Oxidative and excitatory mechanisms of developmental neurotoxicity: transcriptional profiles for chlorpyrifos, diazinon, dieldrin, and divalent nickel in PC12 cells.
BACKGROUND
Oxidative stress and excitotoxicity underlie the developmental neurotoxicity of numerous chemicals.


OBJECTIVE
We compared the effects of organophosphates (chlorpyrifos and diazinon), an organo-chlorine (dieldrin), and a metal [divalent nickel (Ni2+)] to determine how these mechanisms contribute to similar or dissimilar neurotoxic outcomes.


METHODS
We used PC12 cells as a model of developing neurons and evaluated transcriptional profiles for genes for oxidative stress responses and glutamate receptors.


RESULTS
Chlorpyrifos had a greater effect on oxidative-stress-related genes in differentiating cells compared with the undifferentiated state. Chlorpyrifos and diazinon showed significant concordance in their effects on glutathione-related genes, but they were negatively correlated for effects on catalase and superoxide dismutase isoforms and had no concordance for effects on ionotropic glutamate receptors. Surprisingly, the correlations were stronger between diazinon and dieldrin than between the two organophosphates. The effects of Ni2+ were the least similar for genes related to oxidative stress but had significant concordance with dieldrin for effects on glutamate receptors.


CONCLUSIONS
Our results point to underlying mechanisms by which different organophosphates produce disparate neurotoxic outcomes despite their shared property as cholinesterase inhibitors. Further, apparently unrelated neurotoxicants may produce similar outcomes because of convergence on oxidative stress and excitotoxicity. The combined use of cell cultures and microarrays points to specific end points that can distinguish similarities and disparities in the effects of diverse developmental neurotoxicants.
Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710, USA. t.slotkin@duke.edu
Theodore A
TA
Slotkin
Frederic J
FJ
Seidler
D000818:Animals; D002374:Catalase / Q000378:metabolism; D002413:Cations, Divalent / Q000633:toxicity; D002454:Cell Differentiation; D004390:Chlorpyrifos / Q000633:toxicity; D003976:Diazinon / Q000633:toxicity; D004026:Dieldrin / Q000633:toxicity*; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D005982:Glutathione Transferase / Q000378:metabolism; D007306:Insecticides / Q000633:toxicity*; D055495:Neurogenesis / Q000187:drug effects; D009474:Neurons / Q000187:drug effects*; D009532:Nickel / Q000633:toxicity*; D009946:Organothiophosphorus Compounds / Q000633:toxicity*; D016716:PC12 Cells; D051381:Rats; D017470:Receptors, Glutamate / Q000378:metabolism; D013482:Superoxide Dismutase / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects
D002413:Cations, Divalent; D007306:Insecticides; D009946:Organothiophosphorus Compounds; D017470:Receptors, Glutamate; D009532:Nickel; D002374:Catalase; D013482:Superoxide Dismutase; D005982:Glutathione Transferase; D004026:Dieldrin; D004390:Chlorpyrifos; D003976:Diazinon