Insufficient copper (Cu) during perinatal development of rodents has a major impact on the central nervous system leading to altered neurochemistry and behavior even after long-term Cu repletion. Human intakes of Cu during pregnancy and lactation may be suboptimal but current RDA recommendations do not encourage the need for supplements. The long-range goal of this research is to identify the biochemical roles of Cu responsible for severe long-term neurochemical and behavioral consequences of perinatal Cu deficiency.
Four specific aims will test the overall hypothesis that altered cuproenzymes are responsible for the phenotype observed. Research will utilize nutritional and genetic models with Holtzman rats and transgenic mice.
AIM 1 : We will test the hypothesis that limitation in the Cu-dependent enzyme dopamine beta- monooxygenase (DBM) is responsible by treating rats with L-3.4-dihydroxyphenvlserine (L-DOPS) to bypass the DBM step and restore low brain norepinephrine.
AIM 2 : We will test the hypothesis that limitation in Cu.Zn-superoxide dismutase (SOD) is responsible by comparing features of Cu deficiency in SOD -/- mice to wild-type controls Secondly, we will compare these mice to mice with altered SOD activity, Ctrl +/- mice, due to lower copper transport capacity. Thirdly, we will restore the deficit in SOD activity following these treatments with TEMPOL a membrane permeable SOD mimetic.
AIM 3 : We will test the hypothesis that limitation in mitochondrial cytochrome C oxidase (CCO) is responsible by characterizing brain energy metabolism in Cu deficient rats with a rat model of chronic CCO inhibition that uses cyanide.
AIM 4 : We will test the hypothesis that limitation in Cu-dependent ferroxidases lead to lower brain iron and are responsible by comparing rats reared on an iron-fortified diet to restore brain iron.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
3R01HD039708-08S1
Application #
8097127
Study Section
Integrative Nutrition and Metabolic Processes Study Section (INMP)
Program Officer
Vitkovic, Ljubisa
Project Start
2010-07-24
Project End
2011-03-31
Budget Start
2010-07-24
Budget End
2011-03-31
Support Year
8
Fiscal Year
2010
Total Cost
$73,136
Indirect Cost
Name
University of Minnesota Duluth
Department
Biochemistry
Type
Schools of Medicine
DUNS #
071508873
City
Duluth
State
MN
Country
United States
Zip Code
55812
Broderius, Margaret; Mostad, Elise; Prohaska, Joseph R (2012) Suppressed hepcidin expression correlates with hypotransferrinemia in copper-deficient rat pups but not dams. Genes Nutr 7:405-14
Prohaska, Joseph R; Broderius, Margaret (2012) Copper deficiency has minimal impact on ferroportin expression or function. Biometals 25:633-42
Gletsu-Miller, N; Broderius, M; Frediani, J K et al. (2012) Incidence and prevalence of copper deficiency following roux-en-y gastric bypass surgery. Int J Obes (Lond) 36:328-35
Bastian, Thomas W; Anderson, Jeremy A; Fretham, Stephanie J et al. (2012) Fetal and neonatal iron deficiency reduces thyroid hormone-responsive gene mRNA levels in the neonatal rat hippocampus and cerebral cortex. Endocrinology 153:5668-80
Mostad, Elise J; Prohaska, Joseph R (2011) Glycosylphosphatidylinositol-linked ceruloplasmin is expressed in multiple rodent organs and is lower following dietary copper deficiency. Exp Biol Med (Maywood) 236:298-308
Bastian, Thomas W; Lassi, Katie C; Anderson, Grant W et al. (2011) Maternal iron supplementation attenuates the impact of perinatal copper deficiency but does not eliminate hypotriiodothyroninemia nor impaired sensorimotor development. J Nutr Biochem 22:1084-90
Prohaska, Joseph R (2011) Impact of copper limitation on expression and function of multicopper oxidases (ferroxidases). Adv Nutr 2:89-95
Lyons, Jacob A; Prohaska, Joseph R (2010) Perinatal copper deficiency alters rat cerebellar purkinje cell size and distribution. Cerebellum 9:136-44
Bastian, Thomas W; Prohaska, Joseph R; Georgieff, Michael K et al. (2010) Perinatal iron and copper deficiencies alter neonatal rat circulating and brain thyroid hormone concentrations. Endocrinology 151:4055-65
Broderius, Margaret; Mostad, Elise; Wendroth, Krista et al. (2010) Levels of plasma ceruloplasmin protein are markedly lower following dietary copper deficiency in rodents. Comp Biochem Physiol C Toxicol Pharmacol 151:473-9

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