Manganese (Mn), a common naturally-occurring element, is second only to iron in terms of prevalence in the environment. It is considered an essential nutrient and is crucial for maintaining the proper function and regulation of many biological processes such as producing ATP and blood clotting. More prominently, Mn is a constituent of many enzymes involved in carbohydrate (pyruvate carboxylase) and protein (arginase) metabolism, is utilized by various antioxidant enzymes such as superoxide dismutase (MnSOD), and activates the glycosyltransferase necessary for the mucopolysaccharides utilized by cartilage, bone and other connective tissues (For a more detailed review, see: Hurley and Keen). The first reported cases of Mn deficiency were in chickens suffering from perosis, which later was discovered to be due to inadequate glycosyltransferase activity causing the malformed bones. This symptom of Mn deficiency manifests itself during the formation and growth of bones and connective tissues during development. In adult animals, including humans, Mn deficiency, which is extremely rare, is characterized by weight loss and blood clotting problems. Therefore, in humans pathologies associated with abnormal Mn biology revolve around exposure to excessive Mn and not its deficiency.
Mn is used in numerous industries including steel production, formulating gasoline anti-knock additives (methylcyclopentadienyl manganese tricarbonyl; MMT), mining, welding, battery assembly and glass and ceramics manufacturing. Considering this wide-spread use of Mn, it is important to identify populations that may be vulnerable to Mn intoxication, particularly since chronic Mn overexposure results in the onset of a neurological phenotype, known as manganism, which present with motor symptoms resembling those of Parkinson's disease (Aschner and Aschner, 1991
; Pal et al., 1999
; Lee, 2000
). Generally, airborne Mn is considered to be the most relevant route of exposure in occupational settings (Dorman et al., 2002
; Dobson et al., 2003
; Erikson et al., 2004a
; Aschner et al., 2005
; Erikson et al., 2005
). However, dystonia and movement disorders have been described in case reports of adults and children receiving prolonged total parenteral nutrition (TPN) and have been associated with magnetic resonance imaging (MRI) abnormalities suggesting Mn-associated changes in the basal ganglia.
Mn deposition in the brain has potentially important implications for long-term neurodevelopmental outcome in exposed infants. In monkeys and rats, a correlation exists between the severity of central nervous system (CNS) symptoms and Mn brain concentrations, with both the rate and extent of Mn transport into the CNS influencing the clinical outcome (Suzuki et al., 1975
; Roels et al., 1997
). In neonatal rats, high dietary Mn intake resulted in developmental deficits (Tran et al, 2002
). It has been observed that infants who require prolonged parenteral nutrition during their early neonatal course have worse developmental outcomes than gestational age-matched control infants, even after correcting for confounders such as respiratory complications and socioeconomic status (Morris et al., 1999
). While the explanation for this discrepancy in developmental outcomes is undoubtedly complex and multi-factorial, the potential contribution of Mn toxicity to the poor outcomes of infants dependent for an extended time on parenteral nutrition has not been fully acknowledged or studied. Neither is information available on the contribution of co-morbidities such as iron deficiency and cholestasis to the ability of the neonatal brain to regulate Mn uptake. It is known that increases in blood and brain Mn levels have been reported in persons with liver disease (Spahr et al., 1996
; Rose et al., 1999
); and data suggest that iron (Fe) deficiency may be a risk factor for Mn neurotoxicity (Ellingsen et al., 2003
; Erikson et al., 2002a
; Erikson et al., 2004a
). This last point is especially relevant considering the prevalency of Fe deficiency throughout the world (approximately 2 billion people are affected).
This review will focus primarily on the neurotoxicity of Mn in the neonate. We will discuss putative transporters of the metal in the neonatal brain and then focus on the implications of high Mn exposure to the neonate focusing on typical exposure modes (e.g., dietary and parenteral). Although Mn-exposure via parenteral nutrition is uncommon in adults, in premature infants, it is more prevalent, so this mode of exposure becomes salient in this population. We will conclude with a discussion of ripe areas for research in this underreported area.