Elsevier

Neuroscience

Volume 145, Issue 3, 30 March 2007, Pages 1037-1047
Neuroscience

Neuroanatomy
Environmental lead exposure during early life alters granule cell neurogenesis and morphology in the hippocampus of young adult rats

https://doi.org/10.1016/j.neuroscience.2006.12.040Get rights and content

Abstract

Exposure to environmentally relevant levels of lead (Pb2+) 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 Pb2+ during early life altered granule cell neurogenesis and morphology in the rat hippocampus. Control and Pb2+-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 Pb2+-exposed rats was significantly decreased (13%; P<0.001) 1 day after BrdU injections relative to controls. Further, the survival of newborn cells in Pb2+-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 Pb2+ exposure on cellular fate. In Pb2+-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 Pb2+-exposed rats. These findings demonstrate that exposure to environmentally relevant levels of Pb2+ 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 Pb2+-exposed animals.

Section snippets

Animal husbandry and Pb2+ analysis

Female Long-Evans rats (225–250 g) were purchased from Charles River, Inc. (Wilmington, MA, USA) and fed 0 or 1500-ppm Pb2+ acetate. The Pb2+ acetate was incorporated into the rat chow mix (RMH 1000) and the food mixture was made into pellets by the manufacturer (Dyets, Bethlehem, PA, USA). Feeding of the Pb2+-containing and control diets was initiated 10 days before breeding females to untreated Long-Evans male rats. Dams were maintained on their respective diets during gestation and

Blood Pb2+ levels

Whole blood Pb2+ concentrations at PN50 were as follows: control (n=15): 0.75±0.11 μg/dL and Pb2+-exposed (n=14): 25.8±1.28 μg/dL. These blood Pb2+ concentrations are similar to our previous studies (Nihei et al., 2000) and are of the same magnitude as those present in certain segments of the population in the United States and throughout the world (Toscano and Guilarte, 2005).

Effect of Pb2+ exposure on cell proliferation and cellular fate

One day after the last BrdU injection, newly generated cells in the dorsal DG of both control and Pb2+-exposed rats

Discussion

The main finding of the present study is that chronic exposure to environmentally relevant levels of Pb2+ during early life alters granule cell neurogenesis and morphology in the DG of young adult rats. We show that Pb2+ exposure decreased the proliferation of newly generated cells but did not alter their cellular fate. Further, it decreased the survival of newly born granule cells and altered their morphology manifested by reductions in the length density of DCX-labeled apical dendrites and in

Conclusion

In summary, chronic exposure to Pb2+, a ubiquitous environmental pollutant and neurotoxicant, has detrimental effects on granule cell proliferation, survival and morphology in the DG altering the cytoarchitecture of the rat hippocampus. These findings provide a cellular and morphological basis for the deficits in hippocampal LTP and spatial learning documented in Pb2+-exposed animals.

Acknowledgments

This work was supported by grant number ES06189 to T.R.G. from the National Institute of Environmental Health Sciences. The authors give thanks to Dr. Mary Blue for assistance with the MicroBrightField Stereology System.

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