Transcriptional profiles reveal similarities and differences in the effects of developmental neurotoxicants on differentiation into neurotransmitter phenotypes in PC12 cells.
Unrelated developmental neurotoxicants nevertheless converge on common functional and behavioral outcomes. We used PC12 cells, a model of neuronal development, to explore similarities and differences for organophosphate pesticides (chlorpyrifos, diazinon), an organochlorine pesticide (dieldrin) and a metal (Ni(2+)), focusing on transcriptional profiles related to differentiation into acetylcholine, dopamine and norepinephrine phenotypes. Agents were introduced at 30 microM for 24 or 72 h, treatments devoid of cytotoxicity. Using microarrays, we examined the mRNAs encoding the proteins involved in neurotransmitter biosynthesis, storage, and degradation, along with the complete panoply of receptors for each transmitter. All three pesticides evoked concordant patterns of effects on genes involved in neural growth and neurite extension, with a distinctly different pattern for Ni(2+). All four toxicants promoted differentiation into the dopamine phenotype at the expense of the acetylcholine phenotype, involving separable effects of each agent on the various gene families; however, there were major differences in the ability of each to promote or repress the norepinephrine phenotype. Chlorpyrifos and diazinon, although displaying many similarities in their transcriptional profiles, also showed major disparities in keeping with their known differences in synaptic and behavioral outcomes after neonatal exposures to these agents in vivo. Surprisingly, there were closer similarities among diazinon, dieldrin and Ni(2+) than for each agent to chlorpyrifos. Our results illustrate how cell culture systems, combined with microarray technology, can screen for developmental neurotoxicants, serving as a model for alternative approaches to the detection and characterization of the impact of exogenous chemicals on brain development.
Slotkin
Theodore
T
Department of Pharmacology & Cancer Biology, Duke University Medical Centre, Durham, NC 27710, USA. t.slotkin@duke.edu
Seidler
Frederic
F
D000109:Acetylcholine / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology*; D004390:Chlorpyrifos / Q000633:toxicity; D003976:Diazinon / Q000633:toxicity; D004026:Dieldrin / Q000633:toxicity; D004298:Dopamine / Q000378:metabolism; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D007306:Insecticides / Q000633:toxicity; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D018377:Neurotransmitter Agents / Q000378:metabolism*; D009532:Nickel / Q000633:toxicity; D009638:Norepinephrine / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D009943:Organophosphorus Compounds / Q000633:toxicity*; D016716:PC12 Cells; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D014131:Trace Elements / Q000633:toxicity; D014158:Transcription, Genetic / Q000187:drug effects
D007306:Insecticides; D018377:Neurotransmitter Agents; D009943:Organophosphorus Compounds; D012333:RNA, Messenger; D014131:Trace Elements; D009532:Nickel; D004026:Dieldrin; D004390:Chlorpyrifos; D000109:Acetylcholine; D004298:Dopamine; D009638:Norepinephrine; D003976:Diazinon