Developmental neurotoxicants target neurodifferentiation into the serotonin phenotype: Chlorpyrifos, diazinon, dieldrin and divalent nickel.
Developmental exposure to organophosphates (OP) produces long-term changes in serotonin (5HT) synaptic function and associated behaviors, but there are disparities among the different OPs. We contrasted effects of chlorpyrifos and diazinon, as well as non-OP neurotoxicants (dieldrin, Ni(2+)) using undifferentiated and differentiating PC12 cells, a well-established neurodevelopmental model. Agents were introduced at 30 microM for 24 or 72 h, treatments devoid of cytotoxicity, and we evaluated the mRNAs encoding the proteins for 5HT biosynthesis, storage and degradation, as well as 5HT receptors. Chlorpyrifos and diazinon both induced tryptophan hydroxylase, the rate-limiting enzyme for 5HT biosynthesis, but chlorpyrifos had a greater effect, and both agents suppressed expression of 5HT transporter genes, effects that would tend to augment extracellular 5HT. However, whereas chlorpyrifos enhanced the expression of most 5HT receptor subtypes, diazinon evoked overall suppression. Dieldrin evoked even stronger induction of tryptophan hydroxylase, and displayed a pattern of receptor effects similar to that of diazinon, even though they come from different pesticide classes. In contrast, Ni(2+) had completely distinct actions, suppressing tryptophan hydroxylase and enhancing the vesicular monoamine transporter, while also reducing 5HT receptor gene expression, effects that would tend to lower net 5HT function. Our findings provide some of the first evidence connecting the direct, initial mechanisms of developmental neurotoxicant action on specific transmitter pathways with their long-term effects on synaptic function and behavior, while also providing support for in vitro test systems as tools for establishing mechanisms and outcomes of related and unrelated neurotoxicants.
Department of Pharmacology and Cancer Biology Box 3813, Duke University Medical Center, Durham, NC 27710, USA. t.slotkin@duke.edu
Theodore A
TA
Slotkin
Frederic J
FJ
Seidler
D000818:Animals; D002454:Cell Differentiation; D004390:Chlorpyrifos / Q000633:toxicity*; D003976:Diazinon / Q000633:toxicity*; D004026:Dieldrin / Q000633:toxicity*; D005786:Gene Expression Regulation / Q000187:drug effects; D007306:Insecticides / Q000633:toxicity; D020258:Neurotoxicity Syndromes / Q000209:etiology* / Q000503:physiopathology; D009532:Nickel / Q000633:toxicity*; D016716:PC12 Cells; D010641:Phenotype; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011985:Receptors, Serotonin / Q000187:drug effects / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics; D013997:Time Factors; D014365:Tryptophan Hydroxylase / Q000187:drug effects / Q000378:metabolism
D007306:Insecticides; D012333:RNA, Messenger; D011985:Receptors, Serotonin; D050486:Serotonin Plasma Membrane Transport Proteins; D012701:Serotonin; D009532:Nickel; D014365:Tryptophan Hydroxylase; D004026:Dieldrin; D004390:Chlorpyrifos; D003976:Diazinon