Despite significant efforts during the last three decades to reduce lead contamination of the environment, a significant number of children continue to be exposed to this potent and ubiquitous neurotoxicant. A recent report by the Surgeon General of the United States (Satcher, 2000) indicates that """"""""lead poisoning poses one of the greatest environmental threats to children in America"""""""". It further states that the latest data show that in the United States, 1 in 20 children under the age of 6 have blood lead levels exceeding those considered to produce lasting deficits in cognitive function. Unfortunately, this problem is not going to disappear in the near future and we must devise new strategies to ameliorate or modify the devastating effects of lead on the central nervous system. The goal of the work proposed is to continue to elucidate the molecular mechanisms of lead-induced neurotoxicity. Our work has demonstrated that the N-methyI-D-Aspartate (NMDA)-type of glutamate excitatory amino acid receptors is a target for lead in the central nervous system. This is important because NMDA receptor function is essential for a number of physiological processes in the developing and mature brain. One of these processes is the acquisition and consolidation of learning and memory. We have shown that exposure to lead during development produces lasting changes in learning and memory in a rodent model of lead neurotoxicity. Further, the impairment in learning is associated with deficits in long-term potentiation in the hippocampus and alterations in NMDA receptor subunit genes and protein expression. Based on this new knowledge, we tested the hypothesis that environmental enrichment may alter the cognitive and molecular deficits induced by lead. Our studies show that environmental enrichment is able to reverse the cognitive and NMDA receptor deficits induced by developmental exposure to lead. This is an extremely important finding because it demonstrates that some of the lead-induced cognitive and molecular deficits are reversible. Further, environmental enrichment is an intervention that is applicable to children. The goal of our proposed studies is to further our understanding of the neurobiological substrates associated with lead-induced neurotoxicity and its reversibility by environmental enrichment. It is important to determine whether environmental enrichment is an intervention strategy that benefits children of any age and if the benefits are long lasting.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES006189-14
Application #
7081382
Study Section
Alcohol and Toxicology Subcommittee 4 (ALTX)
Program Officer
Kirshner, Annette G
Project Start
1992-12-01
Project End
2008-06-30
Budget Start
2006-07-01
Budget End
2007-06-30
Support Year
14
Fiscal Year
2006
Total Cost
$394,962
Indirect Cost
Name
Johns Hopkins University
Department
Public Health & Prev Medicine
Type
Schools of Public Health
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Wagner, Peter J; Park, Hae-Ryung; Wang, Zhaoxi et al. (2017) In Vitro Effects of Lead on Gene Expression in Neural Stem Cells and Associations between Up-regulated Genes and Cognitive Scores in Children. Environ Health Perspect 125:721-729
Austin, Rachel Narehood; Freeman, Jennifer L; Guilarte, Tomás R (2016) Neurochemistry of lead and manganese. Metallomics 8:561-2
Guariglia, Sara Rose; Stansfield, Kirstie H; McGlothan, Jennifer et al. (2016) Chronic early life lead (Pb2+) exposure alters presynaptic vesicle pools in hippocampal synapses. BMC Pharmacol Toxicol 17:56
Stansfield, K H; Ruby, K N; Soares, B D et al. (2015) Early-life lead exposure recapitulates the selective loss of parvalbumin-positive GABAergic interneurons and subcortical dopamine system hyperactivity present in schizophrenia. Transl Psychiatry 5:e522
Zhang, Xiao-Lei; Guariglia, Sara R; McGlothan, Jennifer L et al. (2015) Presynaptic mechanisms of lead neurotoxicity: effects on vesicular release, vesicle clustering and mitochondria number. PLoS One 10:e0127461
Abazyan, Bagrat; Dziedzic, Jenifer; Hua, Kegang et al. (2014) Chronic exposure of mutant DISC1 mice to lead produces sex-dependent abnormalities consistent with schizophrenia and related mental disorders: a gene-environment interaction study. Schizophr Bull 40:575-84
Neal, April P; Guilarte, Tomas R (2013) Mechanisms of lead and manganese neurotoxicity. Toxicol Res (Camb) 2:99-114
Kang, N; Peng, H; Yu, Y et al. (2013) Astrocytes release D-serine by a large vesicle. Neuroscience 240:243-57
Guilarte, Tomas R; Opler, Mark; Pletnikov, Mikhail (2012) Is lead exposure in early life an environmental risk factor for Schizophrenia? Neurobiological connections and testable hypotheses. Neurotoxicology 33:560-74
Stansfield, Kirstie H; Pilsner, J Richard; Lu, Quan et al. (2012) Dysregulation of BDNF-TrkB signaling in developing hippocampal neurons by Pb(2+): implications for an environmental basis of neurodevelopmental disorders. Toxicol Sci 127:277-95

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