GESTATIONAL EXPOSURE TO METHYLMERCURY ALTERS THE DEVELOPMENTAL PATTERN OF TRK-LIKE IMMUNOREACTIVITY IN THE RAT-BRAIN AND RESULTS IN CORTICAL DYSMORPHOLOGY

Nerve growth factor signal transduction mediated through the trk recep tor has been implicated in neuronal growth, differentiation, and survi val. In this study, we examined the effects of gestational exposure to the developmental neurotoxicant methylmercury (CH3Hg) on the ontogeny of trk-immunoreactivity (IR). Long-Evans dams were dosed on gestation al days 6-15 (p.o.) with 0, 1, or 2 mg/kg CH3Hg dissolved in saline. P ups were sacrificed and perfused with buffered paraformaldehyde on pos tnatal days (PND) 1, 4, 10, 21 and 85. The brains were sectioned sagit ally, Nissl-stained or stained immunohistochemically for trk receptors or glial fibrillary acidic protein (GFAP), and examined throughout th e medial to lateral extent of the brain. The greatest density of IR in neural cell bodies was seen in the olfactory bulb, hippocampus, cereb ral, and cerebellar cortex, striatum, septum, nucleus basalis, inferio r colliculus, pens, and brain stem nuclei. trk IR was not limited to n erve cell bodies, with prominent axonal and dendritic staining in the brainstem, neocortex, hippocampus, cerebellum, and olfactory tract. Th e regional pattern of trk IR varied in an age-dependent manner. In con trols, trk-like IR appeared to peak in most regions between PND4-10 an d decreased dramatically after PND21. This age-related difference in t rk IR was supported by western blot analysis of PND10 and adult neocor tex. This reduced and more adult-like pattern of trk IR was apparent o n PND21 with some persistent trk-like IR in the olfactory bulb, hippoc ampus, neocortex, cerebellum and basal forebrain. In contrast to the n ormal regional patterns of trk IR, CH3Hg produced a dose-related decre ase in trk-like IR in the absence of overt maternal toxicity or neonat al toxicity. CH3Hg-induced decreases in trk-like IR were especially ap parent during the early postnatal period when trk IR was the greatest. The effects of CH3Hg exposure were restricted regionally, with the la rgest decrease in trk-like IR apparent in cortical regions, basal fore brain nuclei, and brain stem nuclei. Subsequent to the effects of CH3H g on cortical trk-like IR were alterations in the development of corti cal laminae on PND10 and 21 of neocortex. These alterations were chara cterized by quantifiable decreases in cell density, cell size and the widths of the layers of posterior neocortex. Not all of the CH3Hg-indu ced effects were characterized by decreased trk-like IR. Robust increa ses in trk IR in glial cells in the corpus callosum and brain stem wer e observed coincident with increased GFAP IR in cells of similar morph ology. The present results localize the cellular and regional ontogeny of trk and suggest that developmental exposure to CH3Hg alters the no rmal ontogeny of this trophic factor receptor which may be associated with the developmental neurotoxicity of this chemical. (C) 1998 Elsevi er Science B.V. All rights reserved.