Protein kinase C is a target for diverse developmental neurotoxicants: transcriptional responses to chlorpyrifos, diazinon, dieldrin and divalent nickel in PC12 cells.
Unrelated developmental neurotoxicants can elicit similar functional outcomes, whereas agents in the same class may differ. We compared two organophosphate insecticides (chlorpyrifos, diazinon) with an organochlorine (dieldrin) and a metal (Ni(2+)) for similarities and differences in their effects on gene expression encoding subtypes of protein kinase C and their modulators, a cell signaling cascade that integrates the actions of neurotrophic factors involved in brain development. We conducted evaluations in PC12 cells, a model for neuronal development, with each agent introduced at 30 microM for 24 or 72 h, treatments devoid of cytotoxicity. Chlorpyrifos evoked by far the largest effect, with widespread upregulation of multiple genes; the effects were greater during neurodifferentiation than when cells were exposed prior to differentiation. Diazinon had smaller and less widespread effects, consistent with its lesser long-term impact on synaptic function and behavior noted for in vivo exposures in developing rats. Surprisingly, the effects of diazinon, dieldrin and Ni(2+) showed basic similarities despite the fact that all three come from different classes of toxicants. Our findings provide some of the first evidence for a specific mechanistic cascade contributing to the cholinesterase-independent developmental neurotoxicant actions of chlorpyrifos and its differences from diazinon, while at the same time identifying mechanistic convergence between otherwise unrelated toxicants that provides predictions about common neurodevelopmental outcomes. These results further show how combined use of cell cultures and microarray technology can guide future in vivo work on diverse developmental neurotoxicants.
Department of Pharmacology & Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA. t.slotkin@duke.edu
Theodore A
TA
Slotkin
Frederic J
FJ
Seidler
D000704:Analysis of Variance; D000818:Animals; D002413:Cations, Divalent / Q000633:toxicity; D004390:Chlorpyrifos / Q000633:toxicity; D003976:Diazinon / Q000633:toxicity; D004026:Dieldrin / Q000633:toxicity; D046228:Microarray Analysis; D055495:Neurogenesis / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D009498:Neurotoxins / Q000633:toxicity*; D009532:Nickel / Q000633:toxicity; D016716:PC12 Cells; D011493:Protein Kinase C / Q000235:genetics* / Q000378:metabolism*; D051381:Rats; D014158:Transcription, Genetic / Q000187:drug effects*
D002413:Cations, Divalent; D009498:Neurotoxins; D009532:Nickel; D011493:Protein Kinase C; D004026:Dieldrin; D004390:Chlorpyrifos; D003976:Diazinon