| Exposure to Organophosphates Reduces the Expression of Neurotrophic Factors in Neonatal Rat Brain Regions: Similarities and Differences in the Effects of Chlorpyrifos and Diazinon on the Fibroblast Growth Factor Superfamily Theodore A. Slotkin,1 Frederic J. Seidler,1 and Fabio Fumagalli2 1Department of Pharmacology & Cancer Biology, Duke University Medical Center, Durham, North Carolina, USA; 2Center of Neuropharmacology, Department of Pharmacological Sciences, University of Milan, Milan, Italy Abstract
Background: The fibroblast growth factor (FGF) superfamily of neurotrophic factors plays critical roles in neural cell development, brain assembly, and recovery from neuronal injury. Objectives: We administered two organophosphate pesticides, chlorpyrifos and diazinon, to neonatal rats on postnatal days 1–4, using doses below the threshold for systemic toxicity or growth impairment, and spanning the threshold for barely detectable cholinesterase inhibition: 1 mg/kg/day chlorpyrifos and 1 or 2 mg/kg/day diazinon. Methods: Using microarrays, we then examined the regional expression of mRNAs encoding the FGFs and their receptors (FGFRs) in the forebrain and brain stem. Results: Chlorpyrifos and diazinon both markedly suppressed fgf20 expression in the forebrain and fgf2 in the brain stem, while elevating brain stem fgfr4 and evoking a small deficit in brain stem fgf22. However, they differed in that the effects on fgf2 and fgfr4 were significantly larger for diazinon, and the two agents also showed dissimilar, smaller effects on fgf11, fgf14, and fgfr1. Conclusions: The fact that there are similarities but also notable disparities in the responses to chlorpyrifos and diazinon, and that robust effects were seen even at doses that do not inhibit cholinesterase, supports the idea that organophosphates differ in their propensity to elicit developmental neurotoxicity, unrelated to their anticholinesterase activity. Effects on neurotrophic factors provide a mechanistic link between organophosphate injury to developing neurons and the eventual, adverse neurodevelopmental outcomes. Key words: brain development, chlorpyrifos, diazinon, fibroblast growth factor, fibroblast growth factor receptors, microarrays, neurotoxicity, organophosphate insecticides. Environ Health Perspect 115:909–916 (2007) . doi:10.1289/ehp.9901 available via http://dx.doi.org/ [Online 27 February 2007]
Address correspondence to T.A. Slotkin, Box 3813 DUMC, Duke University Medical Center, Durham, NC 27710 USA. Telephone: (919) 681-8015. Fax: (919) 684-8197. E-mail: t.slotkin@duke.edu This research was supported by grant ES10356 from the National Institutes of Health. T.A.S. and F.J.S. have provided expert witness testimony on behalf of government agencies, corporations, and/or individuals. F.F. declares he has no competing financial interests. Received 14 November 2006 ; accepted 27 February 2007.
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