EFFECTS OF GESTATIONAL METHYLMERCURY EXPOSURE ON IMMUNOREACTIVITY OF SPECIFIC ISOFORMS OF PKC AND ENZYME-ACTIVITY DURING POSTNATAL-DEVELOPMENT OF THE RAT-BRAIN

Protein kinase C (PKC)-mediated phosphorylation has been implicated in neuronal growth and differentiation [R.S. Turner, R.L. Mazzei, G.J. R aynor, P.R. Girard, J.F. Kuo, Proc. Natl. Acad. Sci. U.S.A., 81 (1984) 3143-3147.]. We examined effects of gestational exposure to the neuro toxicant, methylmercury (CH3Hg), on the developmental profile of immun oreactivity (IR) for alpha, beta, gamma and epsilon PKC isoforms and c ytosolic PKC activity. Long-Evans dams were dosed on gestational days (GD)6-15 (p.o.) with 0, 1, or 2 mg kg(-1) day(-1) CH3Hg dissolved in s aline. Pups were sacrificed and perfused with buffered paraformaldehyd e on post-natal days (PND) 1, 4, 10, 21, 45 and 85. The brains were se ctioned sagittally, stained immunohistochemically, and examined throug hout the medial to lateral extent. IR in neuronal cell bodies for PKC isoforms alpha, beta, gamma, and epsilon was densest in the olfactory bulb, hippocampus, shell of the inferior colliculus, pens, cerebral, p iriform, and cerebellar cortex, whereas axonal staining was prominent in the brainstem, internal capsule, corpus callosum, anterior commissu re, fornix and olfactory tract. In controls, the PKC alpha and epsilon IR was highest on PND1-4, decreased dramatically by PND10, and decrea sed further by PND21. In the neonate, the regional and cellular distri butions of alpha and epsilon IR were similar. The PKC gamma IR was gre ater at post-weaning ages (PND21-85) with the greatest regional densit y apparent in the hippocampus, cortex, and cerebellum. Only the highes t dose of CH3Hg (2 mg kg(-1) day(-1); GD6-15) produced a persistent de crease in regional alpha and epsilon, but not beta or gamma IR during the post-natal period. These regional and time-dependent changes in PK C isoforms were complemented by the examination of PKC activity in cor tex, olfactory bulb, cerebellum and brainstem. Cytosolic PKC activity increased from PND1 to 10 in cortex, olfactory bulb, and cerebellum. O n PND21, PKC activity decreased in the cortex and olfactory bulb, but remained high in the cerebellum. By contrast, PKC activity in the brai nstem was highest on PND1 and 4 and decreased dramatically by PND21. C H3Hg (2 mg kg(-1) day(-1)) significantly decreased PKC activity on PND 1 and 4 in the cortex. The present results characterize the cellular a nd regional ontogeny of PKC isoenzymes alpha, beta, gamma and epsilon, and indicate that developmental exposure to CH3Hg can alter the ontog eny of specific isoforms and regional PKC activity. (C) 1998 Elsevier Science B.V. All rights reserved.