title: Developmental neurotoxicity of different pesticides in PC-12 cells in vitro.
abstract: The detection of developmental neurotoxicity (DNT) of chemicals has high relevance for protection of human health. However, DNT of many pesticides is only little known. Furthermore, validated in vitro systems for assessment of DNT are not well established. Here we employed the rat phaeochromocytoma cell line PC-12 to evaluate DNT of 18 frequently used pesticides of different classes, including neonicotinoids, pyrethroids, organophosphates, organochlorines, as well as quaternary ammonium compounds, the organic compound used in pesticides, piperonyl butoxide, as well as the insect repellent diethyltoluamide (DEET). We determined the outgrowth of neurites in PC-12 cells co-treated with nerve growth factor and different concentrations of biocides for 5days. Furthermore, we determined transcriptional alterations of selected genes that may be associated with DNT, such as camk2α and camk2β, gap-43, neurofilament-h, tubulin-α and tubulin-β. Strong and dose- dependent inhibition of neurite outgrowth was induced by azamethiphos and chlorpyrifos, and dieldrin and heptachlor, which was correlated with up-regulation of gap-43. No or only weak effects on neurite outgrowth and transcriptional alterations occurred for neonicotinoids acetamiprid, clothianidin, imidacloprid and thiamethoxam, the pyrethroids λ-cyhalothrin, cyfluthrin, deltamethrin, and permethrin, the biocidal disinfectants C12-C14-alkyl(ethylbenzyl)dimethylammonium (BAC), benzalkonium chloride and barquat (dimethyl benzyl ammonium chloride), and piperonyl butoxide and DEET. Our study confirms potential developmental neurotoxicity of some pesticides and provides first evidence that azamethiphos has the potential to act as a developmental neurotoxic compound. We also demonstrate that inhibition of neurite outgrowth and transcriptional alterations of gap-43 expression correlate, which suggests the employment of gap-43 expression as a biomarker for detection and initial evaluation of potential DNT of chemicals.
authors.affiliation: University of Applied Sciences and Arts Northwestern Switzerland, School of Life Sciences, Gründenstrasse 40, CH-4132, Muttenz, Switzerland.
authors.forename: Verena
authors.initials: V
authors.lastname: Christen
authors.affiliation: Federal Office of Public Health, Division Chemical Products, 3003 Bern, Switzerland.
authors.forename: Manuel
authors.initials: M
authors.lastname: Rusconi
authors.affiliation: Federal Office of Public Health, Division Chemical Products, 3003 Bern, Switzerland.
authors.forename: Pierre
authors.initials: P
authors.lastname: Crettaz
authors.affiliation: University of Applied Sciences and Arts Northwestern Switzerland, School of Life Sciences, Gründenstrasse 40, CH-4132, Muttenz, Switzerland; Swiss Federal Institute of Technology Zürich (ETH Zürich), Department of Environmental Systems Sciences, Institute of Biogeochemistry and Pollution Dynamics, CH-8092 Zürich, Switzerland. Electronic address: karl.fent@bluewin.ch.
authors.forename: Karl
authors.initials: K
authors.lastname: Fent
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D019922:GAP-43 Protein / Q000235:genetics / Q000378:metabolism; D005819:Genetic Markers; D016501:Neurites / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D055495:Neurogenesis / Q000187:drug effects*; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D020258:Neurotoxicity Syndromes / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D016716:PC12 Cells; D010575:Pesticides / Q000633:toxicity*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D018570:Risk Assessment; D013997:Time Factors; D018675:Toxicity Tests; D014158:Transcription, Genetic / Q000187:drug effects; D015533:Transcriptional Activation / Q000187:drug effects; D015854:Up-Regulation
chemical_list: D019922:GAP-43 Protein; D005819:Genetic Markers; D010575:Pesticides; D012333:RNA, Messenger
keywords: Biocides; Developmental neurotoxicity; Neonicotinoids; Neurite outgrowth; PC-12 cells; Pesticides