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Introduction
Manganese (Mn) is a trace essential element, necessary for physiologic processes such as neuronal function (Prohaska 1987; Sloot and Gramsbergen 1994), protein and energy metabolism, bone growth (Aschner and Aschner 2005; Hurley 1981), and enzyme activation (Erikson and Aschner 2003). During fetal and neonatal development, there is an increased need for manganese due to its critical role in brain function and skeletal development (Hurley 1981). Manganese crosses the placenta via active transport (Yoon et al. 2009), likely reflecting fetal nutrient demand. However, excess or accumulated manganese exposure can be neurotoxic and has been associated with deficits in cognition and motor function (Sanders et al. 2015; Zoni and Lucchini 2013). Little is known about how manganese transfer from the mother is regulated. The way in which manganese is partitioned in the maternal/fetal unit may be an important factor in fetal development (Kopp et al. 2012).
Concerns about heightened potential sensitivity to manganese neurotoxicity during fetal and early life compared to adulthood have recently been raised. Research is complicated by the increased fetal demand for manganese during development, as well as the unique physiology of the fetus and infant in which rapid growth makes it susceptible to nutrient deficiency. Increasing maternal blood manganese levels during pregnancy may by a physiologic response to this fetal demand, but the optimal range of manganese levels has not been determined and it remains unclear at what level maternal blood manganese may become harmful to the fetus. Manganese crosses the blood–brain barrier in the fetus at a higher rate than in adults, based on animal experimental data (Cahill et al. 1980; Kostial et al. 1978; Takeda et al. 1999). Because of the developing brain’s high oxygen and energy consumption, it is sensitive to oxidative stress and damage from free radicals that can result from elevated manganese exposure (Blomgren and Hagberg 2006; Buonocore et al. 2001; Ikonomidou and Kaindl 2011). Given that neurodevelopment occurs as a cascade of well-timed, regulated events, exposure to toxic insults can cause damage at any stage, which may impair subsequent processes and result in developmental disability (Nowakowski and Hayes 1999).
Environmental manganese exposure has been associated with various neurodevelopmental outcomes among school-age children (Bouchard et al. 2011; Khan et al. 2012; Oulhote et al. 2014a; Wasserman et...