Environmental lead exposure during early life alters granule cell neurogenesis and morphology in the hippocampus of young adult rats.
Exposure to environmentally relevant levels of lead (Pb(2+)) during early life produces deficits in hippocampal synaptic plasticity in the form of long-term potentiation (LTP) and spatial learning in young adult rats [Nihei MK, Desmond NL, McGlothan JL, Kuhlmann AC, Guilarte TR (2000) N-methyl-D-aspartate receptor subunit changes are associated with lead-induced deficits of long-term potentiation and spatial learning. Neuroscience 99:233-242; Guilarte TR, Toscano CD, McGlothan JL, Weaver SA (2003) Environmental enrichment reverses cognitive and molecular deficits induced by developmental lead exposure. Ann Neurol 53:50-56]. Other evidence suggests that the performance of rats in the Morris water maze spatial learning tasks is associated with the level of granule cell neurogenesis in the dentate gyrus (DG) [Drapeau E, Mayo W, Aurousseau C, Le Moal M, Piazza P-V, Abrous DN (2003) Spatial memory performance of aged rats in the water maze predicts level of hippocampal neurogenesis. Proc Natl Acad Sci U S A 100:14385-14390]. In this study, we examined whether continuous exposure to environmentally relevant levels of Pb(2+) during early life altered granule cell neurogenesis and morphology in the rat hippocampus. Control and Pb(2+)-exposed rats received bromodeoxyuridine (BrdU) injections (100 mg/kg; i.p.) for five consecutive days starting at postnatal day 45 and were killed either 1 day or 4 weeks after the last injection. The total number of newborn cells in the DG of Pb(2+)-exposed rats was significantly decreased (13%; P<0.001) 1 day after BrdU injections relative to controls. Further, the survival of newborn cells in Pb(2+)-exposed rats was significantly decreased by 22.7% (P<0.001) relative to control animals. Co-localization of BrdU with neuronal or astrocytic markers did not reveal a significant effect of Pb(2+) exposure on cellular fate. In Pb(2+)-exposed rats, immature granule cells immunolabeled with doublecortin (DCX) displayed aberrant dendritic morphology. That is, the overall length-density of the DCX-positive apical dendrites in the outer portion of the DG molecular layer was significantly reduced up to 36% in the suprapyramidal blade only. We also found that the area of Timm's-positive staining representative of the mossy fibers terminal fields in the CA3 stratum oriens (SO) was reduced by 26% in Pb(2+)-exposed rats. These findings demonstrate that exposure to environmentally relevant levels of Pb(2+) during early life alters granule cell neurogenesis and morphology in the rat hippocampus. They provide a cellular and morphological basis for the deficits in synaptic plasticity and spatial learning documented in Pb(2+)-exposed animals.
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Neurotoxicology and Molecular Imaging Laboratory, Department of Environmental Health Sciences, Johns Hopkins University Bloomberg School of Public Health, 615 North Wolfe Street, Room E6622, Baltimore, MD 21205, USA.
Rohde
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Guilarte
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D000375:Aging; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000254:growth & development / Q000502:physiology; D001973:Bromodeoxyuridine / Q000494:pharmacology; D000089662:Doublecortin Protein; D004781:Environmental Exposure; D005260:Female; D006624:Hippocampus / Q000187:drug effects / Q000254:growth & development*; D007855:Lead Poisoning / Q000503:physiopathology*; D009412:Nerve Fibers / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D010641:Phenotype; D051381:Rats; D011917:Rats, Inbred Lew
C000714848:Dcx protein, rat; D000089662:Doublecortin Protein; D001973:Bromodeoxyuridine