Toxicol Appl Pharmacol 2001 Apr 15;172(2):98-107
Lead exposure affects levels of galactolipid metabolic enzymes in the developing rat brain.
Deng W, Poretz RD. Department of Biochemistry and Microbiology, Rutgers University, 76
Lipman Drive, New Brunswick, New Jersey 08901, USA.
Lead poisoning is known to cause myelin defects. Galactolipids are the major lipid
components of myelin and
myelin-competent oligodendrocytes. The present study examines the cellular activity of
enzymes involved in the
galactolipid pathway, tissue concentrations of galactolipids, and the cellular activity of
2',3'-cyclic nucleotide
3'-phosphohydrolase (CNPase) in rat pups exposed to lead in utero and subsequently through
maternal milk from
exposed mothers and in drinking water following weaning. Pups from control and
lead-treated groups (500 or 2000
ppm lead in the drinking water) were euthanized by decapitation on postnatal day 7, 14,
21, 35, or 56. Lead
decreased levels of galactolipids and the oligodendrocyte marker CNPase in the brain to a
similar degree. The
ratios of galactocerebrosides/sulfatides and nonhydroxy fatty acid/hydroxy fatty acid
forms of the galactolipids were
not altered by lead treatment. In contrast, the activities of the galactolipid metabolic
enzymes were reduced to a
degree significantly greater than that of CNPase or galactolipids. These results are
consistent with previously
obtained data indicating that in vitro cultured oligodendroglial progenitor cells are a
target for Pb toxicity. Chronic Pb
exposure may impact on brain development by impairing timely myelin production due to
perturbation of the early
developmental commitment of oligodendroglial progenitors. It is further suggested that
perturbation of the
galactolipid pathway during the developmental maturation of oligodendrocytes may represent
a contributing
mechanism for Pb-induced neurotoxicity. Copyright 2001 Academic Press.
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Int J Dev Neurosci 2000 Dec;18(8):791-5
(Full text is available to CSU students, via Science Direct!)
Lead exposure alters Egr-1 DNA-binding in the neonatal rat brain.
Reddy GR, Zawia NH.
Department of Biology and Life Sciences, Savannah State University, GA 31404, USA.
Zinc finger proteins (ZFP) contain a structural motif (Cys-2 His-2) found in a large
family of eukaryotic transcriptional
regulatory proteins, such as Sp1. Previous studies have shown that Sp1 DNA-binding was
disrupted by exposure to
lead (Pb), due to action on its zinc finger domain. In this paper, we discuss the results
of studies with another ZFP,
Egr-1, an early growth response gene, which is functionally involved in cell proliferation
and differentiation. Egr-1
DNA-binding was studied by gel shift mobility assays in several brain regions of
developing rat pups. We observed
a distinct developmental profile of Egr-1 DNA-binding with a gradual increase from the
early to late postnatal days in
all the brain regions examined. Lactational exposure to Pb resulted in a modulation of
Egr-1 DNA binding
manifested by premature peaks in DNA-binding reminiscent of the in vivo changes previously
reported for Sp1.
These data are consistent with earlier findings that exposure to Pb both in vivo and in
vitro causes a modulation in
the DNA-binding of ZFP such as Sp1, Egr-1 and TFIIIA. The commonality by which Pb exposure
alters the
DNA-binding patterns of ZFP suggests that divalent Pb may be interacting directly with the
Zn moiety of these
proteins.
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Cytobios 2000;103(403):103-9
Alterations in some membrane properties in rat brain following exposure to lead.
Flora GJ, Seth PK.
Division of Developmental Toxicity, Industrial Toxicology Research Centre, M.G. Marg,
Lucknow, India.
The effect of lead exposure on intracellular calcium levels, membrane fluidity, lipid
peroxidation,
acetylcholinesterase and monoamine oxidase activity and its accumulation in different
regions of the brain were
studied to understand the molecular mechanism of lead induced neurotoxicity. Lead
treatment (20 mg/kg lead
nitrate, intraperitoneally, once daily for 15 days) resulted in a significant accumulation
of lead in all brain regions with
the maximum being in the hippocampus. Levels of glutathione, lipid peroxidation,
intracellular calcium and
membrane fluidity, as well as the activity of the membrane bound enzymes,
acetylcholinesterase and monoamine
oxidase, increased to a significant level in certain areas of the rat brain. The results
suggest that lead exerts
neurotoxic effects by altering certain membrane bound enzymes and may cause oxidative
stress.
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Curr Opin Neurol 1998 Dec;11(6):689-93
Selective vulnerability of the developing brain to lead.
Johnston MV, Goldstein GW.
Kennedy Krieger Institute, Baltimore, USA.
Environmental lead exposure in young children who ingest household paint dust or other
sources impairs their
potential intelligence in a linear, dose-dependent fashion in contrast to its far more
subtle effects on other neurologic
functions. Basic investigations have identified three interrelated steps in synaptic
neurotransmission at which low
levels of lead can disrupt signal processing. Lead enhances background transmitter
release, but impairs stimulated
release, inhibits function at the N-methyl-D-aspartate-type glutamate receptor and
stimulates background levels of
the intracellular messenger protein kinase C. Taken together these effects have the effect
of diminishing the
synaptic signal to noise ratio. The ability of lead to enhance 'synaptic noise' during a
critical early period of postnatal
development may permanently disrupt the architecture of cortical processing units by
depriving them of high
resolution environmental signals needed to refine synaptic connections.
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Environ Health Perspect 1990 Nov;89:91-4
Lead poisoning and brain cell function.
Goldstein GW.
Department of Neurology and Pediatrics, Johns Hopkins School of Medicine, Baltimore, MD.
Exposure to excessive amounts of inorganic lead during the toddler years may produce
lasting adverse effects upon
brain function. Maximal ingestion of lead occurs at an age when major changes are
occurring in the density of brain
synaptic connections. The developmental reorganization of synapses is, in part, mediated
by protein kinases, and
these enzymes are particularly sensitive to stimulation by lead. By inappropriately
activating specific protein
kinases, lead poisoning may disrupt the development of neural networks without producing
overt pathological
alterations. The blood-brain barrier is another potential vulnerable site for the
neurotoxic action of lead. Protein
kinases appear to regulate the development of brain capillaries and the expression of the
blood-brain barrier
properties. Stimulation of protein kinase by lead may disrupt barrier development and
alter the precise regulation of
the neuronal environment that is required for normal brain function. Together, these
findings suggest that the
sensitivity of protein kinases to lead may in part underlie the brain dysfunction observed
in children poisoned by this
toxicant.
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Neurochem Res 1999 Mar;24(3):415-21
Related Articles, Books
Protein kinase C in rat brain is altered by developmental lead exposure.
Chen HH, Ma T, Ho IK.
Department of Pharmacology and Toxicology, University of Mississippi Medical Center,
Jackson 39216, USA.
The absence of learning-related redistribution of hippocampal protein kinase C (PKC) has
been correlated with
impairment of learning performance induced by developmental lead (Pb) exposure. This study
was designed to
examine whether the properties of brain PKC are altered by chronic Pb exposure during
development. Two-tenth
percent Pb acetate was administered to pregnant and lactating dams and then administered
to weanlings in
drinking water until postnatal day (PN) 56. Effects of Pb on translocation of PKC were
studied in brain slices
prepared from hippocampus. When the slices were treated with 0.33 microM phorbol-12,
13-dibutyrate (PDBu) for
15 min, a significant increase in PKC activity was observed in the membrane fraction of
hippocampal slices from
Pb-exposed rats, suggesting that chronic Pb exposure potentiates PDBu-activated PKC
translocation. Data
obtained from saturation binding assays in the frontal cortices of Pb-exposed rats showed
a decrease in the
dissociation constant (KD) in both membrane and cytosolic PKC. A decrease in the total
binding sites (Bmax) of
[3H]PDBu binding was only observed in membrane PKC. Furthermore, developmental Pb exposure
decreased
PKC-gamma, but not PKC-alpha, -betaII, and -epsilon in the membrane fraction of the
hippocampus and the frontal
cortex. These results indicate that chronic Pb exposure during development increases
phorbol ester binding affinity,
enhances phorbol ester-induced translocation of PKC, and down-regulates membrane PKC,
mainly PKC-gamma.
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J Pharmacol Exp Ther 1993 Feb;264(2):757-61
Inhibition of brain protein kinase C subtypes by lead.
Murakami K, Feng G, Chen SG.
Department of Biochemical Pharmacology, School of Pharmacy, State University of New York,
Buffalo.
Protein kinase C (PKC) is an important enzyme in mediating cellular signal transduction
and neuronal plasticity.
Extremely low concentrations (picomolar range) of Pb++ have been reported to activate
partially purified PKC from
rat brain (Markovac and Goldstein, 1988). However, the lead activation of PKC at such low
concentrations is still a
matter of discussion (Simons, 1989). To clarify this point, we have examined the lead
effect on highly purified PKC
subtypes. Pb++ was found to be a potent inhibitor for all three PKC subtypes (types I, II
and III) with IC50 of 2 to 10
microM. Characterization of this lead inhibition of PKC suggests that 1) the inhibition is
not due to the competition
with Ca++, 2) the site of action of lead is on the catalytic domain of PKC, 3) the
inhibition is not dependent on the
mode of activation (phosphatidylserine/diacylglycerol vs. cis-unsaturated fatty acid) and
4) the inhibition is totally
reversible.
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SCIENCE CONCENTRATES
February 12, 2001
Volume 79, Number 7
CENEAR 79 7 pp.34
ISSN 0009-2347
Protein fragment allows mice to overeat and stay thin
Could there really be a "magic bullet" for dieters? Harvey F.Lodish of the Whitehead Institute and colleagues there and at Genset Corp. have found what looks like a promising candidate. When theresearchers inject overweight mice with a very low dose of a fragment of a human protein previously identified in Lodish's lab, the mice lose weight and keep it off, even while continuing to consume a diet high in fat and sugar [Proc. Natl. Acad. Sci. USA, 98, 2005 (2001)]. The researchers believe the complete protein, known as Acrp30, is the inactive precursor of a regulatory agent produced only by fat-storage cells. These cells release the protein into the bloodstream where it's cleaved into a signaling molecule that directs muscles to metabolize more of the fatty acids that circulate in the blood. The protein fragment they used presumably contains the signaling part of the molecule. The fragment provides "a unique and novel pharmacological tool" to control body weight without interfering with food intake, the researchers note. However, much more research will be needed before the substance can be tested in humans.
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