Molecular Neurobiology of Lead (Pb2+): Effects on Synaptic Function

Abstract

Lead (Pb 2+ ) is a ubiquitous environmental neurotoxicant that continues to threaten public health on a global scale. Epidemiological studies have demonstrated detrimental effects of Pb 2+ on childhood IQ at very low levels of exposure. Recently, a mechanistic understanding of how Pb 2+ affects brain development has begun to emerge. The cognitive effects of Pb 2+ exposure are believed to be mediated through its selective inhibition of the N-methyl-D-aspartate receptor (NMDAR). Studies in animal models of developmental Pb 2+ exposure exhibit altered NMDAR subunit ontogeny and disruption of NMDAR-dependent intracellular signaling. Additional studies have reported that Pb 2+ exposure inhibits presynaptic calcium (Ca 2+ ) channels and affects presynaptic neurotransmission, but a mechanistic link between presynaptic and postsynaptic effects has been missing. Recent work has suggested that the presynaptic and postsynaptic effects of Pb 2+ exposure are both due to inhibition of the NMDAR by Pb 2+ , and that the presynaptic effects of Pb 2+ may be mediated by disruption of NMDAR activity-dependent signaling of brainderived neurotrophic factor (BDNF). These findings provide the basis for the first working model to describe the effects of Pb 2+ exposure on synaptic function. Here, we review the neurotoxic effects of Pb 2+ exposure and discuss the known effects of Pb 2+ exposure in light of these recent findings. KeywordsLead; Neurotoxicology; NMDA Receptor; BDNF; Synaptogenesis; Neurotransmission Neurotoxicity of Low-Level Pb 2+ Exposure in ChildrenThe neurological effects of Pb 2+ have been a driving factor in reducing the level of human Pb 2+ exposure from anthropogenic and environmental sources. The first report of the effects of Pb 2+ on the cognitive abilities and social behavior in children was in 1943 [1], however, the full implications of these effects were not appreciated until decades later. Studies from the late 1970s to the early 1990s showed effects of Pb 2+ on cognitive abilities at progressively lower exposures [2]. In 1991, the CDC lowered the definition of Pb 2+ intoxication from 25 µg/dL blood lead level (BLL) to 10 µg/dL BLL, which is the current © Springer Science+Business Media, LLC 2010Correspondence to: Tomás R. Guilarte, trguilarte@columbia.edu. [4][5][6][7]. These studies indicate that the majority of the estimated IQ loss in Pb 2+ -exposed children occurs during the first 10 µg/dL of exposure, and suggest that Pb 2+ may be a non-threshold neurotoxicant [4][5][6][7][8]. NIH Public AccessIn addition to the cognitive deficits associated with Pb 2+ exposure, children with elevated BLLs have behavioral deficits. Several studies have reported that school children with elevated BLLs are more likely to be disruptive in class, display anti-social behavior, and have attention problems [1,[9][10][11][12]. These behavioral effects appear to have an attentiondeficit hyperactivity disorder (ADHD) phenotype; in fact, a recent study identified that childhood Pb 2+ exposure was positively associated with...

Adverse Outcome Pathway on chronic binding of antagonist to N-methyl-D-aspartate receptors (NMDARs) during brain development induces impairment of learning and memory abilities

“…Pb2+: Exposure to low levels of Pb2+, during early development, has been implicated in longlasting behavioural abnormalities and cognitive deficits in children (Needleman et al, 1975;Needleman and Gatsonis, 1990;Bellinger et al, 1991;Baghurst et al, 1992;Leviton et al, 1993;Needleman et al, 1996;Finkelstein et al, 1998;Lanphear et al, 2000;Canfield et al, 2003;Bellinger 2004;Lanphear et al, 2005;Surkan et al, 2007;Jusko et al, 2008;Neal and Guilarte, 2010) and experimental animals (Brockel and Cory-Slechta, 1998;Murphy and Regan, 1999;Moreira et al, 2001). Multiple lines of evidence suggest that Pb2+ can impair hippocampus-mediated learning in animal models (reviewed in .…”

“…However, another study suggests that toluene interference with the NMDA receptor might not be exclusively because of the binding to the channel pore (Smothers and Woodward, 2007) but it may involve some other binding sites. Lead (Pb2+) is considered a voltage independent antagonist of NMDA receptors and it is believed that possibly shares the same binding site with Zn2+ (reviewed in Neal and Guilarte, 2010;Traynelis et al, 2010). Mugnaini, M. et al (1996) …”

Contribution of diet to lead exposure among children aged 1 to 7 years in La Plata, Buenos Aires

“…Over the last years, it has been demonstrated that low lead levels are associated with adverse effects on neuropsychological development in the first years of life that may result in decreased intelligence that may even persist after childhood. 5 Since 2012, the United States Centers for Disease Control and Prevention (CDC) have established the reference blood lead level at 5 µg/dL for children, and 97.5% of children younger than 5 years in the US are under this value. 6 However, the threshold for blood lead levels with no adverse events on neurodevelopment has not been established yet.…”

Contribución de la dieta a la exposición al plomo de niños de 1 a 7 años en La Plata, Buenos Aires

“…En los últimos años, se ha demostrado que niveles bajos de plomo se asocian con efectos adversos sobre el desarrollo neuropsicológico en los primeros años de vida, capaces de causar una disminución de la inteligencia que puede persistir aún después de la niñez. 5 Artículo original plomo en sangre en niños en 5 µg/dl, valor por debajo del cual se encuentra el 97,5% de los niños menores de 5 años de EE.UU., 6 pero todavía no se ha establecido un umbral de niveles de plomo en sangre por debajo del cual no haya efectos adversos sobre el neurodesarrollo. 7 Los niños son más vulnerables frente a la exposición al plomo, debido a que tienen un mayor riesgo de ingerir plomo ambiental por su normal actividad mano-boca; la absorción de plomo por el tracto gastrointestinal es mayor en niños (25%) que en adultos (8%) 1 y el sistema nervioso en desarrollo es mucho más vulnerable a los efectos tóxicos del plomo que el cerebro maduro.…”

“…7 Los niños son más vulnerables frente a la exposición al plomo, debido a que tienen un mayor riesgo de ingerir plomo ambiental por su normal actividad mano-boca; la absorción de plomo por el tracto gastrointestinal es mayor en niños (25%) que en adultos (8%) 1 y el sistema nervioso en desarrollo es mucho más vulnerable a los efectos tóxicos del plomo que el cerebro maduro. 5 Varios factores ambientales, socioeconómicos y de hábitos de vida pueden ser considerados como determinantes de niveles de plomo en sangre elevados. 8,9 Particularmente en niños con bajos niveles de exposición (plombemia entre 5 y 10 µg/dL), se cree que el plomo proviene de múltiples fuentes.…”