Skip to main content

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 639))

Breast-milk is arguably the ultimate functional food providing the nursing infant with basic nutrition as well as a complex mixture of immunomodulatory components, bioactive compounds and a vast array of hormones1. Having been breast-fed as an infant has been associated with enhanced cognitive development2 and may also provide protection against cardiovascular disease3,4, obesity5 and type 16 and type 2 diabetes7 later in life. Appropriate trace element intake is essential for optimal growth and development and as such may play a role in some of the positive outcomes associated with breastfeeding. Breast-fed infants are entirely dependent upon the mother to provide an appropriate trace element supply and evidence indicates that trace element requirements of term infants are generally met by exclusive breast-feeding through about the first 6 months of life8. After 6 months of age, introduction of complementary foods with adequate trace element content is essential to meet the nutritional needs of the growing infant. This is due in part to milk iron (Fe), zinc (Zn) and copper (Cu) concentrations declining throughout lactation9. Furthermore, milk Fe, Zn and Cu concentrations are relatively refractory to maternal trace mineral status10, even when the maternal diet varies considerably11. There is currently little information regarding the mechanisms through which the mammary gland regulates milk trace element concentrations. Similarities between humans and rodents12 allow us to use rodent models to examine the regulation of mammary gland mineral transport. Recently, several transporters for Fe, Zn and Cu have been found to control trace element uptake and efflux in various cell types. We have utilised the lactating rat to determine changes in mammary gland Fe, Cu and Zn transporter expression and localisation that occur throughout lactation and in response to maternal trace mineral deficiency in hopes of elucidating some of the changes which may be occurring in lactating women.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 169.00
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 219.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Picciano MF (1998) Human milk: nutritional aspects of a dynamic food. Biol Neonate 74:84–93.

    Article  PubMed  CAS  Google Scholar 

  2. Gomez-Sanchez M, Canete R, Rodero I, Baeza JE, Gonzalez JA (2004) Influence of breast-feeding and parental intelligence on cognitive development in the 24-month-old child. Clin Ped 43:753–761.

    Article  Google Scholar 

  3. Martin RM, Ness AR, Gunnell D, Emmett P, Smith GD (2004) Does breast-feeding in infancy lower blood pressure in childhood? The Avon Longitudinal Study of Parents and Children (ALSPAC). Circulation 109:1259–1266.

    Article  PubMed  Google Scholar 

  4. Lawlor DA, Najman JM, Sterne J, Williams GM, Ebrahim S, Smith GD (2004) Associations of parental, birth, and early life characteristics with systolic blood pressure at 5 years of age: findings from the Mater-University study of pregnancy and its outcomes. Circulation 110:2417–2423.

    Article  PubMed  Google Scholar 

  5. Arenz S, Ruckerl R, Koletzko B, von Kries R (2004) Breast-feeding and childhood obesity-systematic review. Int J Obes 28:1247–1256.

    Article  CAS  Google Scholar 

  6. Dosch HM, Becker DJ (2002) Infant feeding and autoimmune diabetes. Adv Exp Med Biol 503:133–140.

    PubMed  CAS  Google Scholar 

  7. Young TK, Martens PJ, Taback SP et al (2002) Type 2 diabetes mellitus in children: prenatal and early infancy risk factors among native Canadians. Arch Fed Adolesc Med 156:651–655.

    Google Scholar 

  8. Dewey KG (1998) Growth characteristics of breast-fed compared to formula-fed infants. Biol Neonate 74:94–105.

    Article  PubMed  CAS  Google Scholar 

  9. Lönnerdal B, Keen CL, Hurley LS (1981) Iron, copper, zinc and manganese in milk. Ann Rev Nutr 1:149–174.

    Article  Google Scholar 

  10. Lönnerdal B (1986) Effects of maternal dietary intake on human milk composition. J Nutr 116:499–513.

    PubMed  Google Scholar 

  11. Domellof M, Hernell O, Dewey KG, Cohen RJ, Lönnerdal B (2004) Factors influencing concentrations of iron, zinc, and copper in human milk. Adv Exp Med Biol 554:355–358.

    PubMed  Google Scholar 

  12. Keen CL, Lönnerdal B, Clegg M, Hurley LS (1981) Developmental changes in composition of rat milk: trace elements, minerals, protein, carbohydrate and fat. J Nutr 111:226–236.

    PubMed  CAS  Google Scholar 

  13. ACC/SCN (1992) Second Report on the World Nutrition Situation: Volume 1: Global and Regional Results, ed. ACC/SCN. Geneva.

    Google Scholar 

  14. Agarwal RMD, Tripathi AM, Agarwal KN (1983) Cord blood haemoglobin, iron and ferritin status in maternal anemia. Acta Paed Scand 72:545–548.

    Article  Google Scholar 

  15. Keen CL, Lönnerdal B, Clegg M, Hurley L (1981) Developmental changes in composition of rat milk: trace elements, minerals, protein, carbohydrate and fat. J Nutr 111:226–236.

    PubMed  CAS  Google Scholar 

  16. Leong WI, Lönnerdal B (2005) Iron transporters in rat mammary gland: effects of different stages of lactation and maternal iron status. Am J Clin Nutr 81:445–453.

    PubMed  CAS  Google Scholar 

  17. Sigman M, Lönnerdal B (1990) Response of rat mammary gland transferrin receptors to maternal dietary iron during pregnancy and lactation. Am J Clin Nutr 52:446–450.

    PubMed  CAS  Google Scholar 

  18. Georgieff MK, Wobken JK, Welle J, Burdo JR, Connor JR (2000) Identification and localization of divalent metal transporter-1 (DMT-1) in term human placenta. Placenta 21:799–804.

    Article  PubMed  CAS  Google Scholar 

  19. Tabuchi M, Yoshimori T, Yamaguchi K, Yoshida T, Kishi F (2000) Human NRAMP2/DMT1, which mediates iron transport across endosomal membranes, is localized to late endosomes and lysosomes in HEp-2 cells. J Biol Chem 275:22220–22228.

    Article  PubMed  CAS  Google Scholar 

  20. Abboud S, Haile DJ (2000) A novel mammalian iron-regulated protein involved in intracellular metabolism. J Biol Chem 275:19906–19912.

    Article  PubMed  CAS  Google Scholar 

  21. Kelleher SL, Lönnerdal B (2005) Low vitamin A intake affects milk iron level and iron transporters in rat mammary gland and liver. J Nutr 135:27–32.

    PubMed  CAS  Google Scholar 

  22. Chan SM, Nelson EA, Leung SS, Li CY (2001) Postnatal iron status of Hong Kong Chinese women in a longitudinal study of maternal nutrition. Eur J Clin Nutr 55:538–546.

    Article  PubMed  CAS  Google Scholar 

  23. Linder MC, Wooten L, Cerveza P, Cotton S, Shulze R, Lomeli N (1998) Copper transport. Am J Clin Nutr 67:965S–971S.

    PubMed  CAS  Google Scholar 

  24. Reinstein NH, Lönnerdal B, Keen CL, Hurley LS (1984) Zinc-copper interactions in the pregnant rat: fetal outcome and maternal and fetal zinc, copper and iron. J Nutr 114:1266–1279.

    PubMed  CAS  Google Scholar 

  25. Linder MC, Lomeli NA, Donley S et al (1999) Copper transport in mammals. Adv Exp Med Biol 448:1–16.

    PubMed  CAS  Google Scholar 

  26. Keen CL, Lönnerdal B, Sloan MV, Hurley LS (1980) Effect of dietary iron, copper and zinc chelates of nitrilotriacetic acid (NTA) on trace metal concentrations in rat milk and maternal and pup tissues. J Nutr 110:897–906.

    PubMed  CAS  Google Scholar 

  27. Lönnerdal B (1998) Copper nutrition during infancy and childhood. Am J Clin Nutr 67:1046S–1053S.

    PubMed  Google Scholar 

  28. Kelleher SL, Lönnerdal B (2003) Marginal maternal Zn intake in rats alters mammary gland Cu transporter levels and milk Cu concentration and affects neonatal Cu metabolism. J Nutr 133:2141–2148.

    PubMed  CAS  Google Scholar 

  29. Ackland ML, Anikijenko P, Michalczyk A, Mercer JFB (1999) Expression of Menkes copper-transporting ATPase, MNK, in the lactating human breast: possible role in copper transport into milk. J Histochem Cytochem 47:1553–1561.

    PubMed  CAS  Google Scholar 

  30. Michalczyk AA, Reiger J, Allen KJ, Mercer JFB, Ackland ML (2000) Defective localization of the Wilson disease protein (ATP7B) in the mammary gland of the toxic milk mouse and the effects of copper supplementation. Biochem J 352:565–571.

    Article  PubMed  CAS  Google Scholar 

  31. Danks, DM (1995), Disorders of copper transport. In: The Metabolic and Molecular Basis of Inherited Disease, (D Valle, Ed.), McGraw Hill: New York. pp. 2211–2235.

    Google Scholar 

  32. Grimes A, Hearn CJ, Lockhart P, Newgreen DF, Mercer JF (1997) Molecular basis of the brindled mouse mutant (Mo(br)): a murine model of Menkes disease. Hum Molec Gen 6:1037–1042.

    Article  CAS  Google Scholar 

  33. Lee J, Prohaska JR, Dagenais SL, Glover TW, Thiele DJ (2000) Isolation of a murine copper transporter gene, tissue specific expression and functional complementation of a yeast copper transport mutant. Gene 254:87–96.

    Article  PubMed  CAS  Google Scholar 

  34. Lee J, Prohaska JR, Thiele DJ (2001) Essential role for mammalian copper transporter Ctrl in copper homeostasis and embryonic development. PNAS 98:6842–6847.

    Article  PubMed  CAS  Google Scholar 

  35. Zhou B, Gitschier J (1997) hCTRl: a human gene for copper uptake identified by complementation in yeast. PNAS 94:7481–7486.

    Article  PubMed  CAS  Google Scholar 

  36. Lee J, Pena MMO, Nose Y, Thiele DJ (2002) Biochemical characterization of the human copper transporter Ctr1. J Biol Chem 277:4380–4387.

    Article  PubMed  CAS  Google Scholar 

  37. Klomp AEM, Top BBJ, Van Den Berg ET, Berger R, Klomp LWJ (2002) Biochemical characterization and subcellular localization of human copper transporter 1 (hCTRl). Biochem J 364:497–505.

    Article  PubMed  CAS  Google Scholar 

  38. Petris MJ, Smith K, Lee J, Thiele DJ (2002) Copper-stimulated endocytosis and degradation of the human copper transporter, hCtr1. J Biol Chem 278:9639–9646.

    Article  PubMed  Google Scholar 

  39. Huang L, Gitschier J (1997) A novel gene involved in zinc transport is deficient in the lethal milk mouse. Nature Gen 17:292–297.

    Article  CAS  Google Scholar 

  40. King JC (2002) Enhanced zinc utilization during lactation may reduce maternal and infant zinc depletion. Am J Clin Nutr 75:2–3.

    PubMed  CAS  Google Scholar 

  41. Moore CME, Roberto RDJ, Greene HL (1984) Zinc supplementation in lactating women: evidence for mammary control of zinc secretion. J Ped 105:600–602.

    Article  CAS  Google Scholar 

  42. Krebs NT (1998) Zinc supplementation during lactation. Am J Clin Nutr 68:509S–512S.

    PubMed  CAS  Google Scholar 

  43. Luizzi JP, Bobo JA, Cui L, McMahon RJ, Cousins RJ (2003) Zinc transporters 1, 2 and 4 are differentially expressed and localized in rats during pregnancy and lactation. J Nutr 133:342–351.

    Google Scholar 

  44. McMahon RJ, Cousins RJ (1998) Regulation of the zinc transporter ZnT-1 by dietary zinc. PNAS 95:4841–4186.

    Article  PubMed  CAS  Google Scholar 

  45. Kambe T, Narita H, Yamaguchi-Iwai Y et al (2002) Cloning and characterization of a novel mammalian zinc transporter, ZnT-5, abundantly expressed in pancreatic beta-cells. J Biol Chem 277:19049–19055.

    Article  PubMed  CAS  Google Scholar 

  46. Ackland ML, Mercer JF (1992) The murine mutation, lethal milk, results in production of zinc-deficient milk. J Nutr 122:1214–1218.

    PubMed  CAS  Google Scholar 

  47. McMahon RJ, Cousins RJ (1998) Mammalian Zinc transporters. J Nutr 28:667–670.

    Google Scholar 

  48. Kelleher SL, Lönnerdal B (2003) Zn transporter levels and localization change throughout lactation in rat mammary gland and are regulated by Zn in mammary cells. J Nutr 133:3378–3385.

    PubMed  CAS  Google Scholar 

  49. Palmiter RD, Cole TB, Findley SD (1996) ZnT-2, a mammalian protein that confers resistance to zinc by facilitating vesicular sequestration. EMBO 15:1784–1791.

    CAS  Google Scholar 

  50. Murgia C, Vespignani I, Cerase J, Nobili F, Perozzi G (1999) Cloning, expression and vesicular localization of transporter Dri27/ZnT4 in intestinal tissue and cells. Am J Phys 277:G1232–G1239.

    Google Scholar 

  51. Wang F, Dufner-Beattie J, Kim BE, Petris MJ, Andrews GK, Eide DJ (2004) Zinc-stimulated endocytosis controls activity of the mouse ZIP1 and ZIP3 zinc uptake transporters. J Biol Chem 279:24631–24639.

    Article  PubMed  CAS  Google Scholar 

  52. Dufner-Beattie J, Langmade SJ, Wang F, Eide D, Andrews GK (2003) Structure, function and regulation of a subfamily of mouse zinc transporter genes. J Biol Chem 278:50142–50150.

    Article  PubMed  CAS  Google Scholar 

  53. Eide DJ (2003) The SLC39 family of metal ion transporters. In: The ABC of Solute Carriers. (MA Hediger, Editor). Springer-Verlag: New York.

    Google Scholar 

  54. Gaither LA, Eide DJ (2000) Functional expression of the human hZIP2 zinc transporter. J Biol Chem 275:5560–5564.

    Article  PubMed  CAS  Google Scholar 

  55. Gaither LA, Eide DJ (2001) The human ZIP1 transporter mediates zinc uptake in human K562 erythroleukemia cells. J Biol Chem 276:22258–22264.

    Article  PubMed  CAS  Google Scholar 

  56. Moser PB, Reynolds RD (1983) Dietary zinc intake and zinc concentrations of plasma, erythrocytes, and breast milk in antepartum and postpartum lactating and non-lactating women: a longitudinal study. Am J Clin Nutr 38:101–108.

    PubMed  CAS  Google Scholar 

  57. Desrivieres S, Prinz T, Laria NC-P et al (2003) Comparative proteomic analysis of proliferating and functionally differentiated mammary epithelial cells. Molec Cell Proteomics 2:1039–1054.

    Article  CAS  Google Scholar 

  58. Neville MC, McFadden TB, Forsyth I (2002) Hormonal regulation of mammary differentiation and milk secretion. J Mammary Gland Biol Neoplasia 7:49–65.

    Article  PubMed  Google Scholar 

  59. Rillema JA, Hill MA (2003) Prolactin regulation of the pendrin-iodide transporter in the mammary gland. Am J Physiol Endocrinol Metab 284:E25–28.

    PubMed  CAS  Google Scholar 

  60. Rillema JA, Houston TL, Jokn-Pierre-Louis K (2003) Prolactin, cortisol and insulin regulation of nucleoside uptake into mouse mammary gland explants. Exp Biol Med 228:795–799.

    CAS  Google Scholar 

  61. Lkhider M, Depal S, Bousquet MO (1996) Rat prolactin in serum, milk and mammary tissue: characterization and intracellular localization. Endocrinol 137:4969–4979.

    Article  CAS  Google Scholar 

  62. Lkhider M, Delpal S, LeProvost F, Ollivier-Bouquet M (1997) Rat prolactin synthesis by lactating mammary epithelial cells. FEBS Letters 401:117–122.

    Article  PubMed  CAS  Google Scholar 

  63. Iwasaka T, Umemura S, Kakimotot K, Koizumi H, Osamura YR (2000) Expression of prolactin mRNA in rat mammary gland during pregnancy and lactation. J Histochem Cytochem 48:389–395.

    PubMed  CAS  Google Scholar 

  64. Ball RK, Friis RR, Schoenenberger CA, Doppler W, Groner B (1988) Prolactin regulation of beta-casein gene expression and of a cytosolic 120-kd protein in a cloned mouse mammary epithelial cell line. EMBO J 7:2089–2095.

    PubMed  CAS  Google Scholar 

  65. McManaman JL, Hanson L, Neville MC, Wright RM (2000) Lactogenic homones regulate xanthine oxidoreductase and beta-casein levels in mammary epithelial cells by distinct mechanisms. Arch Biochem Biophys 373:318–327.

    Article  PubMed  CAS  Google Scholar 

  66. Geley S, Muller C (2004) RNAi: ancient mechanism with a promising future. Exp Gerentol 39:985–998.

    Article  CAS  Google Scholar 

  67. Wartmann M, Cella N, Hofer P et al (1996) Lactogenic hormone activation of Stat5 and transcription of the beta-casein gene in mammary epithelia cells is independent of the p42 ERK2 mitogen-activated protein kinase activity. J Biol Chem 271:31863–31868.

    Article  PubMed  CAS  Google Scholar 

  68. Winklehner-Jennewein P, Geymayer S, Lechner J et al (1998) A distal enhancer region in the human beta-casein gene mediates the response to prolactin and glucocorticoid hormones. Gene 217:127–139.

    Article  PubMed  CAS  Google Scholar 

  69. Mitev V, Bayat-Sarmandi M, Lemnaouar M, Puissant C, Houdebine LM (1996) The effect of prolactin on casein kinase II, MAP kinase and PKC in rabbit mammary cells and Nb2 rat lymphoid cells. Biochem Pharmacol 52:1719–1727.

    Article  PubMed  CAS  Google Scholar 

  70. Selvaraj NG, Omi E, Gibori G, Rao MC (2000) Janus kinase 2 (JAK2) regulates prolactin-mediated chloride transport in mouse mammary epithelial cells through tyrosine phosphorylation of Na+−K+−2Cl- cotransporter. Molec Cell Endocrinol 14:2054–2065.

    Article  CAS  Google Scholar 

  71. Ollivier-Bousquet M (1978) Early effects of prolactin on lactating rabbit mammary gland. Ultrastructural changes and stimulation of casein secretion. Cell Tiss Res 187:25–43.

    Article  CAS  Google Scholar 

  72. Lkhider M, Petridou B, Aubourg A, Ollivier-Bousquet M (2001) Prolactin signaling to milk protein secretion but not to gene expression depends on the integrity of the Golgi region. J Cell Sci 114:1883–1891.

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2009 Springer Science + Business Media B.V.

About this chapter

Cite this chapter

Kelleher, S.L., Lönnerdal, B. (2009). Nutrient Transfer: Mammary Gland Regulation. In: Goldberg, G., Prentice, A., Prentice, A., Filteau, S., Simondon, K. (eds) Breast-Feeding: Early Influences on Later Health. Advances in Experimental Medicine and Biology, vol 639. Springer, Dordrecht. https://doi.org/10.1007/978-1-4020-8749-3_2

Download citation

Publish with us

Policies and ethics