Lead neurotoxicity: From exposure to molecular effects

doi:10.1016/j.brainresrev.2005.02.004

Brain Research Reviews

Volume 49, Issue 3, November 2005, Pages 529-554

https://doi.org/10.1016/j.brainresrev.2005.02.004 Get rights and content

Abstract

The effects of lead (Pb²⁺) on human health have been recognized since antiquity. However, it was not until the 1970s that seminal epidemiological studies provided evidence on the effects of Pb²⁺ intoxication on cognitive function in children. During the last two decades, advances in behavioral, cellular and molecular neuroscience have provided the necessary experimental tools to begin deciphering the many and complex effects of Pb²⁺ on neuronal processes and cell types that are essential for synaptic plasticity and learning and memory in the mammalian brain. In this review, we concentrate our efforts on the effects of Pb²⁺ on glutamatergic synapses and specifically on the accumulating evidence that the N-methyl-d-aspartate type of excitatory amino acid receptor (NMDAR) is a direct target for Pb²⁺ effects in the brain. Our working hypothesis is that disruption of the ontogenetically defined pattern of NMDAR subunit expression and NMDAR-mediated calcium signaling in glutamatergic synapses is a principal mechanism for Pb²⁺-induced deficits in synaptic plasticity and in learning and memory documented in animal models of Pb²⁺ neurotoxicity.

We provide an introductory overview of the magnitude of the problem of Pb²⁺ exposure to bring forth the reality that childhood Pb²⁺ intoxication remains a major public health problem not only in the United States but worldwide. Finally, the latest research offers some hope that the devastating effects of childhood Pb²⁺ intoxication in a child's ability to learn may be reversible if the appropriate stimulatory environment is provided.

Introduction

Lead (Pb²⁺) is a heavy metal with no apparent biological function. The widespread environmental contamination, the propensity to cause a wide spectrum of toxic effects and the number of individuals affected worldwide makes this ubiquitous neurotoxicant a public health problem of global magnitude [193]. In spite of the extensive documentation of the toxic effects of Pb²⁺ on human health, a complete and detailed explanation on the mechanism(s) by which Pb²⁺ exerts its effects on the central nervous system has yet to be defined. The aim of this review is to summarize the current understanding of molecular mechanisms of Pb²⁺ neurotoxicity by detailing the effect of Pb²⁺ on the NMDA receptor (NMDAR) and NMDAR-mediated signaling pathways that are necessary for learning, memory and synaptic plasticity. Further, this review will focus on the usefulness of animal models in both characterizing the behavioral and electrophysiological effects of Pb²⁺ and the development of novel interventions that reverse the neurotoxic effects of Pb²⁺. In vitro studies of Pb²⁺ effects on specific neuronal systems will only be mentioned in the context of in vivo exposures. The goal of this review is to provide a starting point for discussion and to summarize the existing evidence that supports the hypothesis that the NMDAR is a major target for Pb²⁺ effects on the central nervous system. We should note at the onset that the Pb²⁺ exposure protocols used in most of the experimental animal studies cited in this review result in blood Pb²⁺ concentrations in the 15–40 μg/dL. These blood Pb²⁺ concentrations are “environmentally relevant” since they are present in a large percentage of Pb²⁺-exposed children in the United States and other parts of the world (Fig. 1).

Section snippets

Sources and vectors of Pb²⁺

Pb²⁺ is able to enter biological systems via food, water, air and soil. Before 1995, exposure to Pb²⁺ by contaminated food was most likely to have occurred from cans that contained Pb²⁺ solder in the joints [65]. The removal of Pb²⁺ solder from canned foods is estimated to have reduced the average dietary intake of Pb²⁺ in a 2-year-old child from 30 μg/day in 1982 to about 2 μg/day in 1991 [65], [139], [225]. While banned in the US, Pb²⁺ solder continues to be used in other countries, resulting

Experimental models of Pb²⁺ neurotoxicity

Non-human primates and rodent models have been used to study the effect of developmental Pb²⁺ exposure on behavioral endpoints [42], [179], [180]. In the rhesus monkey, pre- and postnatal Pb²⁺ exposure resulting in blood Pb²⁺ levels between 50 and 70 μg/dl has been demonstrated to result in an impairment of higher-order learning as assessed by the Harlow learning set formation task [241]. This behavioral task involves progressive training on a visual-motor task, a behavior that is impaired in

The NMDA receptor: molecular biology and physiology

Glutamate is the major excitatory neurotransmitter in the mammalian brain and mediates activity-dependent processes critical to both the developing and the mature brain. Ionotropic and metabotropic receptor subtypes mediate the actions of glutamate and activation of the ionotropic NMDAR plays a central role in brain development, learning and memory as well as in neurodegenerative diseases [39], [167], [194]. The NMDAR has unique characteristics that conform to those postulated in the Hebbian

Effect of developmental exposure to Pb²⁺ on NMDA receptor subunit expression and function

The effect of in vivo exposure to Pb²⁺ during development on NMDAR subunit expression has been documented in rodent models of Pb²⁺ neurotoxicity. These studies show that exposure to environmentally relevant levels of Pb²⁺ were effective in producing marked changes in NMDAR subunit gene expression in the developing as well as in the mature brain. The effect of developmental Pb²⁺ exposure on gene expression of NMDAR subunits was first described by Guilarte and McGlothan [67] using in situ

Alterations in NMDAR-mediated calcium signaling pathways in Pb²⁺-exposed rats

The detailed body of data presented in the previous sections suggest that Pb²⁺ exposure inhibits the NMDAR and alters the ontogeny of NMDAR subunit expression. These effects on the NMDAR subunit composition and synaptic localization would be expected to alter the activity and compositions of calcium signaling pathways that convey information from the synapse to the nucleus to activate the expression of genes necessary for learning and memory. NMDAR-mediated calcium signaling is known to

Environmental enrichment: a therapeutic approach that reverses Pb²⁺-induced learning and molecular deficits

There is evidence from the human and experimental animal literature that deficits in cognitive function resulting from exposure to Pb²⁺ during early childhood lasts well into adulthood [104], [237]. In fact, the current thinking is that the neurological damage produced by exposure to Pb²⁺ during early life is irreversible. We have recently questioned this dogma by assessing an intervention strategy, “environmental enrichment”, that may be helpful in reversing the cognitive and molecular

Summary and future studies

Studies from a number of laboratories during the last decade are beginning to provide a workable hypothesis on mechanisms by which developmental Pb²⁺ exposure produces deficits in synaptic plasticity and in learning and memory. Our line of evidence suggests that Pb²⁺ inhibits NMDAR function producing a blockade of glutamatergic synaptic activity thereby altering the activity-dependent regulation of developmental processes. Basic neuroscience studies examining how the level of synaptic activity

Acknowledgments

This work was supported by NIEHS grant number ES06189 to TRG. CDT was supported by NIEHS training grant number ES07141.

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ReviewLead neurotoxicity: From exposure to molecular effects

Abstract

Introduction

Section snippets

Sources and vectors of Pb2+

Experimental models of Pb2+ neurotoxicity

The NMDA receptor: molecular biology and physiology

Effect of developmental exposure to Pb2+ on NMDA receptor subunit expression and function

Alterations in NMDAR-mediated calcium signaling pathways in Pb2+-exposed rats

Environmental enrichment: a therapeutic approach that reverses Pb2+-induced learning and molecular deficits

Summary and future studies

Acknowledgments

Genetic demonstration of a role for PKA in the late phase of LTP and in hippocampus-based long-term memory

Cell

Modified hippocampal long-term potentiation in PKC gamma-mutant mice

Cell

PKC gamma mutant mice exhibit mild deficits in spatial and contextual learning

Cell

Molecular psychology: roles for the ERK MAP kinase cascade in memory

Annu. Rev. Pharmacol. Toxicol.

Lead-poisoning in two distant states of Nigeria: an indication of the real size of the problem

Afr. J. Med. Med. Sci.

Blood lead levels and risk factors for lead poisoning among children in Jakarta, Indonesia

Sci. Total Environ.

Selective blockade of NMDA-activated channel currents may be implicated in learning deficits caused by lead

FEBS Lett.

Impairment of long-term potentiation and learning following chronic lead exposure

Toxicol. Lett.

Effects of maternal lead exposure on functional plasticity in the visual cortex and hippocampus of immature rats

Brain Res. Dev. Brain Res.

Hippocampal CRE-mediated gene expression is required for contextual memory formation

Nat. Neurosci.

Developmental expression of the CaM kinase II isoforms: ubiquitous gamma- and delta-CaM kinase II are the early isoforms and most abundant in the developing nervous system

Brain Res. Mol. Brain Res.

Transgenic calmodulin-dependent protein kinase II activation: dose-dependent effects on synaptic plasticity, learning, and memory

J. Neurosci.

Lead and neuropsychological function in children: progress and problems in establishing brain–behavior relationships

Adv. Child Neuropsychol.

Prevalence of blood lead levels > or = 5 micro g/dL among US children 1 to 5 years of age and socioeconomic and demographic factors associated with blood of lead levels 5 to 10 micro g/dL, Third National Health and Nutrition Examination Survey, 1988–1994

Pediatrics

The potential impacts of climate variability and change on air pollution-related health effects in the United States

Environ. Health Perspect.

Long-lasting potentiation of synaptic transmission in the dentate area of the anaesthetized rabbit following stimulation of the perforant path

J. Physiol.

Blood lead levels in residents of homes with elevated lead in tap water—District of Columbia, 2004

Morb. Mortal Wkly. Rep.

Updating about reductions of air and blood lead concentrations in Turin, Italy, following reductions in the lead content of gasoline

Environ. Res.

Deficient long-term memory in mice with a targeted mutation of the cAMP-responsive element-binding protein

Cell

Nitric oxide synthase regulatory sites. Phosphorylation by cyclic AMP-dependent protein kinase, protein kinase C, and calcium/calmodulin protein kinase; identification of flavin and calmodulin binding sites

J. Biol. Chem.

Molecular mechanisms of lead neurotoxicity

Neurochem. Res.

Functional implications of the subunit composition of neuronal CaM kinase II

J. Biol. Chem.

In situ hybridization histochemistry of Ca2+/calmodulin-dependent protein kinase in developing rat brain

J. Neurosci.

Late effects of lead poisoning on mental development

J. Dis. Child.

Learning-specific, time-dependent increases in hippocampal Ca2+/calmodulin-dependent protein kinase II activity and AMPA GluR1 subunit immunoreactivity

Eur. J. Neurosci.

Rapid and transient learning-associated increase in NMDA NR1 subunit in the rat hippocampus

Neurochem. Res.

Intellectual impairment in children with blood lead concentrations below 10 microg per deciliter

N. Engl. J. Med.

CaMKII-dependent phosphorylation of NR2A and NR2B is decreased in animals characterized by hippocampal damage and impaired LTP

Eur. J. Neurosci.

Activity-dependent decrease in NMDA receptor responses during development of the visual cortex

Science

Developmental models of brain dysfunctions induced by targeted cellular ablations with methylazoxymethanol

Physiol. Rev.

N-methyl-d-aspartate receptor-mediated bidirectional control of extracellular signal-regulated kinase activity in cortical neuronal cultures

J. Biol. Chem.

Developmental lead exposure and two-way active avoidance training alter the distribution of protein kinase C activity in the rat hippocampus

Neurochem. Res.

Developmental lead exposure alters the distribution of protein kinase C activity in the rat hippocampus

Biomed. Environ. Sci.

Perinatal lead exposure alters the expression of neuronal nitric oxide synthase in rat brain

Int. J. Toxicol.

Review
Lead neurotoxicity: From exposure to molecular effects

Sources and vectors of Pb²⁺

Experimental models of Pb²⁺ neurotoxicity

Effect of developmental exposure to Pb²⁺ on NMDA receptor subunit expression and function

Alterations in NMDAR-mediated calcium signaling pathways in Pb²⁺-exposed rats

Environmental enrichment: a therapeutic approach that reverses Pb²⁺-induced learning and molecular deficits