Nutritional Neurosciences Chronic Marginal Iron Intakes during Early Development in Mice Result in Persistent Changes in Dopamine Metabolism and Myelin Composition 1 Catherine L. Kwik-Uribe,* Dorothy Gietzen, † J. Bruce German,** Mari S. Golub ‡ and Carl L. Keen* 2 Departments of *Nutrition, † Anatomy, Physiology and Cell Biology (Veterinary Medicine), **Food Science & Technology and ‡ Internal Medicine, University of California, Davis, CA 95616 ABSTRACT Marginal iron (Fe) deficiency is prevalent in children worldwide, yet the behavioral and biochemical effects of chronic marginal Fe intakes during early development are not well characterized. Using a murine model, previous work in our laboratory demonstrated persistent behavioral disturbances as a consequence of marginal Fe intakes during early development. In the present study, Swiss-Webster mice fed a control Fe diet (75 g Fe/g diet, n = 13 litters) or marginal Fe diet (14 g Fe/g diet, n = 16 litters) during gestation and through postnatal day (PND) 75 were killed on PND 75 for assessment of tissue mineral concentrations, dopamine metabolism, myelin fatty acid composition, and c- and m-aconitase activities. In addition, these outcomes were assessed in a group of offspring (n = 13 litters) fed a marginal Fe diet during gestation and lactation and then fed a control diet from PND 21–75. Marginal Fe mice demonstrated significant differences in brain iron concentrations, dopamine metabolism and myelin fatty acid composition relative to control mice; however, no difference in c- or m-aconitase activity was demonstrated in the brain. The postnatal consumption of Fe-adequate diets among marginal Fe offspring did not fully reverse all of the observed biochemical disturbances. This study demonstrates that chronic marginal Fe intakes during early development can result in significant changes in brain biochemistry. The persistence of some of these biochemical changes after postnatal Fe supplementation suggests that they are an irreversible conse- quence of developmental Fe restriction. J. Nutr. 130: 2821–2830, 2000. KEY WORDS: ● iron deficiency ● marginal iron ● dopamine ● myelin ● c-aconitase ● m-aconitase ● mice Iron (Fe) deficiency is prevalent among infants and young children worldwide. In the United States alone, an estimated 700,000 toddlers are considered iron deficient and another 350,000 toddlers are classified as iron deficient anemic (Alaimo et al. 1994). In numerous epidemiologic studies, improved iron status has been positively correlated with en- hanced cognitive and motor performance (Idjradinata and Pollitt 1993, Pollitt et al. 1997, Seshadri and Gopaldas 1989, Soewondo et al. 1989); however, the long-term effect of iron deficiency during early development on biochemical and be- havioral outcomes has not been established. A recent study by Hurtado et al. (1999) found that early childhood anemia was one factor linked to an increased risk for mental retardation later in life. Although these human studies do not clearly establish dietary iron deficiency as a causative factor in abnor- mal brain development, work in animal models supports the concept that dietary iron restriction can result in early devel- opmental defects. For example, in rodent models, both mod- erate and severe iron deficiency have been shown to cause alterations in activity patterns and motor development (Edg- erton et al. 1972, Kwik-Uribe et al. 1999, Weinberg et al. 1979 and 1980), as well as diminished cognitive performance (Felt and Lozoff 1996, Kwik-Uribe et al. 2000, Massaro and Wid- mayer 1981, Williamson and Ng 1980a and 1980b, Yehuda et al. 1986). Given the higher prevalence of iron deficiency without anemia in children, we recently used a murine model to study the behavioral and biochemical effects of chronic marginal iron intakes during early development. Using this model, we demonstrated that marginal iron status can result in persistent changes in brain iron, as well as disruptions in both motor and cognitive performance (Kwik-Uribe et al. 1999 and 2000). Having observed these outcomes, the objective of our current work was to begin to examine mechanisms that may underlie the observed behavioral changes. Iron, which is localized within dopamine (DA)-rich brain regions, has been shown to have a role in DA metabolism and function. In addition to inducing changes in DA-dependent behaviors (Youdim et al. 1984, Youdim and Yehuda 1985), iron deficiency has been reported to disrupt the concentrations of DA and its metabolites within the brain (Beard et al. 1994, Nelson et al. 1997). Studies have also shown that iron defi- ciency can cause a down-regulation of DA D 2 receptors in the caudate-putamen of iron-deficient rats (Ashkenazi et al. 1982, Ben-Shachar and Youdim 1990, Youdim et al. 1984). Given 1 Supported by United States Department of Agriculture-Food and Agricul- tural Sciences, National Needs Graduate Fellowship (C.L.K.-U.), ES0 – 4190, HD- 01743 and DK-35747. 2 To whom correspondence and reprint requests should be addressed. 0022-3166/00 $3.00 © 2000 American Society for Nutritional Sciences. Manuscript received 11 April 2000. Initial review completed 25 May 2000. 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