Zinc-binding ligands in milk and intestine: a role in neonatal nutrition?

Abstract

The hythesis that a zinc-binding ligand (ZBL) recently discovered in human milk but absent from cow's milk might be related to zinc nutrition in the neonate was investigated. The zinc-binding characteristics of rat milk were examined to determine if the rat was a suitable model. By gel filtration, rat milk was found to contain a ZBL with characteristics similar to those of the ZBL found in human milk. A similar ZBL was identified in the intestinal mucosa of rats 16 days of age and older but was absent in rats from birth to 16 days. These results support the hypothesis that the ZBL of maternal milk may enhance zinc transport in the neonatal period before the development of intestinal mechanisms for zinc absorption. A recent report from this laboratory described the discovery in human milk of a low-molecular-weight zinc-binding ligand (ZBL) that is not present in cow's milk (1). We have proposed (1) that this ZBL is the factor responsible for the therapeutic value of human milk in the treatment of a genetic disorder of zinc metabolism, acrodermatitis enteropathica (AE), and that the ZBL acts by enhancing the absorption of zinc in patients suffering from this condition.AE is a hereditary disease in humans that appears in early infancy and is characterized by severe skin lesions, alopecia, and diarrhea (2). The onset of symptoms is frequently associated with the weaning of infants from breast milk to cow's milk (2-4). Without treatment, there is a relentless progression leading to death within I to 3 years (4). Since 1953, AE has been treated by oral administration of diiodohydroxyquin (Diodoquin) (5). Recently, Moynahan and Barnes (6) reported low plasma zinc levels in AE patients and successful treatment of the disorder with oral administration of zinc, the therapy resulting in an elevation of the plasma zinc and subsequent clearing of the epidermal lesions. The efficacy of zinc in the treatment of AE has been confirmed by other investigators (7,8). These findings indicate that the basic metabolic defect in this disorder is closely, if not directly, related to zinc metabolism, possibly at the level of zinc absorption as we proposed.We have also postulated that an intestinal ZBL necessary for zinc absorption is absent or immature at birth, even in normal individuals without AE, and that the ZBL of human milk may enable or enhance absorption of this element in the neonate until normal mechanisms of zinc absorption develop postnatally (9, 10). To test this hypothesis, we have used the rat as an experimental model. The present report describes the finding of a ZBL in rat milk similar to that present in human milk. In addition, the presence of a ZBL in the rat intestinal mucosa during the first few weeks of life was investigated.The costs of publication of this article were defrayed in part by the payment of page charges from funds made available to support the research which is the subject of the article. This article must therefore be hereby marked "advertisement" in accordance with 18 U. S. C. §1734 solely...

Symptomatic zinc deficiency in a breast-fed preterm infant.

“…The high tissue to medium ratio of 65Zn which was demonstrated in vitro at the time of the first balance exceeded our previously reported ratios in patients with acrodermatitis enteropathica and control subjects.9 This suggests that zinc deficiency induces an adaptive mucosal response analogous to the increased in vitro mucosal uptake of iron which occurs in patients with iron deficiency.14 It has been proposed that human milk contains a ligand which facilitates zinc absorption and that the concentration of this ligand declines during lactation.5 15 Studies in the newborn rat suggest that this ligand no longer enhances zinc absorption after the intestinal mucosa has developed its own intrinsic ligand.5 Our in vitro study, while indicating that our patient's jejunal mucosa was able to concentrate 65Zn, does not exclude the possibility that a quantitative or a qualitative abnormality of such a ligand in the mother's breast milk impaired his in vivo absorption of zinc.…”

“…The plasma zinc and copper rose to 22 tLmol/l (144 ,ug/100 ml) and 12 '6 ,Vmol/l (80 ,ug/100 ml) respectively and the plasma alkaline phosphatase activity to 305 lU/I. 4.7 ,tmol/l (30.7 ,ug/100 ml) (normal range [11][12][13][14][15][16][17][18][19][20][21][22][23][24] ,umol/l (72-157 ,tg/100 ml)) and 8-1 ,umol/l (51.5 tg/100 ml) (normal range 12-26 ,umol/l (76-165 ,ug/100 ml)) respectively. Total serum protein was 0-54 g/100 ml with an albumin content of 0-38 g/100 ml; the plasma alkaline phosphatase activity, a zinc-dependent enzyme, was 78 IU/I (normal range 71-247 IU/l).…”

Acrodermatitis enteropathica and an overview of zinc metabolism

“…Several studies have tried to explain this well-characterized difference and as of yet there is no consensus (please see ''Dietary Zinc'' below for further discussion). [50][51][52] The clinical presentation of AE is similar to deficiency dermatitis caused by low dietary zinc. For example, infants may develop a deficiency dermatitis identical to AE as a result of very low concentrations of zinc in their mother's milk.…”

“…Several studies have tried to explain this well-characterized difference between human breast milk and cow milk. [50][51][52] For example, it has been shown by gel chromatography that the zinc in cow milk is associated with the high moleculareweight fractions, whereas zinc in human milk is associated with a low moleculare weight fraction. 50 It is, therefore, likely that zinc is bound to different molecules in cow versus human milk.…”

Speciation of Zinc

“…Gel chromatography indicated that most of the zinc in cow's milk was associated with HMM fractions, whereas zinc in human milk was associated with LMM fractions. A species difference in zinc-binding ligands may explain why symptoms of AE can be alleviated by feeding human but not cow's milk [50,51]. These studies initiated several investigations on the binding ligands of zinc and other elements in human or bovine milk [52][53][54][55][56][57][58][59][60][61][62][63][64][65], infant formula based on cow's milk [63], and in different biological fluids [66,67].…”