Laboratory of Cell Genetics:

Research group of Micheline Volders

Research Topics

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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