Does Human Lactoferrin in the Milk of Transgenic Mice Deliver Iron to Suckling Neonates?

  • Linda H. Hanson
  • Valerie Sawicki
  • Andrew Lewis
  • Jan H. Nuijens
  • Margaret C. Neville
  • Peifang Zhang
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 501)


Lactoferrin is an iron-binding glycoprotein abundantly present in human milk, and has been postulated both to increase and to decrease intestinal iron absorption. To examine this problem, the interaction of milk iron with pup hemoglobin was studied in controls and in transgenic mice overexpressing human lactoferrin in their milk (2 lines expressing 12 mg/mL and 4 mg/mL, respectively). At day 14 of gestation, pregnant mice were switched from a diet of commercial chow containing iron at 300mg/kg to diets containing 5, 15, or 50 mg iron/kg; controls continued on chow. Nontransgenic pups were cross-fostered to transgenic dams to ensure that any results found in the pups were the effect of milk components. The hemoglobin level in the blood of 10-day-old suckling neonates was measured and calculated as total hemoglobin per pup. The total hemoglobin levels were lower in the pups receiving milk high in human lactoferrin, but the difference reached significance (P < 0.02) only at the highest level of dietary iron. Our findings do not support the hypothesis that lactoferrin functions as an intestinal iron scavenger, at least at high doses.


Human Milk Iron Status Intestinal Brush Border Human Lactoferrin Bovine Lactoferrin 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Azuma N, Mori H, Kaminogawa S, Yamauchi K. Stimulatory effect of human lactoferrin on DNA synthesis in BALB/c 3T3 cells. Agrie Biol Chem 1989;53:31–35.CrossRefGoogle Scholar
  2. Baker EN, Anderson BF, Baker HM, Day CL, Haridas M, Norris GE, Rumball SV, Smith CA, Thomas DH. Three-dimentional structure of lactoferrin in various states. Adv Exp Med Biol 1994;357:227–230.PubMedCrossRefGoogle Scholar
  3. Bezault J, Bhimani R, Wiprovnick J, Furmanski P. Human lactoferrin inhibits growth of solid tumors and development of experimental metastases in mice. Cancer Res 1994;54:2310–2312.PubMedGoogle Scholar
  4. Casey CE, Smith A, Zhang P. Macrominerals in human and animal milks. In: Jensen RE, editor. Handbook of Milk Composition. San Diego: Academic Press; 1995. pp 87–98.Google Scholar
  5. Davidson LA, Lonnerdal B. Lactoferrin and secretory IgA in the feces of exclusively breast-fed infants. Am J Clin Nutr 1987;41:852–861.Google Scholar
  6. Davidson LA, Lonnerdal B. Fe-saturation and proteolysis of human lactoferrin: effect on brush-border receptor-mediated uptake of Fe and Mn. Am J Physiol 1989;257:G390–G394.Google Scholar
  7. Davidson LA, Litov RE, Lonnerdal B. Iron retention from lactoferrin supplemented formulas in infant rhesus monkeys. Pediatr Res 1990;27:170–180.CrossRefGoogle Scholar
  8. Davidson LA, Kastenmayer P, Yuen M, Lonnerdal B, Hurrell RE Influence of lactoferrin on iron absorption from human milk in infants. Pediatr Res 1994;35:117–124.CrossRefGoogle Scholar
  9. Dewey KG, Lonnerdal B. Milk and nutrient intake of breast-fed infants from 1 to 6 months: relation to growth and fatness. J Pediatr Gastroenterol Nutr 1983;2:497–506.PubMedCrossRefGoogle Scholar
  10. Dewey KG, Finley DA, Lonnerdal B. Breast milk volume and composition during late lactation (7–20 months). J Pediatr Gastroenterol Nutr 1984;3:713–720.PubMedCrossRefGoogle Scholar
  11. Ellison RT. The effects of lactoferrin on gram-negative bacteria. Adv Exp Med Biol 1994;357:71–90. Fransson GB, Lonnerdal B. Iron in human milk J Pediatr 1980;96:380–384.Google Scholar
  12. Fransson GB, Thoren-Tolling K, Jones B, Hambracus I, Lonnerdal B. Absorption of lactoferrin iron in suckling pigs. Nutr Res 1983a;3:373–384.CrossRefGoogle Scholar
  13. Fransson GB, Keen CI, Lonnerdal B. Supplementation of milk with iron bound to lactoferrin using weanling mice. I. Effects on hematology and tissue iron. J Pediatr Gastroenterol Nutr 1983b;2:693–700.CrossRefGoogle Scholar
  14. Goldman AS, Garza C, Schanler RJ, Goldblum RM. Molecular forms of lactoferrin in the stool and urine from infants fed human milk. Pediatr Res 1990;27:252–255.PubMedCrossRefGoogle Scholar
  15. Hashizume S, Kuroda K, Murakami H. Identification of lactoferrin as an essential growth factor for human lymphocytic cell lines in serum-free medium. Biochim Biophys Acta 1983;763:377–382.PubMedCrossRefGoogle Scholar
  16. Hennart PF, Brasseur DJ, Delogne-Desnoeck JB, Dramaix MM, Robyn CE. Lysozyme, lactoferrin and secretory immunoglobulin A content in breast milk: influence of duration of lactation, nutritional status, prolactin status and parity of mother. Am J Clin Nutr 1991;53:32–39.PubMedGoogle Scholar
  17. Hu WI, Mazurier J, Montreuil J, Spik G. Isolation and partial characterization of a lactotransferrin receptor from mouse intestinal brush border. Biochemistry 1990;29:535–541.PubMedCrossRefGoogle Scholar
  18. Iyer S, Lonnerdal B. Lactoferrin, lactoferrin receptors and iron metabolism. Eur J Clin Nutr 1993; 47:232–241.Google Scholar
  19. Kume S, Tanabe S. Effect of twinning and supplemental iron-saturated lactoferrin on iron status of newborn calves. J Dairy Sci 1994;77:118–123.CrossRefGoogle Scholar
  20. Kume S, Tanabe S. Effect of supplemental lactoferrin with ferrous iron on iron status of newborn calves. J Dairy Sci 1996;79:459–464.PubMedCrossRefGoogle Scholar
  21. Lonnerdal B. Iron in breast milk. In: Stekel A, editor. Iron Nutrition in Infancy and Childhood. Volume 4, Nestlé Nutrition Workshop Series. New York: Raven Press; 1984. pp. 95–118.Google Scholar
  22. Lonnerdal B. Effects of milk and milk components on calcium, magnesium, and trace element absorption during infancy. Physiol Rev 1997;77:643–669.PubMedGoogle Scholar
  23. Lonnerdal B, Iyer S. Lactoferrin: molecular structure and biological function. Annu Rev Nutr 1995; 15:93–110.PubMedCrossRefGoogle Scholar
  24. Masson PL, Heremans JF. Lactoferrin in milk from different species. Comp Biochem Physiol [B] 1971; 39:119–129.CrossRefGoogle Scholar
  25. Mazurier J, Montreuil J, Spika G. Visualization of lactotransferrin brush-border receptors by ligand blotting. Biochim Biophys Acta 1985;821:453–460.PubMedCrossRefGoogle Scholar
  26. Neville MC, Chatfield K, Hanson L, Lewis A, Monks J, Nuijens J, 011ivier-Bousquet M, Schanbacher F, Sawicki V, Zhang P. Lactoferrin secretion into mouse milk. Development of secretory activity, the localization of lactoferrin in the secretory pathway, and interactions of lactoferrin with milk iron. Adv Exp Med Biol 1998;443:141–153.PubMedGoogle Scholar
  27. Nichols BL, McKee KS, Henry JF, Putman M. Human lactoferrin stimulates thymidine incorporation into DNA of rat crypt cells. Pediatr Res 1987;21:563–567.PubMedCrossRefGoogle Scholar
  28. Nichols BL, McKee KS, Hubers HA. Iron is not required in the lactoferrin stimulation of thymidine incorporation into the DNA of rat crypt enterocytes. Pediatr Res 1990;27:525–528.PubMedCrossRefGoogle Scholar
  29. Nuijens JH, van Berkel PHC, Schanbacher FL. Structure and biological actions of lactoferrin. J Mammary Gland Biol Neoplasia 1996;1:285–295.PubMedCrossRefGoogle Scholar
  30. Nuijens JH, van Berke] PH, Geerts ME, Hartevelt PP, de Boer HA, van Veen HA, Pieper FR. Characterization of recombinant human lactoferrin secreted in milk of transgenic mice. J Biol Chem 1997; 272:8802–8807.PubMedCrossRefGoogle Scholar
  31. Oguchi S, Walker WA, Sanderson IR. Iron saturation alters the effect of lactoferrin on the proliferation and differentiation of human enterocytes (Caco-2 cells). Biol Neonate 1995;67:330–339.PubMedCrossRefGoogle Scholar
  32. Prentice A, Ewing G, Roberts SB, Lucas A, MacCarthy A, Jarjou LM, Whitehead RG. The nutritional role of breast milk IgA and lactoferrin. Acta Pediatr Scand 1987;76:592–598.CrossRefGoogle Scholar
  33. Sanchez L, Ismail M, Liew FY, Brock JH. Iron transport across Caco-2 monolayers. Effect of transferrin, lactoferrin and nitric oxide. Biochim Biophys Acta 1996;1289:291–297.PubMedCrossRefGoogle Scholar
  34. Schanler R, Goldblum R, Garza C, Goldman AS. Enhanced fecal excretion of selected immune factors in very low birth weight infants. Pediatr Res 1986;20:711–715.PubMedCrossRefGoogle Scholar
  35. Slimes MA, Vuori E, Kuitunen P. Breast milk iron: a declining concentration during the course of lactation. Acta Paediatr Scand 1979;68:29–31.Google Scholar
  36. Spik G, Brunet B, Mazunier-Dehaine C, Fontaine G, Montreuil T. Characterization and properties of the human and bovine lactotransferrins extracted from the feces of newborn infants. Acta Pediatr Scand 1982;71:979–985.CrossRefGoogle Scholar
  37. Yoo YC, Watanabe S, Watanabe R, Hata K, Shimazaki K, Azuma I. Bovine lactoferrin and lactoferricin, a peptide derived from bovine lactoferrin, inhibits tumor metastasis in mice. Jpn J Can Res 1997; 88:184–190.CrossRefGoogle Scholar
  38. Zhang P, Sawicki V, Lewis A, Hanson L, Monks J, Neville MC. The effect of serum iron concentration on iron secretion into mouse milk. J Physiol 2000;522(Pt 3):479–491.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2001

Authors and Affiliations

  • Linda H. Hanson
    • 1
  • Valerie Sawicki
    • 1
  • Andrew Lewis
    • 1
  • Jan H. Nuijens
    • 2
  • Margaret C. Neville
    • 1
  • Peifang Zhang
    • 1
  1. 1.Department of Physiology and BiophysicsUniversity of Colorado Health Sciences Center Denver
  2. 2.Pharming BVLeidenThe Netherlands

Personalised recommendations