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J R Prohaska

Publications and source records attributed to J R Prohaska.

At least 37 records · Page 2Linked to original sources
PubMed1993

Persistent regional changes in brain copper, cuproenzymes and catecholamines following perinatal copper deficiency in mice.

Copper levels in the central nervous system are influenced by Cu nutriture during perinatal development. A mouse model of dietary Cu deficiency, initiated during late gestation, was employed to examine putative changes in regional levels of brain Cu, norepinephrine, dopamine and selected enzymes of 4-wk-old female and male offspring. Levels of Cu in six different regions of brain from Cu-deficient (-Cu) mice were reduced 80% or greater compared with levels in Cu-adequate (+Cu) controls. One month following Cu repletion, brain regional Cu levels were only half those measured in +Cu mice. Norepinephrine concentrations were significantly lower in all brain regions of -Cu offspring except the hypothalamus of -Cu female mice. Compared with values in +Cu mice, regional brain dopamine in -Cu mice was markedly elevated in cerebellum and medulla, unchanged in cerebrum and striatum, and elevated variably in hypothalamus and midbrain. Copper repletion normalized alterations in brain norepinephrine and dopamine concentrations. Cytochrome c oxidase activity in brain regions of -Cu mice was 29-53% of that measured in +Cu mice; the drop in midbrain was less than in other regions. Cu,Zn-superoxide dismutase activity (Cu,Zn-SOD) in brain regions of -Cu mice was 70-83% of that measured in +Cu mice. Midbrain Cu,Zn-SOD activity was not altered by Cu deficiency. Repletion of -Cu mice reversed brain regional Cu,Zn-SOD activity changes but not cytochrome c oxidase activity changes. These data extend previous observations and suggest that persistent changes to brain may occur following perinatal Cu deficiency. These data also support the hypothesis that there is brain-regional specificity in response to Cu deficiency and repletion.

Animals↗
PubMed1991

Changes in Cu,Zn-superoxide dismutase, cytochrome c oxidase, glutathione peroxidase and glutathione transferase activities in copper-deficient mice and rats.

Dietary copper deficiency was produced in Swiss albino mice and Sprague Dawley rats to compare changes in selected antioxidant enzymes. A 5-wk dietary treatment was employed, starting approximately 1 wk after birth for mice (initially via dams) and 3 wk after birth for rats. An additional confirmatory experiment was conducted with mice using the postweanling paradigm. Mouse offspring (6 wk of age) and rats (8 wk of age) maintained on a Cu-deficient treatment were compared with Cu-adequate controls. Compared with Cu-adequate animals, Cu-deficient mice and rats were anemic, had lower ceruloplasmin activities and liver copper levels, and had higher relative weights of heart and small intestine. Activity of cytochrome c oxidase (mice) and Cu,Zn-superoxide dismutase (mice and rats) was lower in all seven organs examined from Cu-deficient animals compared with Cu-adequate animals, although there were organ and species differences. Compared with Cu-adequate controls, glutathione peroxidase activity was lower in liver and plasma of Cu-deficient mice and rats. Hepatic glutathione transferase activity was markedly lower in those Cu-deficient mice started on treatment at 1 wk of age but not in those mice or rats subjected to postweanling copper deficiency.

Animals↗
PubMed1990

Effect of dietary copper deficiency on the distribution of dopamine and norepinephrine in mice and rats.

Dietary copper deficiency was produced in Swiss albino mice and Sprague Dawley rats to determine the organ specificity of alterations in norepinephrine (NE) and dopamine (DA) concentrations and the relationship with organ copper levels. A 5-week dietary treatment was used, which started 1 week after birth for mice, initially via dams, and 3 weeks after birth for rats. Mice offspring (6 weeks of age) and rats (8 weeks of age) maintained on a copper-deficient (-Cu) treatment were compared with copper-adequate (+Cu) controls. Compared with +Cu animals, -Cu mice and rats were anemic and had low (<1% of +Cu) ceruloplasmin activities but normal body weights. The -Cu mice had organ copper concentrations ranging between 30% and 65% of +Cu values for eight organs studied, with the thymus being the least depleted. For -Cu rats, the range was 15% to 65%. Significant reductions in NE concentration were observed in the heart, pancreas, and spleen of -Cu mice. Elevated DA levels were observed in all organs except the brain. For -Cu rats, the NE level was lower in the heart and the DA level was higher in both the heart and spleen compared with +Cu rats. Dopamine elevation in the heart and spleen for both -Cu mice and rats was four- and fivefold higher, respectively. Adrenal catecholamine levels were only slightly changed by copper deficiency in mice or rats. Urinary levels of both NE and DA were higher in -Cu rats and mice. Plasma and heart tyrosine levels were not altered in -Cu mice. Elevated DA in -Cu rodents may be due to limiting dopamine-beta-monooxygenase. Higher urinary NE and lower organ NE may be due to a combination of decreased synthesis and enhanced turnover. The magnitude of decreased organ copper was not predictive of altered catecholamine pool size.

Journal Article↗
PubMed1990

Development of the stable isotope tracer approach for studies of copper turnover in the rat and mouse.

The stable isotope tracer approach was explored for long-term investigations of copper turnover in the adult rat and mouse, with inductively coupled plasma mass spectrometry for isotope measurements. The isotopic measurement method permitted precision and accuracy of <1.0%, with an overall sample blank of <0.05 microg copper. Rats were fed a copper-deficient diet and deionized water with (+Cu) or without (-Cu) copper (20 microg/ml). Both groups underwent a single-day replacement of drinking water with 20 microg/ml of (65)Cu. Compared with the baseline isotope ratio ((65)Cu/(63)Cu) of 0.462 +/- 0.002, blood plasma ratios for the +Cu group on days 2, 7, and 14 postdosing were 0.702 +/- 0.021, 0.557 +/- 0.004, and 0.474 +/- 0.001, respectively. The corresponding data for liver were 1.652 +/- 0.018, 0.560 +/- 0.005, and 0.482 +/- 0.001, respectively. For the -Cu group, respective plasma ratios were 1.580 +/- 0.04. 0.917 +/- 0.02, and 0.664 +/- 0.01 for days 2, 7, and 14 postdosing, and the ratios for liver were 0.987 +/- 0.02, 0.876 +/- 0.04, and 0.739 +/- 0.03. Mice previously made copper deficient to varying degrees were given a single-day replacement with the label. When the 24-hour postdosing isotope ratios in the livers of these mice were correlated with the activity of plasma ceruloplasmin, a negative correlation (r = -0.85) was observed. Isotope enrichment in both rats and mice was greater in the copper-deficient animals compared with the controls.

Journal Article↗
PubMed1990

Development of copper deficiency in neonatal mice.

Dietary copper (Cu) deficiency was produced in Swiss albino mice to determine the temporal relationship between depletion of Cu and changes in the cardiovascular and nervous system. Dams were placed on a Cu-deficient diet 4 days after parturition. Half the dams were provided with deionized water and their offspring are referred to as Cu-deficient (-Cu). Half the dams were given cupric sulfate in their drinking water (20 microg Cu/mL) and their offspring are referred to as Cu-adequate (+Cu). At 6 weeks of age a sample of the -Cu mice were repleted with CuSO(4). Mice were sampled 1 day after birth and at weekly intervals for 7 weeks. Both +Cu and -Cu mice grew at the same rate: birth weight increased 16-fold at 6 weeks of age. Liver Cu more than doubled between 1 and 7 days of age. At 2 weeks of age -Cu mice were anemic (lower hematocrit and hemoglobin) and had lower liver Cu and plasma ceruloplasmin activity compared to +Cu mice. Liver Fe was not elevated in -Cu mice until 2 weeks after anemia developed. At weaning first signs of altered catecholamine metabolism included elevation of dopamine in both heart and spleen. Norepinephrine concentrations and content, in contrast, were not both lowered in -Cu mice until 5 weeks of age. Heart weight was first elevated in -Cu mice at 6 weeks of age and relative weight (mg/g body wt) at 4 weeks of age. Liver Cu concentration was lower in 1-week repleted mice than in +Cu mice. Anemia preceded the development of cardiac hypertrophy and altered catecholamine levels in -Cu mice.

Journal Article↗
PubMed1990

Copper-deficient mice have higher cardiac norepinephrine turnover.

Norepinephrine metabolism was investigated in 6-wk-old male Swiss albino copper-deficient and copper-supplemented mice. Beginning 4 d after birth of pups, dams were fed a diet low in copper (Cu) (0.4 mg/kg) and offspring were weaned to this diet at 21 d of age. Half the dams and their respective offspring received Cu (20 micrograms/ml) in the drinking water (+Cu) and served as controls. Unsupplemented offspring (-Cu) had lower liver Cu levels, exhibited anemia, and had increased heart weights but normal body weights compared to +Cu mice. Urinary output of norepinephrine and dopamine was higher, whereas output of creatinine and epinephrine was not different in -Cu mice compared to +Cu mice. Both fractional and calculated turnover of norepinephrine following inhibition of tyrosine 3-monooxygenase by alpha-methyl-p-DL-tyrosine methyl ester (alpha-MT) was higher in hearts from -Cu mice than in those from +Cu mice. Hearts and spleens from -Cu mice appeared to have higher tyrosine 3-monooxygenase activity as judged by increasing rates of L-dihydroxyphenylalanine accumulation following injection of m-hydroxybenzylhydrazine (NSD-1015), an inhibitor of aromatic amino acid decarboxylase. Turnover rates of norepinephrine for cerebellum were not different between +Cu and -Cu mice. Loss of norepinephrine from adrenal glands of mice injected with alpha-MT was not observed in the 8-h period studied. The smaller norepinephrine pool observed in organs of -Cu mice may have resulted from lower synthesis due to limiting dopamine-beta-monooxygenase activity and to higher turnover.

Adrenal Glands↗
PubMed1989

Biochemical and immunological changes in mice following postweaning copper deficiency.

Weanling albino male mice rapidly develop biochemical signs of copper deficiency when fed a purified diet containing 0.5 mg Cu/kg. Plasma ceruloplasmin activity of copper-deficient (-Cu) mice was 5% of that of copper-adequate (+Cu) control mice after only 3 d on the diet. More gradual loss of organ (liver, spleen, and thymus) cytochrome c oxidase activity was observed during the next 4 wk. Body weight was equivalent between +Cu and -Cu mice, but thymus weight dropped faster in -Cu mice than +Cu mice. The number of antibody producing cells to sheep erythrocytes was lower in -Cu mice compared to +Cu mice after 17 d on the diet. Spleen cytochrome oxidase activity of -Cu mice was 50% of that of +Cu mice by 10 d on the diet. Mitogenic response of splenic and thymic lymphocytes to concanavalin A (con A) was not greatly different between +Cu and -Cu mice. Splenocytes from -Cu mice had a 3-fold higher thymidine incorporation rate in the absence of mitogen compared to +Cu mice. The depressed antibody and high mitogenic background responses of -Cu mice were similar to previous work with another strain (C58) of mice that had been started on copper-deficient treatment from birth. However, the normal proliferative response to con A stimulation in postweaning copper deficiency differs from the previous model. Mice of both studies were very copper-deficient as judged by liver copper levels. Timing of the copper-deficient treatment influences the manner in which copper deficiency alters the immune response.

Animals↗
PubMed1989

Effects of dietary copper deficiency on male offspring of heterozygous brindled mice.

Female C57BL mice heterozygous for the brindled gene were mated to normal males and fed on a purified diet low in copper throughout gestation and lactation with (+Cu) or without (-Cu) Cu-supplemented drinking water. Male offspring of two genotypes (control, +/y and brindled, Mobr/y) were compared when 10-12 d old. Brindled mice from dams on the -Cu treatment were smaller and had lower packed cell volumes than brindled mice from dams on the +Cu treatment. The -Cu brindled mice were smaller than their littermate brothers (+/y) but had equivalent biochemical features consistent with severe Cu deficiency. Compared with control mice from dams on the +Cu treatment, caeruloplasmin (EC 1.16.3.1) activity was lower in offspring of all three other groups including Mobr/y mice who were not anaemic. Iron levels were similar in organs and bone marrow from all four groups of offspring. When dietary Cu is limiting in brindled mice a more severe Cu deficiency ensues. Thus, appropriate Cu nutriture is important to the management of Menkes' disease in humans, a genetic analogue of the brindled mouse.

Anemia↗
PubMed1989

Copper deficiency during perinatal development: effects on the immune response of mice.

Dietary copper (Cu) was restricted in Swiss albino mice during five discrete intervals over a 9-wk period of perinatal development: gestation only (G), lactation only (L), 3 wk postlactation (PL), 1 wk after birth through postlactation (2/3L + PL), and lactation plus postlactation (L + PL). Biochemical and immunological status of mice in copper-deficient (-Cu) treatment groups in models G and L did not differ from that of copper-adequate (+Cu) controls. Signs of severe copper deficiency, such as low liver copper levels, and significant reductions in activity of plasma ceruloplasmin and splenocyte Cu-Zn superoxide dismutase were most evident in 6-wk-old mice from two groups, -Cu 2/3L + PL and -Cu L + PL. Mice in these groups were anemic and had small thymuses and enlarged spleens compared to controls receiving +Cu treatment. The -Cu mice demonstrated impaired antibody (plaque-forming cells, PFC) response to sheep erythrocytes, and the attenuation was proportional to copper deficiency, as judged by liver copper levels. Total plasma IgM levels were not greatly altered by -Cu treatment except in model L + PL. Total IgG levels were markedly reduced in this group and in the -Cu 2/3L + PL group. The PFC response of mice in the -Cu PL group was normal even though signs of copper deficiency were evident; however, the PFC response was reduced when -Cu treatment was extended to 5 wk and was reversible by switching to +Cu treatment. Splenocyte reactivity to B- and T-cell mitogens was not greatly different between groups. Incorporation of thymidine into DNA in the absence of mitogen was higher in -Cu mice. It is evident that severity of copper deficiency is related to degree of impaired immunity. Furthermore, severity of copper deficiency is dependent on duration and time of initiation of dietary copper restriction.

Animals↗
PubMed1988

Influence of genetic obesity, food intake and adrenalectomy in mice on selected trace element-dependent protective enzymes.

Experiments were conducted to determine if food intake and adrenalectomy influenced abnormal antioxidant defense mechanisms observed in obese mice. Paired male C57BL/6J mice of two genotypes, obese (ob/ob) and lean (+/?), were fed a nonpurified diet ad libitum or restricted (2.5 g/d) until 3 mo old. Obese mice had larger livers and kidneys but smaller brains than lean mice. Plasma ceruloplasmin activity of obese mice was 240% of that of lean mice. Restricting food intake but not adrenalectomy reduced this difference, but ceruloplasmin activity of obese mice was still 150% of that of restricted-fed lean mice. Glutathione peroxidase (GSH-Px) activity in liver of obese mice was 70% of that in control lean mice; however, in kidney GSH-Px activity was 135% of that in obese mice. Both liver and kidney GSH-Px differences were eliminated by food restriction but not by adrenalectomy. Blood and brain GSH-Px activity was not influenced by the mutation. Liver and kidney copper-zinc superoxide dismutase activity was lower in obese mice than in lean littermates, 30 and 20%, respectively. Food restriction eliminated this difference in liver but not in kidney. Glutathione S-transferase activity using 1-chloro-2,4-dinitrobenzene as substrate was 55% lower in liver (not kidney) of obese mice than in lean mice and this difference was not markedly influenced by food restriction. Obese mice have marked changes in the steady-state activities of a number of protective enzymes that are organ dependent and, in part, due to the hyperphagia associated with this mutation.

Adrenal Glands↗
PubMed1987

Dietary copper deficiency alters protein and lipid composition of murine lymphocyte plasma membranes.

Protein and lipid analyses were conducted on isolated erythrocyte and lymphocyte plasma membranes from 7-wk-old male C57BL copper-deficient and copper-supplemented mice to investigate mechanisms for the altered immunity that accompanies dietary copper deficiency. Beginning at parturition, dams were fed a diet low in copper (0.5 mg/kg) and the offspring were weaned to this diet. Half the dams and their respective offspring received supplemental copper (20 mg/L) in the drinking water (+Cu) and served as controls. Unsupplemented offspring (-Cu) had lower activity of cuproenzymes serum ceruloplasmin, spleen and thymus cytochrome-c oxidase and copper, zinc-superoxide dismutase. The -Cu mice exhibited anemia, splenomegaly and thymic atrophy. Based on the marker enzyme alkaline phosphodiesterase I (APDE-I), lymphocyte plasma membranes were enriched 7- to 10-fold for spleen and thymus, respectively, after discontinuous sucrose density centrifugation. The activity of APDE-I was higher in spleen and thymus samples from -Cu mice than from those of +Cu mice for both crude homogenates and purified plasma membranes. Proteins were fractionated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis followed by silver staining. A yellow-appearing band, Mr 74,000, present in all splenic membrane samples from +Cu mice was not evident in the samples from -Cu mice. Fatty acid methyl esters (FAME) were quantified by gas chromatography. Compared to splenic membranes from +Cu mice, the samples from -Cu mice demonstrated significant changes in all FAME (lower 16:0, 18:0 and 20:3n-6 and higher 18:1n-9, 18:2n-6 and 20:4n-6), including a higher unsaturation index. FAME composition of erythrocyte ghosts from -Cu mice demonstrated similar changes.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1986

Lipid and fatty acid composition of organs from copper-deficient mice.

Experiments were conducted to study the total lipid and fatty acid composition of liver, kidney, brain and heart of 7-wk-old male C57BL mice. Dietary copper deficiency was initiated at birth by feeding dams a purified diet containing 0.5 mg/kg copper. Offspring were fed the copper-deficient diet 4 wk postweaning. Control dams and offspring were fed the same diet but with added copper in the drinking water, 20 mg/L. Compared with controls the copper-deficient mice exhibited hepatomegaly, cardiac hypertrophy and a 4% reduction in brain weight as well as low ceruloplasmin activity (0.5% of control). Total phospholipid concentration in liver and kidney and total triacylglycerol concentration in kidney was lower in copper-deficient mice compared to concentrations measured in liver and kidney of control mice. The major change in essential fatty acid composition in the copper-deficient mice which was consistent between organs and lipid classes was a significantly lower proportion and absolute amount of dihomo-gamma-linolenic acid. Other changes in fatty acid composition were variable.

Animals↗
PubMed1986

Genetic diseases of copper metabolism.

There are several known examples of mutations which influence copper homeostasis in humans and animals. Pleiotropic effects are observed when the mutant gene disturbs copper flux. In some cases, the mutation alters the level of a specific copper ligand (enzyme) and the clinical consequences are unique. The two most widely studied genetic maladies in humans are Menkes' and Wilson's diseases. Menkes' disease is an X-linked fatal disorder in which copper accumulates in some organs (intestine and kidney) and is low in others (liver and brain). Wilson's disease is an autosomal recessive disorder in which copper accumulates, if untreated, in liver and subsequently in brain and kidney. Pathophysiological consequences of copper deficiency and toxicity characterize these two disorders. Specific mutations of human cuproenzymes include overproduction of copper-zinc superoxide dismutase in Down's syndrome, absence of tyrosinase in albinism, hereditary mitochondrial myopathy due to reduction in cytochrome c oxidase, and altered lysyl oxidase in X-linked forms of cutis laxa and Ehlers-Danlos syndrome. Mutations altering copper metabolism are also known in animals. Several murine mutants have been studied. The most extensively investigated mutants are the mottled mice, in particular brindled mice, which have a mutation analogous to that of Menkes' disease. Another recently described murine mutation is toxic milk (tx) an autosomal recessive disorder that is characterized by copper accumulation in liver. Two other mutants, crinkled and quaking, were once thought to exhibit abnormal copper metabolism. Recent data has not confirmed this. A mutation in Bedlington terriers has been described which is very similar to Wilson's disease.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗