Perinatal Iron Deficiency Decreases Cytochrome c Oxidase (CytOx) Activity in Selected Regions of Neonatal Rat Brain

deUngria, Marissa; Rao, Raghavendra; Wobken, Jane D.; Luciana, Mónica; Nelson, Charles A.; Georgieff, Michael

doi:10.1203/00006450-200008000-00009

Cited by 260 publications

(139 citation statements)

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“…Results of both animal and human research suggest that infants of diabetic mothers incur damage to this region (e.g., Jorgenson et al, 2003;Petry et al, 1992;Rao et al, 1999;2003). Specifically, animal models have indicated that low levels of brain iron influence enzyme systems regulating brain growth, myelination, dopamine receptor synthesis, and energy metabolism, which may lead to adverse neurocognitive behavioral sequelae (e.g., for discussion and elaboration see Beard, 2003;de Ungria et al, 2000;Lozoff, 2000), and several investigations have suggested a selective influence of iron deficiency on neuronal energy metabolism in regions of the hippocampus and in the prefrontal cortex (deUngria et al, 2000;Rao et al, 2003), both of which are regions associated with explicit memory performance. Taken together, these studies suggest a relation between prenatal iron deficiency due to maternal diabetes and deficits in explicit memory performance.…”

Section: Discussionmentioning

confidence: 99%

“…The adverse environment associated with the diabetic pregnancy consists of multiple neurologic risk factors including: 1) chronic hypoxia (Widness et al, 1981), 2) hyperglycemia/reactive hypoglycemia, and 3) iron deficiency (Petry et al, 1992), which, on the basis of animal models, have been shown to act selectively on regions of the fetal brain that are involved in explicit memory (e.g., the hippocampus, Barks et al, 1995;de Ungria, et al, 2000). Based on the known Several studies have demonstrated that neurobehavioral outcomes in human children who were born to diabetic mothers are inversely correlated with the quality of metabolic regulation during pregnancy (e.g., Rizzo et al, 1997).…”

Section: Introductionmentioning

confidence: 99%

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Explicit memory performance in infants of diabetic mothers at 1 year of age

DeBoer

Wewerka

Bauer

et al. 2007

Developmental Medicine &Amp; Child Neurology

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The aim of the present research was to investigate the impact of abnormal fetal environment on explicit memory performance. Based on animal models, it was hypothesized that infants of diabetic mothers (IDMs) experience perturbations in memory performance due to exposure to multiple neurologic risk factors including: chronic hypoxia, hyperglycemia/reactive hypoglycemia, and iron deficiency. Memory performance, as measured by the elicited/deferred imitation paradigm, was compared between 13 IDMs (7 female, 6 male; mean age 365 days, SD 11) and 16 typically developing children (7 female, 9 male; mean age 379 days, SD 9). The IDM group was characterized by shorter gestational age (mean 38 weeks, SD 2), greater standardized birth weight scores (mean 3797 grams, SD 947), and lower iron stores (mean ferritin concentration 87 μg/L, SD 68) in comparison with the control group (mean gestational age: 40 weeks, SD 1; mean birth weight: 3639 grams, SD 348; mean newborn ferritin concentration 140 μg/L, SD 46). After statistically controlling for both gestational age and global cognitive abilities, IDMs demonstrated a deficit in the ability to recall multi-step event sequences when a delay was imposed. These findings underscore the importance of the prenatal environment on subsequent mnemonic behavior and suggest a connection between metabolic abnormalities during the prenatal period, development of memory circuitry, and behavioral mnemonic performance.Infants of diabetic mothers (IDMs) comprise a compelling group in which to examine associations between fetal risk factors and subsequent memory performance. The adverse environment associated with the diabetic pregnancy consists of multiple neurologic risk factors including: 1) chronic hypoxia (Widness et al., 1981), 2) hyperglycemia/reactive hypoglycemia, and 3) iron deficiency (Petry et al., 1992), which, on the basis of animal models, have been shown to act selectively on regions of the fetal brain that are involved in explicit memory (e.g., the hippocampus, Barks et al., 1995;de Ungria, et al., 2000). Based on the known Several studies have demonstrated that neurobehavioral outcomes in human children who were born to diabetic mothers are inversely correlated with the quality of metabolic regulation during pregnancy (e.g., Rizzo et al., 1997). However, these investigations have typically examined global cognitive development in children well downstream from the proposed insult, and are not necessarily related to specific risk factors or areas of injury. The purpose of the present research was to further characterize outcomes related to development in an abnormal prenatal environment by examining the relation between IDM's abnormal prenatal environment and behavioral explicit memory performance using the elicited imitation paradigm. Risk FactorsPrenatal hypoxia and hyperglycemia/reactive hypoglycemia have been associated with both poor behavioral and neurologic outcomes. Specifically, prenatal hypoxia is linked with motor and cognitive deficits in humans (e.g., Low et...

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Explicit memory performance in infants of diabetic mothers at 1 year of age

DeBoer

Wewerka

Bauer

et al. 2007

Developmental Medicine &Amp; Child Neurology

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“…Iron deficiency in children is associated with difficulties in performing cognitive tasks and retardation in the development of the CNS (21,22). Prenatal iron deficiency causes loss of cytochrome c oxidase (complex IV) in selected regions in the brain of rats (23) and causes a decrease in ferrochelatase (17). Iron deficiency also occurs in the elderly (24), but surprisingly little work has been reported concerning heme and iron deficiency in brain dysfunction with age.…”

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confidence: 99%

Heme deficiency may be a factor in the mitochondrial and neuronal decay of aging

Atamna¹,

Killilea²,

Killilea³

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

197

150

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Heme, a major functional form of iron in the cell, is synthesized in the mitochondria by ferrochelatase inserting ferrous iron into protoporphyrin IX. Heme deficiency was induced with N-methylprotoporphyrin IX, a selective inhibitor of ferrochelatase, in two human brain cell lines, SHSY5Y (neuroblastoma) and U373 (astrocytoma), as well as in rat primary hippocampal neurons. Heme deficiency in brain cells decreases mitochondrial complex IV, activates nitric oxide synthase, alters amyloid precursor protein, and corrupts iron and zinc homeostasis. The metabolic consequences resulting from heme deficiency seem similar to dysfunctional neurons in patients with Alzheimer's disease. Heme-deficient SHSY5Y or U373 cells die when induced to differentiate or to proliferate, respectively. The role of heme in these observations could result from its interaction with heme regulatory motifs in specific proteins or secondary to the compromised mitochondria. Common causes of heme deficiency include aging, deficiency of iron and vitamin B6, and exposure to toxic metals such as aluminum. Iron and B6 deficiencies are especially important because they are widespread, but they are also preventable with supplementation. Thus, heme deficiency or dysregulation may be an important and preventable component of the neurodegenerative process.iron ͉ complex IV ͉ amyloid precursor protein (APP) ͉ nitric oxide synthase ͉ oxidative stress

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“…In humans, early life iron deficiency leads to long-term cognitive deficits and behavioral abnormalities (39), which have been phenotypically reproduced in preclinical rodent models (13,23,39). Moreover, iron-deficient (ID) rat pups have decreased energy metabolism, abnormal neuronal morphology and neurotransmission, and reduced expression of genes critical for neural plasticity in the hippocampus, particularly during the period of peak hippocampal dendritogenesis, synaptogenesis, and myelination (10,16,21,34,35,48,51,60). These abnormalities in gene expression and neuronal morphology can persist beyond the period of early iron deficiency into adulthood (10, 61).…”

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confidence: 99%

Gestational-neonatal iron deficiency suppresses and iron treatment reactivates IGF signaling in developing rat hippocampus

Tran

Fretham

Wobken

et al. 2012

American Journal of Physiology-Endocrinology and Metabolism

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Tran PV, Fretham SJ, Wobken J, Miller BS, Georgieff MK. Gestational-neonatal iron deficiency suppresses and iron treatment reactivates IGF signaling in developing rat hippocampus. Am J Physiol Endocrinol Metab 302: E316 -E324, 2012. First published November 8, 2011; doi:10.1152/ajpendo.00369.2011.-Gestationalneonatal iron deficiency, a common micronutrient deficiency affecting the offspring of more than 30% of pregnancies worldwide, leads to long-term cognitive and behavioral abnormalities. Preclinical models of gestational-neonatal iron deficiency result in reduced energy metabolism and expression of genes critical for neuronal plasticity and cognitive function, which are associated with a smaller hippocampal volume and abnormal neuronal dendrite growth. Because insulin-like growth factor (IGF) modulates early postnatal cellular growth, differentiation, and survival, we used a dietary-induced rat model to assess the effects of gestational iron deficiency on activity of the IGF system. We hypothesized that gestational iron deficiency attenuates postnatal hippocampal IGF signaling and results in downstream effects that contribute to hippocampal anatomic and functional deficits. At postnatal day (P) 15 untreated gestational-neonatal iron deficiency markedly suppressed hippocampal IGF activation and protein kinase B signaling, and reduced neurogenesis, while elevating extracellular signal-regulated kinase 1/2 signaling and hypoxia-inducible factor-1␣ expression. Iron treatment beginning at P7 restored IGF signaling, increased neurogenesis, and normalized all parameters by the end of rapid hippocampal differentiation (P30). Expression of the neuronspecific synaptogenesis marker, disc-large homolog 4 (PSD95), increased more rapidly than the glia-specific myelination marker, myelin basic protein, following iron treatment, suggesting a more robust response to iron therapy in IGF-I-dependent neurons than IGF-IIdependent glia. Collectively, our findings suggest that IGF dysfunction is in part responsible for hippocampal abnormalities in untreated iron deficiency. Early postnatal iron treatment of gestational iron deficiency reactivates the IGF system and promotes neurogenesis and differentiation in the hippocampus during a critical developmental period. hippocampal development; micronutrient deficiency; insulin receptor; insulin-like growth factor I receptor; neurogenesis; extracellular signal-regulated kinase; protein kinase B IRON DEFICIENCY IS THE MOST COMMON nutrient deficiency, affecting approximately two billion people and 30 -50% of pregnancies and their fetuses worldwide (49). Common clinical conditions during pregnancy such as severe maternal iron deficiency anemia, intrauterine insufficiency due to maternal hypertension (i.e., intrauterine growth restriction), and maternal diabetes mellitus as well as nonclinical conditions such as cigarette smoking result in fetal iron deficiency (15,28, 46,57). In humans, early life iron deficiency leads to long-term cognitive deficits and behavioral abnormalities (39), which...

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Perinatal Iron Deficiency Decreases Cytochrome c Oxidase (CytOx) Activity in Selected Regions of Neonatal Rat Brain

Cited by 260 publications

References 39 publications

Explicit memory performance in infants of diabetic mothers at 1 year of age

Explicit memory performance in infants of diabetic mothers at 1 year of age

Heme deficiency may be a factor in the mitochondrial and neuronal decay of aging

Gestational-neonatal iron deficiency suppresses and iron treatment reactivates IGF signaling in developing rat hippocampus

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