title: Developmental exposure to organophosphates triggers transcriptional changes in genes associated with Parkinson's disease in vitro and in vivo.
abstract: Epidemiologic studies support a connection between organophosphate pesticide exposures and subsequent risk of Parkinson's disease (PD). We used differentiating, neuronotypic PC12 cells to compare organophosphates (chlorpyrifos, diazinon), an organochlorine (dieldrin) and a metal (Ni(2+)) for their effects on the transcription of PD-related genes. Both of the organophosphates elicited significant changes in gene expression but with differing patterns: chlorpyrifos evoked both up- and downregulation whereas diazinon elicited overall reductions in expression. Dieldrin was without effect but Ni(2+) produced a pattern resembling that of diazinon. We then exposed neonatal rats to chlorpyrifos or diazinon for the first 4 days after birth and examined the expression of PD-related genes in the brainstem and forebrain. Chlorpyrifos had no significant effect whereas diazinon produced significant increases and decreases in expression of the same PD genes that were targeted in vitro. Our results provide some of the first evidence for a mechanistic relationship between developmental organophosphate exposure and the genes known to confer PD risk in humans; but they also point to disparities between different organophosphates that reinforce the concept that their neurotoxic actions do not rest solely on their shared property as cholinesterase inhibitors. The parallel effects of diazinon and Ni(2+) also show how otherwise unrelated developmental neurotoxicants can nevertheless produce similar outcomes by converging on common molecular pathways, further suggesting a need to examine metals such as Ni(2+) as potential contributors to PD risk.
authors.affiliation: Department of Pharmacology & Cancer Biology, Duke University Medical Center, Box 3813 DUMC, Durham, NC 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
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000187:drug effects / Q000502:physiology; D004390:Chlorpyrifos / Q000494:pharmacology*; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D003976:Diazinon / Q000494:pharmacology*; D004026:Dieldrin / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects*; D020869:Gene Expression Profiling; D006801:Humans; D046228:Microarray Analysis; D009532:Nickel / Q000494:pharmacology; D010755:Organophosphates / Q000494:pharmacology; D016716:PC12 Cells / Q000187:drug effects; D010300:Parkinson Disease / Q000209:etiology / Q000235:genetics; D051381:Rats; D014158:Transcription, Genetic / Q000187:drug effects*
chemical_list: D002800:Cholinesterase Inhibitors; D010755:Organophosphates; D009532:Nickel; D004026:Dieldrin; D004390:Chlorpyrifos; D003976:Diazinon