Acute and chronic effects of developmental iron deficiency on mRNA expression patterns in the brain.
ABSTRACT Because of the multiple biochemical pathways that require iron, iron deficiency can impact brain metabolism in many ways. The goal of this study was to identify a molecular footprint associated with ongoing versus long term consequences of iron deficiency using microarray analysis. Rats were born to iron-deficient mothers, and were analyzed at two different ages: 21 days, while weaning and iron-deficient; and six months, after a five month iron-sufficient recovery period. Overall, the data indicate that ongoing iron deficiency impacts multiple pathways, whereas the long term consequences of iron deficiency on gene expression are more limited. These data suggest that the gene array profiles obtained at postnatal day 21 reflect a brain under development in a metabolically compromised setting that given appropriate intervention is mostly correctable. There are, however, long term consequences to the developmental iron deficiency that could underlie the neurological deficits reported for iron deficiency.
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ABSTRACT: Abnormal iron accumulation within the brain is associated with various neurodegenerative diseases; however, there is debate about whether milder disorders of systemic iron loading, such as haemochromatosis, affect the brain. Arguments on both sides of the debate are often based on some common assumptions that have not been rigorously tested by appropriate experimentation. Recent research from our lab has applied high-throughput molecular techniques such as microarray to models of dietary and genetic iron loading to identify subtle but important effects on molecular systems in the brain that may go undetected by other methods commonly used in the field. In this chapter, we review the existing research in animal models and human patients and discuss the strengths and limitations of the different approaches commonly used. Using our findings as an example, we argue that transcriptomic methods can provide unique insights into how systemic iron loading can affect the brain and suggest some basic guidelines for extracting the most robust and reliable information from microarray studies.Metal Ions in Neurological Systems, Edited by Wolfgang Linert, Henryk Kozlowski, 01/2012: chapter Brain changes in iron loading disorders: pages 17-29; Springer-Verlag.
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ABSTRACT: It is well known that iron overload can result in pancreatic iron deposition, beta-cell destruction, and diabetes in humans. Recent studies in animals have extended the link between iron status and pancreatic function by showing that iron depletion confers protection against beta-cell dysfunction and diabetes. The aim of the present study was to identify genes in the pancreas that are differentially expressed in response to iron deficiency or overload. Weanling male Sprague-Dawley rats (n = 6/group) were fed iron-deficient, iron-adequate, or iron-overloaded diets for 3 weeks to alter their iron status. Total RNA was isolated from the pancreases and pooled within each group for microarray analyses in which gene expression levels were compared to those in iron-adequate controls. In iron-deficient pancreas, a total of 66 genes were found to be differentially regulated (10 up, 56 down), whereas in iron-overloaded pancreas, 164 genes were affected (82 up, 82 down). The most up-regulated transcript in iron-deficient pancreas was arachidonate 15-lipoxygenase (Alox15), which has been implicated in the development of diabetes. In iron-overloaded pancreas, the most upregulated transcripts were Reg1a, Reg3a, and Reg3b belonging to the regenerating islet-derived gene (Reg) family. Reg expression has been observed in response to pancreatic stress and is thought to facilitate pancreatic regeneration. Subsequent qRT-PCR validation indicated that Alox15 mRNA levels were 4 times higher in iron-deficient than in iron-adequate pancreas and that Reg1a, Reg3a, and Reg3b mRNA levels were 17-36 times higher in iron-overloaded pancreas. The elevated Alox15 mRNA levels in iron-deficient pancreas were associated with 8-fold higher levels of Alox15 protein as indicated by Western blotting. Overall, these data raise the possibility that Reg expression may serve as a biomarker for iron-related pancreatic stress, and that iron deficiency may adversely affect the risk of developing diabetes through up-regulation of Alox15.PLoS ONE 01/2014; 9(1):e86019. DOI:10.1371/journal.pone.0086019 · 3.53 Impact Factor
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ABSTRACT: Gestational iron deficiency in humans and rodents produces long-term deficits in cognitive and socioemotional function and alters expression of plasticity genes in the hippocampus that persist despite iron treatment. Prenatal choline supplementation improves cognitive function in other rodent models of developmental insults.Journal of Nutrition 11/2014; 144(11):1858-65. DOI:10.3945/jn.114.198739 · 4.23 Impact Factor