Physico-chemical determinants of toxicity: a rational approach
towards safer nanostructured materials
Nanomaterials are engineered structures with
dimensions of 100 nm or less, which achieve unique mechanical,
optical, electrical
and magnetic properties. Although these materials are already
widely used in different applications, ranging from cosmetics
and tires to medical applications, concerns about their effects
on human health, in occupational settings and possibly for the
consumer and the general population at large, are raised. A number
of research reports have pointed towards their harmful effects
on different target organs, which include the respiratory tract,
the brain, the cardio-vascular system, the skin and the liver.
Understanding how nanomaterials exert toxic effects and identifying
physico-chemical determinants of nanomaterials toxicity are the
main issues that will be investigated in collaboration with three
other research groups (UCL-TOXI, KULeuven-LUNG and KULeuven-COK).
A single model material, i.e. silicon-based nanoparticles (SNP),
will be used to assess genotoxicity and apoptosis in epithelial,
endothelial and mesothelial cells by a reverse combinatorial
approach. These in vitro data together with the in vitro data
from the other research groups, concerning the production of
inflammatory mediators by macrophages and platelet aggregation
and coagulation, will be used to develop a paradigm for SNP
toxicity that will be critically tested in vivo in two species
(rat and
mouse) with contrasting sensitivity. Additionally, the cellular
and molecular mechanisms underlying the response to SNP toxicity
will be investigated, focusing on interactions with the cytoskeletal
proteins, induction of aneuploidy, effects on the DNA repair
capacity and on cellular trafficking.
Molecular and genetic
research for the mechanisms leading to toxicity and apoptosis
induced
by cobalt-containing dust
Occupational exposure to cobalt-containing dust has been
associated with pulmonary toxicity including asmathic reactions,
fibrosing
alveolitis (hard metal disease) and lung cancer. The mechanisms
for lung fibrosis versus cancer induction by hard metal
(WC-Co) are not yet clearly understood. While the asthmatic responses
are caused by cobalt species, the development of cancer
and
fibrosing alveolitis is mainly ascribed to the simultaneous
exposure to
cobalt and tungsten carbide particles. In vitro in human
PBMC and in vivo in rat pneumocytes, it has been shown
that WC-Co
is inducing genotoxicity and apoptosis.
To define the underlying molecular mechanisms of hard metal
exposure in peripheral blood mononucleated cells (reporter
cells for biomonitoring),
primary monocytes and alveolar epithelial cells A549
(target cells for cancer inducing effects on the lung) high-throughput
transcriptional analysis tools -such as microarray and
RT-qPCR- are applied. As such, the global modulated gene
expression
levels can be analyzed, and the involvement of new genes
can be evaluated.
A better knowledge of the different signalization pathways
would give a better understanding about the modulating
effects of apoptosis
on the induction of fibrosis and lung cancer.
Genetic polymorphisms and frequency of genotoxicity biomarkers
in occupationally exposed people
Inter-individual variability
in human responses to mutagens/carcinogens has been
the subject of much research lately. It is well known that
humans differ
in their susceptibility to cancer. This may be due
to a number of factors, including health, nutritional status,
gender
and genetic background. Inherited (or aquired) genetic
polymorphisms in genes responsible for the metabolic
activation
and detoxification
of mutagens/carcinogens, for the fidelity of DNA
replication (mismatch repair), DNA repair and/or chromosome segregation
have the potential to influence the amount of individual
DNA
damage
and the cancer risk. Therefore, the identification
of
higher risk individuals caring genetic polymorphisms
responsible
for increased activation, and reduced detoxification/repair
of
mutagen/carcinogen-induced DNA damage has substantial
preventive implications as these individuals
could be targeted for primary cancer prevention.
To evaluate the influence of genetic polymorphisms
on the baseline or induced frequency of genotoxicity
biomarkers
[chromosomal
aberrations (CAs), micronuclei (MN), sister chromatid
exchanges
(SCE), high frequency cells (HFC), Comet tail (TD)]
in human lymphocytes, several occupational exposure
studies
have been
performed (e.g., cobalt-containing dust, ionizing
radiation, styrene, arsenic compounds, mustard
gas). For each
study, the influence of genetic polymorphisms on
the levels
of genotoxicity biomarkers was modeled by means
of regression analysis (e.g.,
multivariate, Poisson) and adjusted for age, gender,
smoking/nutrition
status, and occupational exposure. The effect of
genetic variation
on the levels of genotoxicity biomarkers will be
further evaluated by pooling together the individual
occupational
exposure datasets.
This approach has the advantage of increasing the
statistical power and resolving discrepancies among
individual
studies.
Assessment of the possible modifying effect of
genetic polymorphisms on the levels of genotoxicity
biomarkers,
could provide a
valuable tool for policy makers and regulatory
bodies in assessing the
various factors contributing to individual DNA
damage and cancer risk.
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