Gestational exposure to methylmercury alters neurotrophin- and carbachol-stimulated phosphatidylinositide hydrolysis in cerebral cortex of neonatal rats.
Neurotrophin-stimulated signal transduction through the Trk receptors has been implicated in the development and survival of the nervous system. Phospholipase Cgamma (PLCgamma) is an early downstream effector for the Trk receptors, and catalyzes the hydrolysis of phosphatidylinositides (PI) to inositol phosphates (IPs) and diacylglycerol. The current study demonstrated that PI hydrolysis can be used as a measure of Trk stimulation in slices from neonatal rat brain, and examined changes in the ontogeny of neurotrophin-stimulated PI hydrolysis in animals exposed to MeHg during gestation. Neurotrophin-3 (NT-3) and brain-derived neurotrophic factor (BDNF) stimulated PI hydrolysis in neocortical and cerebellar slices from neonatal rats in a concentration-dependent manner (30-1000 ng/ml). The neurotrophin-stimulated PI hydrolysis was completely blocked by K-252a, a compound known to inhibit Trk autophosphorylation. To examine the effects of MeHg on PI hydrolysis, Long-Evans dams were dosed p.o. on gestational days 6-15 with 0 or 2 mg/kg/day MeHg dissolved in saline. Pups were sacrificed on postnatal days (PND) 1, 4, 10, 14, and 21 and brain slices prepared from the neocortex and cerebellum. Neurotrophin-stimulated PI hydrolysis was highest on PND 1-4 and decreased with age in slices from both regions. Prior exposure to MeHg had no effect on NT-3 or BDNF-stimulated PI hydrolysis in the cerebellum; however, in the neocortex carbachol-stimulated PI hydrolysis and NT-3-stimulated PI hydrolysis were decreased on PND 1. In addition, NT-3-stimulated PI hydrolysis was increased on PND 14 compared to controls. Nerve growth factor (NGF), which had no effect in controls, increased PI hydrolysis in MeHg exposed animals. Acute exposure to 10 micro M MeHg increased basal PI hydrolysis in cortical slices and increased NT-3- and BDNF-stimulated PI hydrolysis in slices from the cerebellum. These data indicate that gestational exposure to MeHg can alter neurotrophin signaling in the neocortex at early postnatal times.
Mundy
W M
WM
Neurotoxicology Division, National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, NC 27711, USA. mundy.william@epamail.epa.gov
Parran
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D
Barone
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