Developmental methylmercury administration alters cerebellar PSA-NCAM expression and Golgi sialyltransferase activity

Brain dysmorphogenesis and persistent psychomotor disturbances are hallmark s of developmental methylmercury (MeHg) exposure, but the molecular mechani sms underlying these effects are poorly understood. Targets of developmenta l MeHg exposure include neural cell adhesion molecules (NCAMs), sialoglycoc onjugate molecules whose proper temporal and spatial expression is importan t at all stages of neurodevelopment and especially during synaptic structur ing. To investigate the effects of MeHg on the temporal expression of NCAM during development, rat pups were dosed with 7.0 mg/kg MeHgCl (s.c.) on alt ernate days from postnatal days (PNDs) 3-13 and killed on PNDs 15, 30 and 6 0. Brain MeHg concentrations were determined in a subset of litters injecte d with (CH3Hg)-Hg-203. Expression of NCAM180 protein and of NCAM180 polysia lylation was examined in whole cerebellum homogenates, cerebellar synaptoso mes and isolated cerebellar growth cones by Western blotting and immunocyto chemical staining. NCAM sialyltransferase activity was assayed in preparati ons of purified Golgi apparatus from the cerebelli of rats treated in vivo, or following in vitro incubation with 0, 1, 2.5, or 7.5 mu M MeHg for 2 h. At PND15, no change in NCAM180 protein expression was observed in any cere bellar preparations, but decreased polysialylation of NCAM180 was observed in cerebellar whole homogenates, synaptosomes and isolated growth cones. At PND30, both NCAM180 protein expression and NCAM180 polysialylation were el evated in whole homogenate preparations but not in synaptosomes. NCAM180 ex pression in MeHg-treated rats was similar to controls at PND60, 47 days aft er the last methylmercury administration. In vivo studies of cerebellar Gol gi sialyltransferase activity revealed significant reductions in PND15 MeHg -treated rats as compared to controls, but no changes in sialyltransferase activity in PND30 and PND60 animals. In vitro experiments revealed decreasi ng sensitivity of cerebellar sialyltransferases to MeHg as the developmenta l age of the rat increased. Toxic perturbation of the developmentally-regul ated expression of polysialylated NCAM during brain formation may disturb t he stereotypic formation of neuronal contacts and could contribute to the b ehavioral and morphological disturbances observed following MeHg poisoning. (C) 1999 Elsevier Science B.V. All rights reserved.