Targeting of neurotrophic factors, their receptors, and signaling pathways in the developmental neurotoxicity of organophosphates in vivo and in vitro.
Neurotrophic factors control neural cell differentiation and assembly of neural circuits. We previously showed that organophosphate pesticides differentially regulate members of the fibroblast growth factor (fgf) gene family. We administered chlorpyrifos and diazinon to neonatal rats on postnatal days 1-4 at doses devoid of systemic toxicity or growth impairment, and spanning the threshold for barely-detectable cholinesterase inhibition. We evaluated the impact on gene families for different classes of neurotrophic factors. Using microarrays, we examined the regional expression of mRNAs encoding the neurotrophins (ntfs), brain-derived neurotrophic factor (bdnf), nerve growth factor (ngf), the wnt and fzd gene families and the corresponding receptors. Chlorpyrifos and diazinon both had widespread effects on the fgf, ntf, wnt and fzd families but much less on the bdnf and ngf groups. However, the two organophosphates showed disparate effects on a number of key neurotrophic factors. To determine if the actions were mediated directly on differentiating neurons, we tested chlorpyrifos in PC12 cells, an in vitro model of neural cell development. Effects in PC12 cells mirrored many of those for members of the fgf, ntf and wnt families, as well as the receptors for the ntfs, especially during early differentiation, the stage known to be most susceptible to disruption by organophosphates. Our results suggest that actions on neurotrophic factors provide a mechanism for the developmental neurotoxicity of low doses of organophosphates, and, since effects on expression of the affected genes differed with test agent, may help explain regional disparities in effects and critical periods of vulnerability.
Slotkin
Theodore A
TA
Department of Pharmacology & Cancer Biology, Duke University Medical Center, Box 3813 DUMC, Durham, NC 27710, USA. t.slotkin@duke.edu
Seidler
Frederic J
FJ
Fumagalli
Fabio
F
D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000187:drug effects* / Q000254:growth & development* / Q000378:metabolism; D019208:Brain-Derived Neurotrophic Factor / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D004390:Chlorpyrifos / Q000633:toxicity; D002800:Cholinesterase Inhibitors / Q000633:toxicity; D003976:Diazinon / Q000633:toxicity; D051157:Frizzled Receptors / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D020932:Nerve Growth Factor / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D009414:Nerve Growth Factors / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D010755:Organophosphates / Q000633:toxicity*; D016716:PC12 Cells; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017475:Receptors, Nerve Growth Factor / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D051153:Wnt Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism
D019208:Brain-Derived Neurotrophic Factor; D002800:Cholinesterase Inhibitors; D051157:Frizzled Receptors; D009414:Nerve Growth Factors; D010755:Organophosphates; D012333:RNA, Messenger; D017475:Receptors, Nerve Growth Factor; D051153:Wnt Proteins; D020932:Nerve Growth Factor; D004390:Chlorpyrifos; D003976:Diazinon