title: Unrelated developmental neurotoxicants elicit similar transcriptional profiles for effects on neurotrophic factors and their receptors in an in vitro model.
abstract: Diverse developmental neurotoxicants can often produce similar functional and behavioral outcomes. We examined an organophosphate pesticide (diazinon), an organochlorine pesticide (dieldrin) and a metal (Ni(2+)) for effects on the expression of neurotrophic factors and their receptors and modulators in differentiating PC12 cells, an in vitro model of neuronal development. Each agent was introduced at 30 microM for 24 or 72 h, treatments devoid of cytotoxicity. Using microarrays, we examined the mRNAs encoding members of the fibroblast growth factor (fgf) family, the neurotrophins (ntfs), brain-derived neurotrophic factor (bdnf), nerve growth factor (ngf), the wnt and fzd gene families, and the receptors and modulators for each class. All three agents evoked highly concordant patterns of effects on genes encoding the fgf family, whereas the correlations were poor for the group comprising bdnf, ngf and their respective receptors. For wnt, fzd and their receptors/modulators, the relationships between diazinon and dieldrin were highly concordant, whereas the effect of Ni(2+) was less similar, albeit still significantly correlated with the others. Our results show that otherwise disparate developmental neurotoxicants converge on common sets of neurotrophic pathways known to control neuronal differentiation, likely contributing to similarities in functional outcomes. Further, cell culture models can provide a useful initial screen to identify members of a given class of compounds that may be greater or lesser risks for developmental neurotoxicity, or to provide an indication of agents in different classes that might produce similar effects.
authors.affiliation: Department of Pharmacology & Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710, USA. t.slotkin@duke.edu
authors.forename: Theodore A
authors.initials: TA
authors.lastname: Slotkin
authors.forename: Frederic J
authors.initials: FJ
authors.lastname: Seidler
authors.forename: Fabio
authors.initials: F
authors.lastname: Fumagalli
mesh_terms: D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism; D003976:Diazinon / Q000633:toxicity*; D004026:Dieldrin / Q000633:toxicity*; D005346:Fibroblast Growth Factors / Q000235:genetics / Q000378:metabolism; D051157:Frizzled Receptors / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects*; D007306:Insecticides / Q000633:toxicity; D020932:Nerve Growth Factor / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D009532:Nickel / Q000633:toxicity*; D016716:PC12 Cells; D051381:Rats; D014131:Trace Elements / Q000633:toxicity; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D051157:Frizzled Receptors; D007306:Insecticides; D014131:Trace Elements; D051153:Wnt Proteins; D005346:Fibroblast Growth Factors; D009532:Nickel; D020932:Nerve Growth Factor; D004026:Dieldrin; D003976:Diazinon