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Letter to the Editor

Response to letter of Dr. Elise Malecki

Department of Nutrition, University of California at Davis, Davis, CA 95616

Dear Editor,

We are writing this letter in response to the letter from Dr. Elise Malecki regarding our most recent publication in The Journal of Nutrition (1) . Although Dr. Malecki raises some interesting points, there are some issues that require comment.

First, although Dr. Malecki’s letter focuses on a comment we made concerning the possibility that the increase in brain manganese we observed in our iron-deficient animals may be due to an increase in transferrin-mediated tissue manganese uptake, it is important to stress the fact that the focus of our paper was to characterize some of the changes in brain biochemistry that occur in developing animals exposed to chronic marginal iron deficiency. The goal of the paper was to view these changes with respect to some of the behavioral abnormalities that can be observed in animals exposed to the same dietary restriction. One consequence of marginal iron deficiency during early development can be an increase in brain manganese concentrations. Although we agree with Dr. Malecki that this has long been recognized, we considered it important to remind the reader of this point because the increase in brain manganese may contribute to some of the observed behavioral and biochemical changes. In this regard, it is also worth noting that gender differences in the biochemical and behavioral response of rodents to chronic iron deficiency were observed (2) and have been reported previously (3 ,4) . These differences are expressed in a number of ways, including differences in behavior, as well as in tissue iron and manganese concentrations. Although we consider it unlikely that the subtle changes in manganese concentrations we observed play a major role in the different behavioral or biochemical responses, a minor role cannot be ruled out.

Second, we would like to note that we did not state that the increase in brain manganese was due exclusively to an enhanced transferrin-mediated uptake of the element. It is our opinion that the increase in brain manganese may have several explanations, including alterations in transferrin-independent uptake pathways, alterations in the uptake and release of manganese from select cells and an increased association of manganese with cellular sites that would normally bind iron. We agree that work by Malecki et al. (5) , as well as others (6) , utilizing the hypotransferrinemic mouse model (hpx/hpx) clearly demonstrates the existence of transferrin-independent pathways for brain manganese uptake. However, we would argue that the fact that alternative transport systems can be used to transport manganese as well as iron into the brain does not provide definitive evidence against the concept that transferrin can facilitate the uptake of these metals in the transferrin-intact animal. It is also important to note that the studies done using the hpx/hpx model were conducted in adult iron-sufficient animals. Several investigators have reported that in the brain, the abundance of proteins critical to iron homeostasis, including tranferrin and transferrin receptor can be regulated developmentally (7) , regionally (8) and by cell type (9) . Thus, transferrin may have a different role in brain iron (and manganese) uptake in the young, compared with the adult animal. For these reasons, it is quite possible that the transferrin/transferrin receptor mechanism for brain manganese accumulation after chronic iron deficiency may be one of several pathways contributing to the observed increase in brain manganese concentrations.

We, like Dr. Malecki, acknowledge here and in our paper that other possible mechanisms for manganese uptake into the brain do exist and are likely contributing to the changes that we observed. Our specific mention of the transferrin/transferrin receptor was due to our measurements of c- and m-aconitase, and their relationship to iron regulation through IRP/IRE interactions. To our knowledge, the only transport system to date that has been shown to be translationally responsive to changes in iron status is the transferrin receptor; thus we felt warranted in our discussion of this as a possible mechanism.

We hope that this response helps to clarify our perspective.

REFERENCES

1. Kwik-Uribe C. L., Gietzen D. W., German J. B., Golub M. S., Keen C. L. Chronic marginal iron intakes during early development in mice result in persistent changes in dopamine metabolism and myelin composition. J. Nutr. 2000;130:2821-2830[Abstract/Free Full Text]

2. Kwik-Uribe C. L., Golub M. S., Keen C. L. Chronic marginal iron intakes during early development in mice alter brain iron concentrations and behavior despite postnatal iron supplementation. J. Nutr. 2000;130:2040-2048[Abstract/Free Full Text]

3. Dallman P. R., Siimes M. N., Manies E. C. Brain iron: persistent deficiency following short term iron deprivation in the young rat. Br. J. Haemotol. 1975;31:209-215[Medline]

4. Kwik-Uribe C. L., Golub M. S., Keen C. L. Behavioral consequences of marginal iron deficiency during development in a murine model. Neurotoxicol. Teratol. 1999;21:661-672[Medline]

5. Malecki E. A., Cook B. M., Devenyi A. G., Beard J. L., Connor J. R. Transferrin is required for normal distribution of ⁵⁹Fe and ⁵⁴Mn in brains of mice. J. Neurol. Sci. 1999;170:112-118[Medline]

6. Takeda A., Ishiwatari S., Okada S. Influence of transferrin on manganese uptake in rat brain. J. Neurosci. Res. 2000;59:542-552[Medline]

7. Roskams A. J., Connor J. R. Iron, transferrin, and ferritin in the rat brain during development and aging. J. Neurochem. 1994;63:709-716[Medline]

8. Pinero D. J., Li N. Q., Connor J. R., Beard J. L. Variations in dietary iron alter brain iron metabolism in developing rats. J. Nutr. 2000;130:254-263[Abstract/Free Full Text]

9. Connor J. R., Menzies S. L. Cellular management of iron in the brain. J. Neurol. Sci. 1995;134:33-44

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