010755:Organophosphates / Q000494:pharmacology*; D016716:PC12 Cells / Q000187:drug effects; D051381:Rats; D013223:Statistics as Topic; D013997:Time Factors
D027322:Amino Acid Transport System X-AG; D002800:Cholinesterase Inhibitors; D009498:Neurotoxins; D010755:Organophosphates; D018698:Glutamic Acid; D003553:Cystine; D020932:Nerve Growth Factor; D004390:Chlorpyrifos; D003976:Diazinon