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Is early-life iron exposure critical in neurodegeneration?

Nature Reviews Neurology volume 11, pages 536–544 (2015)Cite this article

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Abstract

The effects of iron deficiency are well documented, but relatively little is known about the long-term implications of iron overload during development. High levels of redox-active iron in the brain have been associated with neurodegenerative disorders, most notably Parkinson disease, yet a gradual increase in brain iron seems to be a feature of normal ageing. Increased brain iron levels might result from intake of infant formula that is excessively fortified with iron, thereby altering the trajectory of brain iron uptake and amplifying the risk of iron-associated neurodegeneration in later life. In this Perspectives article, we discuss the potential long-term implications of excessive iron intake in early life, propose the analysis of iron deposits in teeth as a method for retrospective determination of iron exposure during critical developmental windows, and call for evidence-based optimization of the chemical composition of infant dietary supplements.

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Figure 1: Mechanisms of uptake of dietary iron in the developing brain.
Figure 2: Proposed progression of iron accumulation in the brain when dietary iron levels vary at an early age.
Figure 3: A novel dental biomarker of metal intake in early life.

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References

  1. Beard, J. L. Iron biology in immune function, muscle metabolism and neuronal functioning. J. Nutr. 131, 568S–579S (2001).

    Article  CAS  PubMed  Google Scholar 

  2. Weinberg, E. D. The Lactobacillus anomaly: total iron abstinence. Perspect. Biol. Med. 40, 578–583 (1997).

    Article  CAS  PubMed  Google Scholar 

  3. Aguirre, J. D. et al. A manganese-rich environment supports superoxide dismutase activity in a Lyme disease pathogen, Borrelia burgdorferi. J. Biol. Chem. 288, 8468–8478 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Beard, J. L., Connor, J. R. & Jones, B. C. Iron in the brain. Nutr. Rev. 51, 157–170 (1993).

    Article  CAS  PubMed  Google Scholar 

  5. Beard, J. Iron deficiency alters brain development and functioning. J. Nutr. 133, 1468S–1472S (2003).

    Article  CAS  PubMed  Google Scholar 

  6. Ziegler, E. E., Nelson, S. E. & Jeter, J. M. Iron supplementation of breastfed infants from an early age. Am. J. Clin. Nutr. 89, 525–532 (2009).

    Article  CAS  PubMed  Google Scholar 

  7. Lozoff, B. & Georgieff, M. K. Iron deficiency and brain development. Semin. Pediatr. Neurol. 13, 158–165 (2006).

    Article  PubMed  Google Scholar 

  8. Carter, R. C. et al. Iron deficiency anemia and cognitive function in infancy. Pediatrics 126, e427–e434 (2010).

    Article  PubMed  Google Scholar 

  9. World Health Organization. Worldwide prevalence of anaemia 1993–2005: WHO global database on anaemia. World Health Organization Institutional Repository for Information Sharing [online], (2008).

  10. Zimmermann, M. B. & Hurrell, R. F. Nutritional iron deficiency. Lancet 370, 511–520 (2007).

    Article  CAS  PubMed  Google Scholar 

  11. Horta, B., Victora, C. & World Health Organization. Long-term effects of breastfeeding: a systematic review. World Health Organization Institutional Repository for Information Sharing [online]. (2013).

    Google Scholar 

  12. Ibanez, G. et al. Prevalence of breastfeeding in industrialized countries. Rev. Epidemiol. Sante Publique 60, 305–320 (2012).

    Article  CAS  PubMed  Google Scholar 

  13. Kong, S. K. & Lee, D. T. Factors influencing decision to breastfeed. J. Adv. Nurs. 46, 369–379 (2004).

    Article  PubMed  Google Scholar 

  14. Obladen, M. Historic records on the commercial production of infant formula. Neonatology 106, 173–180 (2014).

    Article  CAS  PubMed  Google Scholar 

  15. Forsyth, S. Non-compliance with the International Code of Marketing of Breast Milk Substitutes is not confined to the infant formula industry. J. Public Health (Oxf.) 35, 185–190 (2013).

    Article  Google Scholar 

  16. Lucas, A. et al. Efficacy and safety of long-chain polyunsaturated fatty acid supplementation of infant-formula milk: a randomised trial. Lancet 354, 1948–1954 (1999).

    Article  CAS  PubMed  Google Scholar 

  17. Saarinen, U. M. Need for iron supplementation in infants on prolonged breast feeding. J. Pediatr. 93, 177–180 (1978).

    Article  CAS  PubMed  Google Scholar 

  18. Siimes, M. A., Salmenperä, L. & Perheentupa, J. Exclusive breast-feeding for 9 months: risk of iron deficiency. J. Pediatr. 104, 196–199 (1984).

    Article  CAS  PubMed  Google Scholar 

  19. Lowe, C. U. et al. Iron balance and requirements in infancy. Pediatrics 43, 134–142 (1969).

    Google Scholar 

  20. McMillan, J. A., Landaw, S. A. & Oski, F. A. Iron sufficiency in breast-fed infants and the availability of iron from human milk. Pediatrics 58, 686–691 (1976).

    CAS  PubMed  Google Scholar 

  21. [No authors listed] American Academy of Pediatrics Committee on Nutrition: Iron-fortified infant formulas. Pediatrics 84, 1114–1115 (1989).

  22. [No authors listed] Iron fortification of infant formulas. American Academy of Pediatrics. Committee on Nutrition. Pediatrics 104, 119–123 (1999).

  23. Baker, R. D., Greer, F. R. & Committee on Nutrition American Academy of Pediatrics. Diagnosis and prevention of iron deficiency and iron-deficiency anemia in infants and young children (0–3 years of age). Pediatrics 126, 1040–1050 (2010).

    Article  PubMed  Google Scholar 

  24. Koletzko, B. et al. Global standard for the composition of infant formula: recommendations of an ESPGHAN coordinated international expert group. J. Pediatr. Gastroenterol. Nutr. 41, 584–599 (2005).

    Article  PubMed  Google Scholar 

  25. Domellöf, M. et al. Iron requirements of infants and toddlers. J. Pediatr. Gastroenterol. Nutr. 58, 119–129 (2014).

    Article  CAS  PubMed  Google Scholar 

  26. MacLean, W. C. Jr et al. Upper levels of nutrients in infant formulas: comparison of analytical data with the revised Codex infant formula standard. J. Food Comp. Anal. 23, 44–53 (2010).

    Article  CAS  Google Scholar 

  27. Singhal, A. et al. Clinical safety of iron-fortified formulas. Pediatrics 105, E38 (2000).

    Article  CAS  PubMed  Google Scholar 

  28. Sachdev, H., Gera, T. & Nestel, P. Effect of iron supplementation on mental and motor development in children: systematic review of randomised controlled trials. Public Health Nutr. 8, 117–132 (2005).

    Article  PubMed  Google Scholar 

  29. Friel, J. K. et al. A double-masked, randomized control trial of iron supplementation in early infancy in healthy term breast-fed infants. J. Pediatr. 143, 582–586 (2003).

    Article  CAS  PubMed  Google Scholar 

  30. Berglund, S., Westrup, B. & Domellöf, M. Iron supplements reduce the risk of iron deficiency anemia in marginally low birth weight infants. Pediatrics 126, e874–e883 (2010).

    Article  PubMed  Google Scholar 

  31. Lozoff, B., Castillo, M., Clark, K. M. & Smith, J. B. Iron-fortified vs low-iron infant formula: developmental outcome at 10 years. Arch. Pediatr. Adolesc. Med. 166, 208–215 (2012).

    Article  PubMed  Google Scholar 

  32. Hernell, O. & Lönnerdal, B. Recommendations on iron questioned. Pediatrics 127, e1099–e1101 (2011).

    Article  PubMed  Google Scholar 

  33. Furman, L. M. Exclusively breastfed infants: iron recommendations are premature. Pediatrics 127, e1098–e1099 (2011).

    Article  PubMed  Google Scholar 

  34. AAP Section on Breastfeeding et al. Concerns with early universal iron supplementation of breastfeeding infants. Pediatrics 127, e1097 (2011).

  35. de la Flor St Remy, R. R., Sánchez, M. L., Sastre, J. B. & Sanz-Medel, A. Multielemental distribution patterns in premature human milk whey and pre-term formula milk whey by size exclusion chromatography coupled to inductively coupled plasma mass spectrometry with octopole reaction cell. J. Anal. At. Spectrom. 19, 1104–1110 (2004).

    Article  CAS  Google Scholar 

  36. Arosio, P., Ferrero, R. & Ponzone, A. Ferritin in human milk. Acta Paediatr. Scand. 73, 271–272 (1984).

    Article  CAS  PubMed  Google Scholar 

  37. Lönnerdal, B. Bioactive proteins in breast milk. J. Paediatr. Child Health 49 (Suppl. 1), 1–7 (2013).

    Article  PubMed  Google Scholar 

  38. Lönnerdal, B. Infant formula and infant nutrition: bioactive proteins of human milk and implications for composition of infant formulas. Am. J. Clin. Nutr. 99, 712S–717S (2014).

    Article  CAS  PubMed  Google Scholar 

  39. Domellöf, M., Lönnerdal, B., Dewey, K. G., Cohen, R. J. & Hernell, O. Iron, zinc, and copper concentrations in breast milk are independent of maternal mineral status. Am. J. Clin. Nutr. 79, 111–115 (2004).

    Article  PubMed  Google Scholar 

  40. Rai, D. et al. Longitudinal changes in lactoferrin concentrations in human milk: a global systematic review. Crit. Rev. Food Sci. Nutr. 54, 1539–1547 (2014).

    Article  CAS  PubMed  Google Scholar 

  41. Davidsson, L., Kastenmayer, P., Yuen, M., Lönnerdal, B. O. & Hurrell, R. F. Influence of lactoferrin on iron absorption from human milk in infants. Pediatr. Res. 35, 117–124 (1994).

    Article  CAS  PubMed  Google Scholar 

  42. Fairweather-Tait, S. J., Balmer, S. E., Scott, P. H. & Minski, M. J. Lactoferrin and iron absorption in newborn infants. Pediatr. Res. 22, 651–654 (1987).

    Article  CAS  PubMed  Google Scholar 

  43. Stekel, A. et al. Absorption of fortification iron from milk formulas in infants. Am. J. Clin. Nutr. 43, 917–922 (1986).

    Article  CAS  PubMed  Google Scholar 

  44. Abrams, S. A., Wen, J. & Stuff, J. E. Absorption of calcium, zinc, and iron from breast milk by five- to seven-month-old infants. Pediatr. Res. 41, 384–390 (1997).

    Article  CAS  PubMed  Google Scholar 

  45. Mainous, A. G. 3rd, Wells, B., Carek, P. J., Gill, J. M. & Geesey, M. E. The mortality risk of elevated serum transferrin saturation and consumption of dietary iron. Ann. Fam. Med. 2, 139–144 (2004).

    Article  PubMed  PubMed Central  Google Scholar 

  46. Acikyol, B. et al. Brain transcriptome perturbations in the transferrin receptor 2 mutant mouse support the case for brain changes in iron loading disorders, including effects relating to long-term depression and long-term potentiation. Neuroscience 235, 119–128 (2013).

    Article  CAS  PubMed  Google Scholar 

  47. Nandar, W. & Connor, J. R. HFE gene variants affect iron in the brain. J. Nutr. 141, 29S–739S (2011).

    Article  CAS  Google Scholar 

  48. Sobotka, T. J. et al. Neurobehavioral dysfunctions associated with dietary iron overload. Physiol. Behav. 59, 213–219 (1996).

    Article  CAS  PubMed  Google Scholar 

  49. Fredriksson, A., Schröder, N., Eriksson, P., Izquierdo, I. & Archer, T. Neonatal iron exposure induces neurobehavioural dysfunctions in adult mice. Toxicol. Appl. Pharmacol. 159, 25–30 (1999).

    Article  CAS  PubMed  Google Scholar 

  50. Piñero, D. J., Li, N. Q., Connor, J. R. & Beard, J. L. Variations in dietary iron alter brain iron metabolism in developing rats. J. Nutr. 130, 254–263 (2000).

    Article  PubMed  Google Scholar 

  51. Dornelles, A. S. et al. mRNA expression of proteins involved in iron homeostasis in brain regions is altered by age and by iron overloading in the neonatal period. Neurochem. Res. 35, 564–571 (2010).

    Article  CAS  PubMed  Google Scholar 

  52. Miwa, C. P. et al. Neonatal iron treatment increases apoptotic markers in hippocampal and cortical areas of adult rats. Neurotox. Res. 19, 527–535 (2011).

    Article  CAS  PubMed  Google Scholar 

  53. Fernandez, L. L. et al. Early post-natal iron administration induces astroglial response in the brain of adult and aged rats. Neurotox. Res. 20, 193–199 (2011).

    Article  CAS  PubMed  Google Scholar 

  54. Saarinen, U. M., Siimes, M. A. & Dallman, P. R. Iron absorption in infants: high bioavailability of breast milk iron as indicated by the extrinsic tag method of iron absorption and by the concentration of serum ferritin. J. Pediatr. 91, 36–39 (1977).

    Article  CAS  PubMed  Google Scholar 

  55. Lönnerdal, B. & Bryant, A. Absorption of iron from recombinant human lactoferrin in young US women. Am. J. Clin. Nutr. 83, 305–309 (2006).

    Article  PubMed  Google Scholar 

  56. Rao, R. et al. Iron supplementation dose for perinatal iron deficiency differentially alters the neurochemistry of the frontal cortex and hippocampus in adult rats. Pediatr. Res. 73, 31–37 (2013).

    Article  CAS  PubMed  Google Scholar 

  57. Unger, E. L. et al. Behavior and monoamine deficits in prenatal and perinatal iron deficiency are not corrected by early postnatal moderate-iron or high-iron diets in rats. J. Nutr. 142, 2040–2049 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Lugonja, N. et al. Differences in direct pharmacologic effects and antioxidative properties of mature breast milk and infant formulas. Nutrition 29, 431–435 (2013).

    Article  CAS  PubMed  Google Scholar 

  59. Zecca, L., Youdim, M. B., Riederer, P., Connor, J. R. & Crichton, R. R. Iron, brain ageing and neurodegenerative disorders. Nat. Rev. Neurosci. 5, 863–873 (2004).

    Article  CAS  PubMed  Google Scholar 

  60. Ghadery, C. et al. R2* mapping for brain iron: associations with cognition in normal aging. Neurobiol. Aging 36, 925–932 (2015).

    Article  CAS  PubMed  Google Scholar 

  61. Rodrigue, K. M., Haacke, E. M. & Raz, N. Differential effects of age and history of hypertension on regional brain volumes and iron. Neuroimage 54, 750–759 (2011).

    Article  PubMed  Google Scholar 

  62. Callaghan, M. F. et al. Widespread age-related differences in the human brain microstructure revealed by quantitative magnetic resonance imaging. Neurobiol. Aging 35, 1862–1872 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  63. Ward, R. J., Zucca, F. A., Duyn, J. H., Crichton, R. R. & Zecca, L. The role of iron in brain ageing and neurodegenerative disorders. Lancet Neurol. 13, 1045–1060 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Berg, D. & Youdim, M. B. Role of iron in neurodegenerative disorders. Top. Magn. Reson. Imaging 17, 5–17 (2006).

    Article  PubMed  Google Scholar 

  65. Berg, D. et al. Brain iron pathways and their relevance to Parkinson's disease. J. Neurochem. 79, 225–236 (2001).

    Article  CAS  PubMed  Google Scholar 

  66. Lhermitte, J., Kraus, W. M. & McAlpine, D. On the occurrence of abnormal deposits of iron in the brain in parkinsonism with special reference to its localisation. J. Neurol. Psychopathol. 5, 195–208 (1924).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Sulzer, D. et al. Neuromelanin biosynthesis is driven by excess cytosolic catecholamines not accumulated by synaptic vesicles. Proc. Natl Acad. Sci. USA 97, 11869–11874 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Zecca, L. et al. Substantia nigra neuromelanin: structure, synthesis, and molecular behaviour. Mol. Pathol. 54, 414–418 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Bohic, S. et al. Intracellular chemical imaging of the developmental phases of human neuromelanin using synchrotron X-ray microspectroscopy. Anal. Chem. 80, 9557–9566 (2008).

    Article  CAS  PubMed  Google Scholar 

  70. Lei, P. et al. Tau deficiency induces parkinsonism with dementia by impairing APP-mediated iron export. Nat. Med. 18, 291–295 (2012).

    Article  CAS  PubMed  Google Scholar 

  71. Ayton, S. et al. Ceruloplasmin dysfunction and therapeutic potential for Parkinson disease. Ann. Neurol. 73, 554–559 (2013).

    Article  CAS  PubMed  Google Scholar 

  72. Jin, L. et al. Decreased serum ceruloplasmin levels characteristically aggravate nigral iron deposition in Parkinson's disease. Brain 134, 50–58 (2011).

    Article  PubMed  Google Scholar 

  73. Wang, Z. et al. DJ-1 modulates the expression of Cu/Zn-superoxide dismutase-1 through the Erk1/2-Elk1 pathway in neuroprotection. Ann. Neurol. 70, 591–599 (2011).

    Article  CAS  PubMed  Google Scholar 

  74. Rouault, T. A. Iron metabolism in the CNS: implications for neurodegenerative diseases. Nat. Rev. Neurosci. 14, 551–564 (2013).

    Article  CAS  PubMed  Google Scholar 

  75. Lovell, M. A., Robertson, J. D., Teesdale, W. J., Campbell, J. L. & Markesbery, W. R. Copper, iron and zinc in Alzheimer's disease senile plaques. J. Neurol. Sci. 158, 47–52 (1998).

    Article  CAS  PubMed  Google Scholar 

  76. Smith, M. A., Harris, P. L., Sayre, L. M. & Perry, G. Iron accumulation in Alzheimer disease is a source of redox-generated free radicals. Proc. Natl Acad. Sci. USA 94, 9866–9868 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Schrag, M., Mueller, C., Oyoyo, U., Smith, M. A. & Kirsch, W. M. Iron, zinc and copper in the Alzheimer's disease brain: a quantitative meta-analysis. Some insight on the influence of citation bias on scientific opinion. Prog. Neurobiol. 94, 296–306 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Duce, J. A. et al. Iron-export ferroxidase activity of β-amyloid precursor protein is inhibited by zinc in Alzheimer's disease. Cell 142, 857–867 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Smith, M. A. et al. Increased iron and free radical generation in preclinical Alzheimer disease and mild cognitive impairment. J. Alzheimers Dis. 19, 363–372 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Antharam, V. et al. High field magnetic resonance microscopy of the human hippocampus in Alzheimer's disease: quantitative imaging and correlation with iron. Neuroimage 59, 1249–1260 (2012).

    Article  PubMed  Google Scholar 

  81. Raven, E. P., Lu, P. H., Tishler, T. A., Heydari, P. & Bartzokis, G. Increased iron levels and decreased tissue integrity in hippocampus of Alzheimer's disease detected in vivo with magnetic resonance imaging. J. Alzheimers Dis. 37, 127–136 (2013).

    Article  CAS  PubMed  Google Scholar 

  82. Hametner, S. et al. Iron and neurodegeneration in the multiple sclerosis brain. Ann. Neurol. 74, 848–861 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Faux, N. G. et al. An anemia of Alzheimer's disease. Mol. Psychiatr. 19, 1227–1234 (2014).

    Article  CAS  Google Scholar 

  84. Pichler, I. et al. Serum iron levels and the risk of parkinson disease: a Mendelian randomization study. PLoS Med. 10, e1001462 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Ali-Rahmani, F., Schengrund, C. L. & Connor, J. R. HFE gene variants, iron, and lipids: a novel connection in Alzheimer's disease. Front. Pharmacol. 5, 165 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. de Lau, L. M. & Breteler, M. M. Epidemiology of Parkinson's disease. Lancet Neurol. 5, 525–535 (2006).

    Article  PubMed  Google Scholar 

  87. Zhu, X., Raina, A. K., Perry, G. & Smith, M. A. Alzheimer's disease: the two-hit hypothesis. Lancet Neurol. 3, 219–226 (2004).

    Article  CAS  PubMed  Google Scholar 

  88. Doraiswamy, P. M. & Finefrock, A. E. Metals in our minds: therapeutic implications for neurodegenerative disorders. Lancet Neurol. 3, 431–434 (2004).

    Article  CAS  PubMed  Google Scholar 

  89. Devos, D. et al. Targeting chelatable iron as a therapeutic modality in Parkinson's disease. Antioxid. Redox Signal. 21, 195–210 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Kaur, D. et al. Genetic or pharmacological iron chelation prevents MPTP-induced neurotoxicity in vivo: a novel therapy for Parkinson's disease. Neuron 37, 899–909 (2003).

    Article  CAS  PubMed  Google Scholar 

  91. Kaur, D. et al. Increased murine neonatal iron intake results in Parkinson-like neurodegeneration with age. Neurobiol. Aging 28, 907–913 (2007).

    Article  CAS  PubMed  Google Scholar 

  92. Fernandez, L. L. et al. Effects of increased iron intake during the neonatal period on the brain of adult AβPP/PS1 transgenic mice. J. Alzheimers Dis. 19, 1069–1080 (2010).

    Article  CAS  PubMed  Google Scholar 

  93. Becerril-Ortega, J., Bordji, K., Fréret, T., Rush, T. & Buisson, A. Iron overload accelerates neuronal amyloid-β production and cognitive impairment in transgenic mice model of Alzheimer's disease. Neurobiol. Aging 35, 2288–2301 (2014).

    Article  CAS  PubMed  Google Scholar 

  94. Erikson, K. M., Pinero, D. J., Connor, J. R. & Beard, J. L. Regional brain iron, ferritin and transferrin concentrations during iron deficiency and iron repletion in developing rats. J. Nutr. 127, 2030–2038 (1997).

    Article  CAS  PubMed  Google Scholar 

  95. Powers, K. M. et al. Parkinson's disease risks associated with dietary iron, manganese, and other nutrient intakes. Neurology 60, 1761–1766 (2003).

    Article  CAS  PubMed  Google Scholar 

  96. Benarroch, E. E. Brain iron homeostasis and neurodegenerative disease. Neurology 72, 1436–1440 (2009).

    Article  PubMed  Google Scholar 

  97. Morris, C. M. et al. Brain iron homeostasis. J. Inorg. Biochem. 47, 257–265 (1992).

    Article  CAS  PubMed  Google Scholar 

  98. Zecca, L. et al. The role of iron and copper molecules in the neuronal vulnerability of locus coeruleus and substantia nigra during aging. Proc. Natl Acad. Sci. USA 101, 9843–9848 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Hare, D. J. et al. An iron–dopamine index predicts risk of parkinsonian neurodegeneration in the substantia nigra pars compacta. Chem. Sci. 5, 2160–2169 (2014).

    Article  CAS  Google Scholar 

  100. Hunt, J. R., Zito, C. A. & Johnson, L. K. Body iron excretion by healthy men and women. Am. J. Clin. Nutr. 89, 1792–1798 (2009).

    Article  CAS  PubMed  Google Scholar 

  101. Arora, M. & Austin, C. Teeth as a biomarker of past chemical exposure. Curr. Opin. Pediatr. 25, 261–267 (2013).

    Article  CAS  PubMed  Google Scholar 

  102. Hare, D., Austin, C., Doble, P. & Arora, M. Elemental bio-imaging of trace elements in teeth using laser ablation-inductively coupled plasma-mass spectrometry. J. Dent. 39, 397–403 (2011).

    Article  CAS  PubMed  Google Scholar 

  103. Gunier, R. B. et al. Determinants of manganese in prenatal dentin of shed teeth from CHAMACOS children living in an agricultural community. Environ. Sci. Technol. 47, 11249–11257 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Arora, M., Hare, D., Austin, C., Smith, D. R. & Doble, P. Spatial distribution of manganese in enamel and coronal dentine of human primary teeth. Sci. Total Environ. 409, 1315–1319 (2011).

    Article  CAS  PubMed  Google Scholar 

  105. Austin, C. et al. Barium distributions in teeth reveal early-life dietary transitions in primates. Nature 498, 216–219 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Bauminger, E., Ofer, S., Gedalia, I., Horowitz, G. & Mayer, I. Iron uptake by teeth and bones: a Mossbauer effect study. Calcif. Tissue Int. 37, 386–389 (1985).

    Article  CAS  PubMed  Google Scholar 

  107. Garfunkel, A., Kantzuker, M., Gedalia, I. & Chevion, M. Iron concentration in teeth of patients with and without beta-thalassaemia major. Arch. Oral Biol. 24, 829–831 (1979).

    Article  CAS  PubMed  Google Scholar 

  108. Ash, M. M. & Nelson, S. J. Wheeler's Dental Anatomy, Physiology and Occlusion 8th edn (WB Saunders, 2003).

    Google Scholar 

  109. Fildes, V. Breasts, Bottles and Babies—A History of Infant Feeding (Edinburgh University Press, 1986).

    Google Scholar 

  110. Bermejo, P. et al. Speciation of iron in breast milk and infant formulas whey by size exclusion chromatography–high performance liquid chromatography and electrothermal atomic absorption spectrometry. Talanta 50, 1211–1222 (2000).

    Article  CAS  PubMed  Google Scholar 

  111. Björklund, K. L. et al. Metals and trace element concentrations in breast milk of first time healthy mothers: a biological monitoring study. Environ. Health 11, 92 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Ejezie, F. E., Nwagha, U. I., Ikekpeazu, E., Ozoemena, O. & Onwusi, E. Assessment of iron content of breast milk in preterm and term mothers in Enugu urban. Ann. Med. Health Sci. Res. 1, 85–90 (2011).

    PubMed  PubMed Central  Google Scholar 

  113. Krachler, M., Prohaska, T., Koellensperger, G., Rossipal, E. & Stingeder, G. Concentrations of selected trace elements in human milk and in infant formulas determined by magnetic sector field inductively coupled plasma-mass spectrometry. Biol. Trace Elem. Res. 76, 97–112 (2000).

    Article  CAS  PubMed  Google Scholar 

  114. Leotsinidis, M., Alexopoulos, A. & Kostopoulou-Farri, E. Toxic and essential trace elements in human milk from Greek lactating women: association with dietary habits and other factors. Chemosphere 61, 238–247 (2005).

    Article  CAS  PubMed  Google Scholar 

  115. Maru, M., Birhanu, T. & Tessema, D. A. Calcium, magnesium, iron, zinc and copper, compositions of human milk from populations with cereal and 'enset' based diets. Ethiop. J. Health Sci. 23, 90–97 (2013).

    PubMed  PubMed Central  Google Scholar 

  116. Mello-Neto, J. et al. Iron supplementation in pregnancy and breastfeeding and iron, copper and zinc status of lactating women from a human milk bank. J. Trop. Pediatr. 59, 140–144 (2013).

    Article  PubMed  Google Scholar 

  117. Mello-Neto, J. et al. Iron concentrations in breast milk and selected maternal factors of human milk bank donors. J. Hum. Lact. 26, 175–179 (2010).

    Article  PubMed  Google Scholar 

  118. World Health Organization & International Atomic Energy Agency. Minor and trace elements in breast milk: report of a joint WHO/IAEA collaborative study. World Health Organization Institutional Repository for Information Sharing [online], (1989).

  119. Johnson, M. A., Smith, M. M. & Edmonds, J. T. Copper, iron, zinc, and manganese in dietary supplements, infant formulas, and ready-to-eat breakfast cereals. Am. J. Clin. Nutr. 67 (5 Suppl.), 1035S–1040S (1998).

    Article  CAS  PubMed  Google Scholar 

  120. Ljung, K., Palm, B., Grandér, M. & Vahter, M. High concentrations of essential and toxic elements in infant formula and infant foods—a matter of concern. Food Chem. 127, 943–951 (2011).

    Article  CAS  PubMed  Google Scholar 

  121. Saarinen, U. M. & Siimes, M. A. Iron absorption from infant milk formula and the optimal level of iron supplementation. Acta Paediatr. Scand. 66, 719–722 (1977).

    Article  CAS  PubMed  Google Scholar 

  122. Walter, T., Pino, P., Pizarro, F. & Lozoff, B. Prevention of iron-deficiency anemia: comparison of high- and low-iron formulas in term healthy infants after six months of life. J. Pediatr. 132, 635–640 (1998).

    Article  CAS  PubMed  Google Scholar 

  123. Chemizmu, K. & Fentona, R. Fenton reaction—controversy concerning the chemistry. Ecol. Chem. Eng. S. 16, 347–358 (2009).

    Google Scholar 

  124. Bartzokis, G. et al. Brain ferritin iron may influence age- and gender-related risks of neurodegeneration. Neurobiol. Aging 28, 414–423 (2007).

    Article  CAS  PubMed  Google Scholar 

  125. Schipper, H. M. Heme oxygenase-1: role in brain aging and neurodegeneration. Exp. Gerontol. 35, 821–830 (2000).

    Article  CAS  PubMed  Google Scholar 

  126. Schipper, H. M. Brain iron deposition and the free radical–mitochondrial theory of ageing. Ageing Res. Rev. 3, 265–301 (2004).

    Article  CAS  PubMed  Google Scholar 

  127. Chen, J. H., Singh, N., Tay, H. & Walczyk, T. Imbalance of iron influx and efflux causes brain iron accumulation over time in the healthy adult rat. Metallomics 6, 1417–1426 (2014).

    Article  CAS  PubMed  Google Scholar 

  128. Kaplan, J. Strategy and tactics in the evolution of iron acquisition. Semin. Hematol. 39, 219–226 (2002).

    Article  CAS  PubMed  Google Scholar 

  129. Quinn, E. A. Too much of a good thing: evolutionary perspectives on infant formula fortification in the United States and its effects on infant health. Am. J. Hum. Biol. 26, 10–17 (2014).

    Article  PubMed  Google Scholar 

  130. Williams, R. J. Iron in evolution. FEBS Lett. 586, 479–484 (2012).

    Article  CAS  PubMed  Google Scholar 

  131. Grandjean, P. & Landrigan, P. J. Neurobehavioural effects of developmental toxicity. Lancet Neurol. 13, 330–338 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Engelhardt, B. & Liebner, S. Novel insights into the development and maintenance of the blood–brain barrier. Cell Tissue Res. 355, 687–699 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Abbott, N. J., Patabendige, A. A., Dolman, D. E., Yusof, S. R. & Begley, D. J. Structure and function of the blood–brain barrier. Neurobiol. Dis. 37, 13–25 (2010).

    Article  CAS  PubMed  Google Scholar 

  134. Jones, H. C., Keep, R. F. & Butt, A. M. The development of ion regulation at the blood–brain barrier. Prog. Brain Res. 91, 123–131 (1992).

    Article  CAS  PubMed  Google Scholar 

  135. Xu, J. & Ling, E. A. Studies of the ultrastructure and permeability of the blood–brain barrier in the developing corpus callosum in postnatal rat brain using electron dense tracers. J. Anat. 184, 227–237 (1994).

    PubMed  PubMed Central  Google Scholar 

  136. Morgan, E. H. & Moos, T. Mechanism and developmental changes in iron transport across the blood–brain barrier. Dev. Neurosci. 24, 106–113 (2002).

    Article  CAS  PubMed  Google Scholar 

  137. Taylor, E. M. & Morgan, E. H. Developmental changes in transferrin and iron uptake by the brain in the rat. Brain Res. Dev. Brain. Res. 55, 35–42 (1990).

    Article  CAS  PubMed  Google Scholar 

  138. Dani, C. et al. Effect of blood transfusions on oxidative stress in preterm infants. Arch. Dis. Child Fetal Neonatal Ed. 89, F408–F411 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. McCarthy, R. C. & Kosman, D. J. Iron transport across the blood–brain barrier: development, neurovascular regulation and cerebral amyloid angiopathy. Cell Mol. Life Sci. 72, 709–727 (2015).

    Article  CAS  PubMed  Google Scholar 

  140. Wu, L. J. et al. Expression of the iron transporter ferroportin in synaptic vesicles and the blood–brain barrier. Brain Res. 1001, 108–117 (2004).

    Article  CAS  PubMed  Google Scholar 

  141. Moos, T. & Rosengren Nielsen, T. Ferroportin in the postnatal rat brain: implications for axonal transport and neuronal export of iron. Semin. Pediatr. Neurol. 13, 149–157 (2006).

    Article  PubMed  Google Scholar 

  142. Simpson, I. A. et al. A novel model for brain iron uptake: introducing the concept of regulation. J. Cereb. Blood Flow Metab. 35, 48–57 (2015).

    Article  CAS  PubMed  Google Scholar 

  143. Bradbury, M. W. Transport of iron in the blood–brain–cerebrospinal fluid system. J. Neurochem. 69, 443–454 (1997).

    Article  CAS  PubMed  Google Scholar 

  144. Moos, T. & Morgan, E. H. Kinetics and distribution of [59Fe–125I]transferrin injected into the ventricular system of the rat. Brain Res. 790, 115–128 (1998).

    Article  CAS  PubMed  Google Scholar 

  145. Chen, J. H., Shahnavas, S., Singh, N., Ong, W. Y. & Walczyk, T. Stable iron isotope tracing reveals significant brain iron uptake in adult rats. Metallomics 5, 167–173 (2013).

    Article  CAS  PubMed  Google Scholar 

  146. Maynard, C. J. et al. Overexpression of Alzheimer's disease amyloid-β opposes the age-dependent elevations of brain copper and iron. J. Biol. Chem. 277, 44670–44676 (2002).

    Article  CAS  PubMed  Google Scholar 

  147. Bilgic, B., Pfefferbaum, A., Rohlfing, T., Sullivan, E. V. & Adalsteinsson, E. MRI estimates of brain iron concentration in normal aging using quantitative susceptibility mapping. Neuroimage 59, 2625–2635 (2012).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The authors' research was supported by a University of Technology, Sydney Chancellor's Postdoctoral Fellowship to D.J.H.; a National Institute of Environmental Health Sciences grant (DP2ES025453—National Institute of Health Director's New Innovator Award; R00ES019597) to M.A.; a Michael J. Fox Foundation for Parkinson's Research grant to D.I.F.; Australian Research Council Linkage Project grants (LP100200254, LP120200081) to D.J.H. and P.A.D.; and Australian National Health and Medical Research Council grants to D.I.F. (APP1043992, APP1044542) and to A.I.B (APP1002222, GNT1037234, APP1044542).

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Authors and Affiliations

  1. Elemental Bio-imaging Facility, University of Technology Sydney, 15 Broadway, Ultimo, 2007, NSW, Australia

    Dominic J. Hare & Philip A. Doble

  2. Department of Preventive Medicine, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, 10029-9574, NY, USA

    Manish Arora

  3. The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, 30 Royal Parade, Parkville, 3052, VIC, Australia

    Nicole L. Jenkins, David I. Finkelstein & Ashley I. Bush

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Contributions

D.J.H. and M.A. researched the data for and wrote the article. N.I.J., D.I.F., P.A.D. and A.I.B. contributed to discussion of the content and the reviewing and/or editing of the manuscript before submission.

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Correspondence to Dominic J. Hare.

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Competing interests

D.I.F. is a paid consultant to and a shareholder of Prana Biotechnology. A.I.B. is a shareholder of Prana Biotechnology, Mesoblast, Cogstate, Brighton and Eucalyptus, and is a paid consultant for Collaborative Medicinal Discovery and Brighton. D.J.H., M.A., N.L.J. and P.A.D. declare no competing interests.

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Hare, D., Arora, M., Jenkins, N. et al. Is early-life iron exposure critical in neurodegeneration?. Nat Rev Neurol 11, 536–544 (2015). https://doi.org/10.1038/nrneurol.2015.100

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