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1998
Award Recipients |
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The Role of Environmental
Nitrogen Oxide Species in the Induction of Cholesterol
Accumulation in Vascular Cells
Liana Asatryan, Ph.D., post-doctoral student, Department
of Molecular Pharmacology and Toxicology, USC |
| Abstract:
The role of NOx species as environmental oxidants
in the development of atherosclerosis has not been
studied sufficiently. LDL oxidation is a crucial
event in early atherogenesis and specific NOx species
(i.e., NO) have been implicated in the disease etiology.
The investigators have recently found a novel, hemoglobin-dependent
mechanism for mildly oxidized LDL formation in whole
blood. This LDL bears higher electronegative charge
(LDL-) and has atherogenic properties. NOx are able
to cause intravascular hemolysis and react avidly
with hemoglobin. The aim of this project was to
determine whether exposure to environmental NOx
can lead to increased LDL- levels via hemolysis
and if this modified LDL promotes cholesterol accumulation
in vascular cells. |
| Final Report:
The aim of this pilot project was to determine whether
environmental NOx pollutants facilitated the formation
of an atherogenic electronegative LDL subfraction
(LDL-) formation in blood via a hemoglobin (Hb)-dependent
mechanism. Human whole blood exposure to different
concentrations of sodium nitrite (10, 100, 160 and
360 mg/l) resulted in a dose-dependent and sustained
increase in plasma Hb levels and a rapid (within
minutes) autooxidation of oxy-Hb to met-Hb. The
latter is a parameter of intravascular hemolysis.
The reaction was accompanied by an equimolar conversion
of nitrite into nitrate in a dose-dependent manner.
A dose- and time-dependent increase in LDL- formation
was observed which correlated with metHb levels.
This LDL- revealed increased susceptibility to Cu2+-mediated
oxidation. The low levels of lipid peroxidation
products in LDL- support the possible involvement
of a Hb-mediated mechanism involving direct protein
modification. The latter is a novel mechanism for
LDL modification which occurs through intermolecular
covalent binding of Hb fragments and LDL protein,
ApoB100. Hb-LDL- carries catalytically active heme
and exhibits low uptake rates by vascular endothelial
cells and macrophages. |
| For further studies, experiments can focus on
the characterization of the lipid and protein components
of this LDL- and evaluation of the role of nitrosylation
in this process. Recent studies have shown that
LDL oxidation by inflammatory cells (notably macrophages)
is markedly facilitated in the presence of nitrite
where the catalytic action of the heme protein myeloperoxidase
is implicated. This implicates nitric oxide formation
as a mediator of myeloperoxide mediated nitrosylation
and modification of LDL. It also indicates that
other sources of exposures to nitrates and NOx can
contribute to LDL modification in blood. In vitro
experimental conditions will be elaborated for NOx-mediated
LDL- formation in presence of Hb oxidized species.
Also molecular mechanisms activated by this specific
LDL- leading to atherosclerosis development will
be addressed. |
Publications:
Ziouzenkova O, Asatryan L, and Sevanian A. Oxidative
stress resulting from hemolysis and formation of
catalytically active hemoglobin: Protective strategies.
Int J Clin Pharmacol Ther V. 37, PP. 125-132,1999.
Ziouzenkova O, Asatryan L, Akmal M, Wratten ML,
Tetta C, Heinecke J, Loseto-Wich G, and Sevanian
A. Oxidative Crosslinking of ApoB 100 and Hemoglobin
results in Low Density Lipoprotein Modification
in blood: Relevance to Atherogenesis caused by Hemodialysis.
J Biol Chem, 274(27):18916-18924, 1999.
Podrez EA, Schmitt D, Hoff HF and Hazen SL. Myeloperoxidase-generated
reactive nitrogen species convert LDL into an atherogenic
form in vitro. J Clin Invest 103:1547-1560, 1999.
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Use of GIS to Characterize
Air Toxics Hot Spots in the South Coast Air Basin
L. Donald Duke, Ph.D., PE, Principal Investigator
and doctoral student Michelle Wilhelm, School of
Public Health, UCLA |
| Abstract:
This research uses Geographic Information System
methods to investigate the distribution of air toxics
sources and to identify populations that may be
disproportionately exposed to emissions potentially
harmful to health. The specific focus is the spatial
distribution of diesel exhaust sources in the South
Coast Air Basin. Both mobile sources (such as trucks
and passenger vehicles) and stationary sources (such
as delivery trucks idling for long periods at industrial
facilities) will be investigated. Expected contributions
from this pilot project include: (1) indication
of the approximate contribution of mobile versus
stationary sources to overall diesel emissions;
(2) identification of communities potentially at
risk from exposure to diesel exhaust and which may
require localized air monitoring; and (3) identification
of data gaps in regard to diesel emissions characterization
in the South Coast Air Basin. |
| Final report:
The objective of this research was to determine
whether local high activity of truck traffic in
industrial and commercial areas generates such high
level of diesel emissions as to produce locally
high ambient concentrations of air toxics, compared
against the background of high concentrations produced
by freeway and roadway vehicle traffic throughout
the South Coast basin. Results are important to
guide current agency and policy-making activities
in risk assessment, health effects characterization,
and pollutant control policies aimed at protecting
human health from toxic air emissions from diesel
vehicles. The research first identified locally
high concentrations of facilities generating high
truck delivery activities, using existing databases
from previous research. Next, the research gathered
data on truck activity for two selected case study
locations, both within the Pico Rivera area of the
South Coast region, and both in close proximity
to residential neighborhoods with potentially high
groupings of human receptors. Then, the research
modeled emissions of pollutants originating with
diesel exhaust and the exposures of individuals
in the two case study areas, focusing on particulate
matter. Finally, the research developed comparable
estimates for concentrations originating from the
other major source of the same pollutants, vehicles
on freeways where emissions would affect the same
areas; and similarly comparable estimates for other
representative freeways elsewhere in the region. |
Publications:
Characterization of Diesel Exhaust 'Hot Spots' in
the South Coast Air Basin. (Poster Presentation)
University of California Toxic Substances Research
& Teaching Program (UC TSR&TP) Annual Symposium,
April 9-10, 1999, Santa Barbara, California.
Characterization of Diesel Exhaust 'Hot Spots' in
the South Coast Air Basin. (Poster Presentation)
Southern California Society for Risk Assessment
(SCSRA) Twelfth Annual Workshop and Chapter Meeting,
May 29, 1999, University of California, Los Angeles.
Identifying Air Toxics Hot Spots from Diesel Truck
Emissions in Industrial Zones: Case Study in Los
Angeles, CA. Journal of the Air and Waste Management
Association. Projected submittal date: January 15,
2000
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Development of Respiratory
Biomarkers in Spectrum
Frank Gilliland, M.D., Ph.D., Department of Preventive
Medicine, USC |
| Abstract:
This pilot study investigates the use of biomarkers
in sputum to study respiratory carcinogenesis in
former smokers using a molecular epidemiology approach
to these groups. The need for research is evident.
Lung cancer remains a pressing worldwide public
health problem. New techniques of molecular and
cellular biology may also provide markers for studying
the effects of air pollution as well as the longitudinal
process of carcinogenesis, for screening, and for
use in intervention trials. The long-range goals
are to describe and validate markers for lung cancer
and effects of air pollution, and to use these markers
to further characterize the respiratory effects
of air pollution and quantitative lung cancer risks
after cessation of smoking. In this pilot project,
methods will be developed and feasibility will be
assessed for using biomarkers in exfoliated respiratory
tract cells from sputum in molecular epidemiologic
studies. |
Final Report:
Sputum containers, instructions and questionnaires
were sent to each household. Participants were given
2-3 weeks from the date the kit was mailed to return
the container and questionnaire. After expensive
follow-up only 37 containers were received from
the 120 participants who agreed to participate during
the initial telephone interview. The low response
rate indicates that the sputum collection process
was a major barrier for participation. It appears
that former smokers can produce specimens at home,
but nonsmokers and those exposed to ETS have greater
difficulty and may require induced sputum. A comparison
between induced and spontaneous produced specimens
is also needed as well as assessments over time.
Based on this pilot study the investigators concluded
that collection of sputum by mail is possible, but
requires substantial resources to complete and that
any collection is likely to come from a select population
that is unlikely to be representative of the population
at risk. Other collection methods need to be assessed
including home visits or clinic visits. Collection
of sputum will likely require substantial personnel
efforts including home or clinic visits. The investigators
plan to seek additional resources to develop such
methods.
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Modification of
Colorectal Cancer Risk Factors by MPO and NQO1 Genotype
Sue Ingles, Ph.D., USC/Norris Comprehensive Cancer
Center |
| Abstract:
This is a study to determine whether risk factors
for colorectal cancer might be modified by polymorphisms
in two genes that encode carcinogen-metabolizing
enzymes. The NQO1 gene encodes the enzyme NAD(P)H:quinone
oxidoreductase, an enzyme that catalyzes reductive
activation of certain environmental carcinogens,
including nitroaromatic compounds and heterocyclic
amines. The second gene, MPO, encodes myeloperoxidase,
which catalyzes the endogenous formation of free
radicals and activates benzo[a]pyrene and aromatic
amines. Both heterocyclic amine exposure and smoking
are risk factors for colorectal cancer. Both of
these risk factors have been found to be associated
with risk of colorectal adenomas in an ongoing case-control
study being conducted at two Kaiser Medical Centers
in Los Angeles County. Using DNA that is available
for these subjects, the investigators propose to
genotype the MPO and NQO1 polymorphisms, and to
re-examine the effects of smoking and heterocyclic
amine exposure within genotypically defined strata. |
Final Report:
The investigators found that a functionally significant
A/G polymorphism in the MPO gene promoter was associated
with risk of colorectal polyps. Among African-Americans
15% carried the A/A genotype, which was associated
with a more than 2-fold increased risk of both rectal
and left colon polyps (OR=2.83, 95% CI=1.02-7.82).
Among other ethnic groups, the A/A genotype was
associated only with rectal polyps (OR=3.05, 95%
CI=1.11-9.07). Since only 1% of Asians and 3% of
whites and Hispanics carried the A/A genotype, an
additional 600 subjects have been genotyped (from
wave 2 of the Kaiser study) so that analysis of
effect-modification by environmental risk factors
may be carried out. The data from this study will
be used as pilot data for a grant investigating
genetic & environmental contributions to oxidative
damage and risk of colon cancer.
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Respiratory Health
and Air Pollution in Los Angeles and Mexico City
Rob McConnell, M.D., Department of Preventive Medicine,
USC |
| Abstract:
This pilot project will compare results from the
Mexican and Los Angeles studies of children's respiratory
health and chronic exposure to air pollution. The
feasibility of merging data sets and the consistency
of cross sectional results from the two countries
will be determined. The studies have similar designs,
in which lung function of children has been examined
cross sectionally and is being followed longitudinally.
The 2000 Mexican children are recruited from schools
in 10 communities in Mexico City, some of which
have exposures to ozone and PM-10 two or three times
the U.S. standards. To the extent feasible, the
same analytic models and variables will be used
in this analysis as in the L.A. study to see if
the associations between air pollution and lung
function observed in L.A. are confirmed. Weak associations
observed in L.A. will be evaluated in the context
of the higher exposures to pollutants in Mexico. |
| Final Report:
This pilot project is intended 1) to assist Mexican
investigators with the analysis of data from a longitudinal
study of lung function growth in school children
and air pollution, which is similar in design to
the Children's Health Study at the SCEHSC; 2) to
explore the possibility of combining data sets from
the two studies (or conducting complementary analyses),
in order to examine the effect of air pollution
both at the slightly lower levels observed in Southern
California and at the higher exposures observed
in Mexico City; and 3) to develop preliminary data
to support a more extensive joint assessment of
data from the two studies. The investigators have
worked closely with Dr. Justino Regalado, a faculty
member at the National Institute of Respiratory
Disease, on an analysis of acute effects of ozone
on lung function. Dr. Regalado is finalizing these
analyses and is in the process of preparing a manuscript
with the Mexican team, which includes also the National
Center for Environmental Health and the General
Directorate of Environmental Health. For future
visits by Mexican investigators there are plans
to examine further whether it is possible to overcome
obstacles the investigators have identified to conducting
successful joint analyses of chronic effects. These
obstacles include, among others, the considerably
larger lung volumes observed at baseline in Mexican
children, compared with those in Southern California.
The Mexican co-investigators have approached the
Health Effects Institute to support further follow-up
of their cohort (beyond the 4 years to date), and
the USC investigators are exploring the possibility
of developing a joint proposal. This project also
is supported by the Fogarty International Center
training grant to UCLA, for which Dr. John Froines
of the SCEHSC is the P.I. |
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