Chlorpyrifos exerts opposing effects on axonal and dendritic growth in primary neuronal cultures.
Evidence that children are widely exposed to organophosphorus pesticides (OPs) and that OPs cause developmental neurotoxicity in animal models raises significant concerns about the risks these compounds pose to the developing human nervous system. Critical to assessing this risk is identifying specific neurodevelopmental events targeted by OPs. Observations that OPs alter brain morphometry in developing rodents and inhibit neurite outgrowth in neural cell lines suggest that OPs perturb neuronal morphogenesis. However, an important question yet to be answered is whether the dysmorphogenic effect of OPs reflects perturbation of axonal or dendritic growth. We addressed this question by quantifying axonal and dendritic growth in primary cultures of embryonic rat sympathetic neurons derived from superior cervical ganglia (SCG) following in vitro exposure to chlorpyrifos (CPF) or its metabolites CPF-oxon (CPFO) and trichloropyridinol (TCP). Axon outgrowth was significantly inhibited by CPF or CPFO, but not TCP, at concentrations > or =0.001 microM or 0.001 nM, respectively. In contrast, all three compounds enhanced BMP-induced dendritic growth. Acetylcholinesterase was inhibited only by the highest concentrations of CPF (> or =1 microM) and CPFO (> or =1 nM); TCP had no effect on this parameter. In summary, these compounds perturb neuronal morphogenesis via opposing effects on axonal and dendritic growth, and both effects are independent of acetylcholinesterase inhibition. These findings have important implications for current risk assessment practices of using acetylcholinesterase inhibition as a biomarker of OP neurotoxicity and suggest that OPs may disrupt normal patterns of neuronal connectivity in the developing nervous system.
Howard
Angela S
AS
Department of Environmental Health Sciences, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD, USA.
Bucelli
Robert
R
Jett
David A
DA
Bruun
Donald
D
Yang
Dongren
D
Lein
Pamela J
PJ
D000818:Animals; D001369:Axons / Q000187:drug effects* / Q000502:physiology; D002478:Cells, Cultured; D004390:Chlorpyrifos / Q000031:analogs & derivatives / Q000378:metabolism / Q000633:toxicity*; D002800:Cholinesterase Inhibitors / Q000633:toxicity*; D003712:Dendrites / Q000187:drug effects* / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D007306:Insecticides / Q000633:toxicity*; D051381:Rats
D002800:Cholinesterase Inhibitors; D007306:Insecticides; C009618:O,O-diethyl O-3,5,6-trichloro-2-pyridyl phosphate; D004390:Chlorpyrifos