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Acute and Chronic Effects of Developmental Iron Deficiency On J Neural Transm (2006) [Suppl] 71: 173–196 # Springer-Verlag 2006 Acute and chronic effects of developmental iron deficiency on mRNA expression patterns in the brain S. L. Clardy1, X. Wang1, W. Zhao2,W.Liu2, G. A. Chase2, J. L. Beard3, B. True Felt4, J. R. Connor1 1 Department of Neurosurgery, M.S. Hershey Medical Center, Hershey, USA 2 Department of Health Evaluation Sciences, M.S. Hershey Medical Center, Hershey, USA 3 Department of Nutrition, Pennsylvania State University, College Park, USA 4 Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, USA Summary Because of the multiple biochemical pathways that require iron, behavior and physiological responsiveness (Weinberg et al., iron deficiency can impact brain metabolism in many ways. The goal of this 1979). Decreased motor activity and reversed circadi- study was to identify a molecular footprint associated with ongoing versus long term consequences of iron deficiency using microarray analysis. Rats an rhythms of thermoregulation and motor activity were were born to iron-deficient mothers, and were analyzed at two different found in another study of rats that were iron-deprived for ages: 21 days, while weaning and iron-deficient; and six months, after a five 28 days postnatally, indicating the major role iron plays in month iron-sufficient recovery period. Overall, the data indicate that on- going iron deficiency impacts multiple pathways, whereas the long term the normal function of the dopaminergic system in the consequences of iron deficiency on gene expression are more limited. These brain (Youdim et al., 1981). More recent animal studies data suggest that the gene array profiles obtained at postnatal day 21 reflect have distinguished differences between pre- and post-natal a brain under development in a metabolically compromised setting that given appropriate intervention is mostly correctable. There are, however, recovery from iron deficiency. If the iron deficiency occurs long term consequences to the developmental iron deficiency that could during neonatal and post-weaning periods, and an iron suf- underlie the neurological deficits reported for iron deficiency. ficient diet is given two-to four weeks postnatally, recovery occurs upon iron repletion (Chen et al., 1995; Erikson et al., Introduction 1997; Pinero et al., 2000), but the effects of iron deficiency in utero appear irreversible, even after iron repletion Insufficient amounts of body iron affect up to one billion (Felt and Lozoff, 1996; Kwik-Uribe, Gietzen et al., 2000; people worldwide (Andrews, 2000). Iron is especially cru- Kwik-Uribe et al., 2000). cial during development, as it is required for proper In humans, a study of second grade children who were myelination, and is also a cofactor for enzymes in neuro- anemic in infancy revealed that the learning achievement transmitter synthesis (Larkin, 1990; Beard and Connor, score and the positive task orientation was significantly 2003; Beard et al., 2003). Studies in animals dating back lower in the anemic group than in the non-anemic control over three decades have documented the damage resulting group. Data were controlled for maternal education and sex from iron deficiency. Dallman et al. demonstrated that even of child (Palti et al., 1985). A more recent study by Lozoff after iron-deficient rats were returned to a normal iron et al. found that children who had iron deficiency in infancy diet for several days, non-heme iron remained depressed, scored lower on tests of mental and motor functioning as did ferritin in brain (Dallman et al., 1975). Weinberg as teens (greater than ten years later) than those infants et al. also noted that rats exposed to iron deficiency for who were not iron-deficient as infants. Additionally, more the first 28 days of life never recovered, exhibiting a per- of the previously iron-deficient infants had repeated a grade, sistent deficit in brain non-heme iron, as well as changes in had been referred for special services, and=or was the ob- ject of parental and teacher concern regarding anxiety, de- pression, social difficulties, or attention problems (Lozoff Correspondence: J. R. Connor, 500 University Drive, Department of Neurosurgery, H110, Hershey, PA 17033, USA et al., 2000). A study of iron deficiency anemia in young e-mail: [email protected] South African anemic mothers of full-term infants found 174 S. L. Clardy et al. that the infants of anemic mothers were developmentally RNA preparation and microarray analysis delayed at 10 weeks. At nine months, despite normalization Frozen brain tissue was homogenized and extracted with TRIzol reagent of iron status in some mothers, the developmental delays (Gibco BRL Life Technologies, Baltimore, MD, USA) and further purified with the Qiagen RNeasy kit (Qiagen, Valencia, CA) utilizing the clean-up were not diminished in the infants. The iron deficiency also step according to the manufacturer’s instructions. RNA quality was evalu- affected the mothers, and even nine months post-partum, ated by A260=A280 ratio. Randomly selected samples were further ana- anemic mothers were more negative, less engaged, and less lyzed for RNA integrity using an Agilent 2100 Bioanalyzer (Agilent Technologies, Palo Alto, CA, USA); all samples analyzed demonstrated responsive toward their babies than were control mothers. acceptable quality. Synthesis of double-stranded DNA and biotinylated Mothers treated for iron deficiency exhibited behaviors cRNA from total RNA, and its subsequent hybridization to the chips, were similar to controls (Perez et al., 2005). A study of South performed according to Affymetrix (Santa Clara, CA) recommendations. African women by Beard et al. (2005) found that iron Streptavidin-phycoerythrin staining of arrays after hybridization also fol- lowed Affymetrix recommendations. Biotin-labeled and fragmented RNA treatment of anemic mothers up to nine months postpartum was hybridized to Rat Genome U34A Gene Chips containing approximately resulted in 25% improvement of depression, stress, and 7000 full-length sequences and 1000 expressed sequence tag (EST) clusters. cognitive function, further suggesting the importance of The microarrays were scanned by the Affymetrix gene array system (http:==www.affymetrix.com). Preliminary data analyses were performed maternal iron status on infant development (Beard et al., with the Affymetrix GCOS software package and the Affymetrix Data 2005). These studies highlight the need to study iron defi- Mining Tool. ciency over time, from infancy onward, and hint at the differences between ID at different stages in life (birth, Real-time PCR infancy, and motherhood). Total RNA was prepared for qualitative real-time PCR using Invitrogen’s It is now accepted that dietary iron deficiency lowers SuperScript(tm) III First-Strand Synthesis System for RT-PCR (Invitrogen brain iron and interferes with protein synthesis in the brain Corporation, Carlsbad, CA). PCR was performed using TaqMan detection probe and primers either purchased from inventory or designed with the (Beard and Connor, 2003). There is, however, a notable online software Custom TaqMan+ Gene Expression Assay File Builder lack of research into the effects of such early iron defi- (Applied Biosystems, Foster City, CA). Real-time PCR amplification of ciency in later, adult life. In these studies, we obtained a cDNA was performed using TaqMan Universal PCR Master Mix (Applied gene expression profile of rat brain to identify the molecu- Biosystems). Values were normalized to those obtained for ribosomal 18s mRNA. lar footprint of the iron-deficient brain. This information may point to the specific pathways causing the underlying Statistical analysis pathophysiology of both acute iron deficiency and its long- term, chronic effects. A benefit of microarrays in the analy- Before testing significant changes in gene expression, expression signals were normalized by using the R-Affy package from Bioconductor (version sis of iron-deficient brain is the ability to investigate global 1.2, Irizarry et al., 2003) to remove background noise and non-biological gene changes without the bias of a priori hypotheses. We variations among arrays. The background noise was removed from the PM also wanted to examine as broad a range of systems as pos- (perfect match) probe intensities using the ‘‘RMA’’ method (Irizarry, 2003), which assumes a global model for the distribution of probe intensities and sible in this first pass analysis in the iron-deficient brains, models the PM probe intensities as the sum of a normal noise component and and thus we tested the entire brain in our analysis to gain an an exponential signal component. Normalization was performed according understanding of the most dramatic and global changes to the quantile normalization method (Bolstad, 2003). Quantile normal- caused by iron deficiency. ization assumes that the expression of majority of genes on the arrays does not change in different treatments, and that the distribution of probe intensities for each array in the dataset is the same. For each probe set, the logs of the background corrected, normalized PM intensities were fitted Methods and materials with an additive multi-chip linear model, which had a chip-wise abundance term and a probe-wise affinity term. The robust median polish procedure was utilized for fitting (Tukey, 1977). Estimates were reported on the log2 Animal characteristics scale. Because approximately thirty percent of the probes were found with The studies reported here were performed in compliance with the animal MM (mismatch)
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