skip to main content
OSTI.GOV title logo U.S. Department of Energy
Office of Scientific and Technical Information

Title: Copper deficiency in neonatal mice alters brain catecholamine levels

Abstract

Copper (Cu) deficiency was investigated in Swiss albino mice to develop a model that alters brain catecholamine metabolism without serious growth impairment. Cu deficiency was induced by feeding a diet low in Cu to dams beginning either 7 days (d) prior, 4d prior, 4d after, or on the day of parturition. All 4-week-old male Cu-deficient ({minus}Cu) offspring were anemic and exhibited biochemical characteristics of Cu deficiency when compared to their respective +Cu control mice. However, the best model, which resulted in altered catecholamine metabolism characterized by elevation of dopamine (DA) and depression in norepinephrine (NE) in brain, heart, and spleen, was when treatment began 4d prior to birth. Body and brain weight were not altered. However, levels of Cu in brain and liver of {minus}Cu mice were markedly reduced to 21% and 31% of those measured in +Cu controls, respectively. Furthermore, brain NE and DA concentrations of {minus}Cu mice were 72% and 132% of those quantified in +Cu offspring, respectively. A plausible explanation is that dietary Cu deficiency results in lower activity of brain dopamine-{beta}-monooxygenase, the Cu dependent enzyme that catalyzes conversion of DA to NE. It is not yet known if these changes in Ne and DA pool sizemore » altered the quantity or characteristics of the neuronal catecholamine receptors, and more importantly, whether or not the observed changes are reversible by nutritional intervention.« less

Authors:
;  [1]
  1. (Univ. of Minnesota, Duluth (United States))
Publication Date:
OSTI Identifier:
5213033
Alternate Identifier(s):
OSTI ID: 5213033
Report Number(s):
CONF-9104107--
Journal ID: ISSN 0892-6638; CODEN: FAJOE
Resource Type:
Conference
Resource Relation:
Journal Name: FASEB Journal (Federation of American Societies for Experimental Biology); (United States); Journal Volume: 5:5; Conference: 75. annual meeting of the Federation of American Societies for Experimental Biology (FASEB), Atlanta, GA (United States), 21-25 Apr 1991
Country of Publication:
United States
Language:
English
Subject:
63 RADIATION, THERMAL, AND OTHER ENVIRON. POLLUTANT EFFECTS ON LIVING ORGS. AND BIOL. MAT.; CATECHOLAMINES; METABOLISM; COPPER; BIOLOGICAL EFFECTS; BRAIN; DOPAMINE; MICE; NEONATES; NORADRENALINE; NUTRITIONAL DEFICIENCY; RECEPTORS; ADRENAL HORMONES; AMINES; ANIMALS; AROMATICS; AUTONOMIC NERVOUS SYSTEM AGENTS; BODY; CARDIOTONICS; CARDIOVASCULAR AGENTS; CENTRAL NERVOUS SYSTEM; DRUGS; ELEMENTS; HORMONES; HYDROXY COMPOUNDS; MAMMALS; MEMBRANE PROTEINS; METALS; NERVOUS SYSTEM; NEUROREGULATORS; ORGANIC COMPOUNDS; ORGANS; PHENOLS; POLYPHENOLS; PROTEINS; RODENTS; SYMPATHOMIMETICS; TRANSITION ELEMENTS; VERTEBRATES 560300* -- Chemicals Metabolism & Toxicology

Citation Formats

Bailey, W.R., and Prohaska, J.R. Copper deficiency in neonatal mice alters brain catecholamine levels. United States: N. p., 1991. Web.
Bailey, W.R., & Prohaska, J.R. Copper deficiency in neonatal mice alters brain catecholamine levels. United States.
Bailey, W.R., and Prohaska, J.R. Fri . "Copper deficiency in neonatal mice alters brain catecholamine levels". United States. doi:.
@article{osti_5213033,
title = {Copper deficiency in neonatal mice alters brain catecholamine levels},
author = {Bailey, W.R. and Prohaska, J.R.},
abstractNote = {Copper (Cu) deficiency was investigated in Swiss albino mice to develop a model that alters brain catecholamine metabolism without serious growth impairment. Cu deficiency was induced by feeding a diet low in Cu to dams beginning either 7 days (d) prior, 4d prior, 4d after, or on the day of parturition. All 4-week-old male Cu-deficient ({minus}Cu) offspring were anemic and exhibited biochemical characteristics of Cu deficiency when compared to their respective +Cu control mice. However, the best model, which resulted in altered catecholamine metabolism characterized by elevation of dopamine (DA) and depression in norepinephrine (NE) in brain, heart, and spleen, was when treatment began 4d prior to birth. Body and brain weight were not altered. However, levels of Cu in brain and liver of {minus}Cu mice were markedly reduced to 21% and 31% of those measured in +Cu controls, respectively. Furthermore, brain NE and DA concentrations of {minus}Cu mice were 72% and 132% of those quantified in +Cu offspring, respectively. A plausible explanation is that dietary Cu deficiency results in lower activity of brain dopamine-{beta}-monooxygenase, the Cu dependent enzyme that catalyzes conversion of DA to NE. It is not yet known if these changes in Ne and DA pool size altered the quantity or characteristics of the neuronal catecholamine receptors, and more importantly, whether or not the observed changes are reversible by nutritional intervention.},
doi = {},
journal = {FASEB Journal (Federation of American Societies for Experimental Biology); (United States)},
number = ,
volume = 5:5,
place = {United States},
year = {Fri Mar 15 00:00:00 EST 1991},
month = {Fri Mar 15 00:00:00 EST 1991}
}

Conference:
Other availability
Please see Document Availability for additional information on obtaining the full-text document. Library patrons may search WorldCat to identify libraries that hold this conference proceeding.

Save / Share:
  • The total PFK activity as well as the nature of the isozyme pools which are present in situ are dependent on the types and amounts of PFK subunits which are available to randomly combine. In order to better understand the mechanisms that dictate subunit levels and consequently the isozyme pools during neonatal development, they have measured subunit levels as well as rates of (/sup 14/C)-phenylalanine incorporation into each subunit. In the near-term fetal liver, muscle, heart and brain, all three subunits were present, but their fate following birth was highly variable. That is, subunit levels were found to decrease, disappear,more » remain nearly constant, increase several-fold, or increase an order of magnitude. The loss of the L-type and C-type subunits from maturing muscle was preceded by a cessation of synthesis prior to disappearance. However, the large accumulation of the M-type subunit in developing muscle was not due to increased synthesis but rather decreased degradation. Similar results were found for the increased levels of the L-type subunit in liver. In other tissues, subunit levels did not vary during maturation although rates of synthesis decreased. In most cases the subunit synthesis rates in adult tissues were less than that found in early neonatal tissue. It is clear from this work that, during neonatal development, regulation of subunit levels is a complex phenomenon involving alteration of rates of synthesis as well as rates of degradation.« less
  • Mice homozygous for the recessive toxic milk allele (tx/tx) accumulate vast amounts of hepatic copper. Despite this, their offspring are born severely copper deficient. To follow patterns of copper uptake, the authors have measured hepatic copper levels and {sup 67}Cu uptake in fetuses and neonates from normal and mutant (TX) females. Increases in liver weight are equivalent in fetuses from both genotypes. As copper bound to the protein metallothionein accumulates, the ratio of concentration to oliver weight remains constant, but is higher in normal than in TX; comparable differences in {sup 67}Cu uptake are shown. In placentae, copper levels andmore » {sup 67}Cu uptake are similarly markedly reduced in TX, indicating that hepatic copper deficiency is not due to blockage and placental accumulation. Although TX neonates are severely copper deficient at birth, they appear to be otherwise normal; this coupled with the fact that they can be rescued and thrive following a single dose of Cu as late as the sixth postnatal day, suggests that copper accumulation via binding to metallothionein may serve to prevent copper toxicity to the fetus rather than as a mechanism for storage of copper for later use. Neonates continue to show copper levels dictated by the genotype of their dams through the second week, but during the third postnatal week levels shift to reflect their own genotype.« less
  • Adult toxic milk mice exhibit over ten times normal amounts of hepatic copper. Patterns of hepatic copper accumulation were followed in neonates born both to normal (+/-/+/-, +/-/tx/-) and mutant (tx/-/tx/-) mothers. At birth all offspring of normal dams have high hepatic copper levels which then decline over the next two weeks; after this time levels in normal neonates continue to decline while in mutant neonates levels rise sharply, both genotypes attaining adult levels by six weeks. Conversely, all offspring of mutant females are born severely copper deficient, a condition exacerbated by ingestion of the copper deficient milk that thesemore » females produce, which leads to death during the second week. Such infants can be rescued if fostered to normal lactating females at birth; copper levels rise for two weeks and then fall in normal infants but continue to rise in mutant infants. Beginning at the third postnatal week then, hepatic copper levels are attributable to infant genotype, while prior to this time concentrations reflect maternal genotype. The pattern of uptake of /sup 67/Cu by neonates is consistent with the copper content observed above. Those hepatic cuproproteins which vary according to genotype also indicate that the third week is the time when infant genotype becomes expressed in phenotype. The significant accumulation of copper in the livers of fetuses carried by normal dams is compared to that occurring in the livers of suckling mutants.« less
  • Cu deficiency results in altered levels of catecholamines in peripheral tissues and specific regions of the CNS in rodents. Because catecholamines can affect feeding behavior, meal patterns of control and Cu deficient rats were compared using a computerized system. Cu deficiency was induced by feeding dams a low Cu diet beginning at 17d of pregnancy and weaning pups to the same diet. Between 4.5 and 6.5 wk-of-age, rats fed {minus}Cu diet ate fewer meals during the light period than did controls. However, total food intake and meal size during light and dark periods were similar for the two groups. Atmore » 6.5 wk-of-age, Cu deficiency was confirmed by stunted growth, low tissue Cu and enlarged hearts. Cardiac CA was increased 4.3-fold in Cu deficient rats, while the NE level in heart of Cu deficient rats was 54% that of control. The concentrations of both DA and NE were increased in ventromedial hypothalamus of Cu deficient rats. These results indicate that alterations in catecholamine status of ventromedial hypothalamus associated with severe Cu deficiency fail to markedly affect feeding behavior.« less
  • Exposure to apparently unrelated neurotoxicants can nevertheless converge on common neurodevelopmental events. We examined the long-term effects of developmental exposure of rats to terbutaline, a {beta}-adrenoceptor agonist used to arrest preterm labor, and the organophosphorus insecticide chlorpyrifos (CPF) separately and together. Treatments mimicked the appropriate neurodevelopmental stages for human exposures: terbutaline on postnatal days (PN) 2-5 and CPF on PN11-14, with assessments conducted on PN45. Although neither treatment affected growth or viability, each elicited alterations in CNS cell signaling mediated by adenylyl cyclase (AC), a transduction pathway shared by numerous neuronal and hormonal signals. Terbutaline altered signaling in the brainstemmore » and cerebellum, with gender differences particularly notable in the cerebellum (enhanced AC in males, suppressed in females). By itself, CPF exposure elicited deficits in AC signaling in the midbrain, brainstem, and striatum. However, sequential exposure to terbutaline followed by CPF produced larger alterations and involved a wider spectrum of brain regions than were obtained with either agent alone. In the cerebral cortex, adverse effects of the combined treatment intensified between PN45 and PN60, suggesting that exposures alter the long-term program for development of synaptic communication, leading to alterations in AC signaling that emerge even after adolescence. These findings indicate that terbutaline, like CPF, is a developmental neurotoxicant, and reinforce the idea that its use in preterm labor may create a subpopulation that is sensitized to long-term CNS effects of organophosphorus insecticides.« less