Academic journal article Environmental Health Perspectives

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

Academic journal article Environmental Health Perspectives

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

Article excerpt

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]

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The developmental neurotoxicity of organophosphate pesticides represents a biological conundrum that has important ramifications for human exposures (for review see Colborn 2006; Costa 2006; Landrigan 2001; Mileson et al. 1998; Slotkin 2005; Weiss et al. 2004). All of the organophosphates produce systemic toxicity by inhibiting acetylcholinesterase, resulting in overt symptoms of cholinergic hyperstimulation; these effects have therefore been assumed to be the common mechanism underlying adverse developmental consequences (Mileson et al. 1998). However, the fetus and neonate recover from cholinesterase inhibition much more quickly than adults (Chakraborti et al. 1993; Lassiter et al. 1998), yet display greater overall toxicity and damage to the central nervous system (for review see Pope 1999; Slotkin 2004, 2005). Indeed, evidence accumulating over the past decade implicates a host of other mechanisms in the developmental neurotoxicity of the organophosphates that depend instead upon the direct targeting of events specific to the developing brain (for review see Barone et al. 2000; Pope 1999; Rice and Barone 2000; Slotkin 2004). Importantly, many of these processes are vulnerable to organophosphates at doses below those necessary to elicit signs of systemic toxicity and even below the threshold for significant inhibition of cholinesterase (Pope 1999; Slotkin 2004, 2005).

Although a wide variety of intermediate events in brain development connect the initial effects of organophosphates on neural cell differentiation to the eventual synaptic and behavioral defects (Pope 1999; Slotkin 2004, 2005), little information is currently available about specific cellular mechanisms that render the developing brain so vulnerable to these agents. Indeed, many events in differentiation and assembly of neural circuits are affected, including the processes of neuronal and glial cell replication and differentiation, specification of neurotransmitter phenotypes, axonogenesis and synaptogenesis, and synaptic function (Barone et al. …

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