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Introduction
As a pervasive environmental toxicant, lead (Pb) particularly impairs the functions of the neural system (Bellinger 2013; Toscano and Guilarte 2005). While policy limiting the use of Pb has been successful in reducing blood Pb levels in U.S. children (Jones et al. 2009), Pb levels in the environment remain high in many countries where Pb has not-or has only recently-been phased out from gasoline, paint, and other applications. In the United States, more than half a million 1- to 5-year-old children still have blood Pb levels exceeding 10 μg/dL, twice the current threshold of concern defined by the Centers for Disease Control and Prevention (CDC) (Jones et al. 2009). Pb exposure in children has been consistently linked to impaired neurological development and cognitive dysfunction as well as persistent antisocial and delinquent behavior (Bellinger et al. 1987; Canfield et al. 2003; Needleman et al. 1996). Recent incidences of Pb contamination in drinking water in several U.S. cities highlight the continued threat of Pb to public health, especially to children’s health (Bellinger 2016; Levin 2016).
Pb neurotoxicity is determined by intricate interplays between the metal and target neural cells, and there is overwhelming evidence documenting the detrimental effects of Pb in neurons. Seminal studies by Alkondon et al. (1990) and Guilarte and Miceli (1992) showed that Pb potently inhibits the NMDA receptor, which plays an essential role in brain development, synaptic plasticity, and learning and memory. Pb also inhibits the vesicular release of BDNF (brain-derived neurotrophic factor) and subsequent TrkB (tropomyosin-related kinase B) activation in the presynaptic neuron (Neal et al. 2010, 2011; Stansfield et al. 2012).
Pb exposure at the early stages of brain development has long-lasting effects on neurocognitive function. Prenatal Pb exposure has been associated with lower mental development index scores (Bellinger et al. 1987; Hu et al. 2006), and increased risk of schizophrenia later in life (Opler et al. 2004, 2008). In predictive models of mental developmental index (MDI), first trimester Pb exposure assessed in maternal blood was the most pronounced and statistically significant predictor when compared to exposure at any later stages (Hu et al. 2006). The particular susceptibility of early brain development to Pb exposure may be explained, in part, by the metal’s effects on neural stem cells (NSCs). As...