New and evolving concepts in the neurotoxicology of lead

L.D. WHITE, D.A. CORY-SLECHTA, M.E. GILBERT, E. TIFFANY-CASTIGLIONI,N.H. ZAWIA, M. VIRGOLINI, A. ROSSI-GEORGE, S.M. LASLEY, Y. QIAN, MD. RIYAZ.BASHA.

TOXICOLOGY AND APPLIED PHARMACOLOGY

ACADEMIC PRESS INC ELSEVIER SCIENCE

Año: 2007 vol. 225 p. 1 - 27

0041-008X

Lead (Pb) is a xenobiotic metal with no known essential function in cellular growth, proliferation, or signaling. Decades of research characterizingthe toxicology of Pb have shown it to be a potent neurotoxicant, especially during nervous system development. New concepts in the neurotoxicologyof Pb include advances in understanding the mechanisms and cellular specificity of Pb. Experimental studies have shown that stress can significantlyalter the effects of Pb, effects that could potentially be mediated through alterations in the interactions of glucocorticoids with the mesocorticolimbicdopamine system of the brain. Elevated stress, with corresponding elevated glucocorticoid levels, has been postulated to contribute to the increasedlevels of many diseases and dysfunctions in low socioeconomic status populations. Cellular models of learning and memory have been utilized toinvestigate the potential mechanisms of Pb-induced cognitive deficits. Examination of long-term potentiation in the rodent hippocampus has revealedPb-induced increases in threshold, decreases in magnitude, and shorter retention times of synaptic plasticity. Structural plasticity in the form of adultneurogenesis in the hippocampus is also impacted by Pb exposure. The action of Pb on glutamate release, NMDA receptor function, or structuralplasticity may underlie perturbations in synaptic plasticity and contribute to learning impairments. In addition to providing insight into potentialmechanisms of Pb-induced cognitive deficits, cellular models offer an opportunity to investigate direct effects of Pb on isolated biological substrates.A target of interest is the 78-kDa molecular chaperone glucose-regulated protein (GRP78). GRP78 chaperones the secretion of the cytokineinterleukin-6 (IL-6) by astrocytes. In vitro evidence shows that Pb strongly binds to GRP78, induces GRP78 aggregation, and blocks IL-6 secretion inastroglial cells. These findings provide evidence for a significant chaperone deficiency in Pb-exposed astrocytes in culture. In the long term,chaperone deficiency could underlie protein conformational diseases such as Alzheimer?s Disease (AD). Lead exposure in early life has beenimplicated in subsequent progression of amyloidogenesis in rodents during old age. This exposure resulted in an increase in proteins associated withAD pathology viz., beta-amyloid precursor protein (β-APP), and beta-amyloid (Aβ). These four new lines of research comprise compelling evidencethat exposures to Pb have adverse effects on the nervous system, that environmental factors increase nervous system susceptibility to Pb, and thatexposures in early life may cause neurodegeneration in later life.© 2007 Elsevier Inc. All rights reserved.