Gene expression profiling reveals potential biomarkers for early detection of DNA damage.

Increased levels of DNA damage and ineffective repair mechanisms are the underlying bio-molecular events in the pathogenesis of most of the life-threatening diseases like cancer. During puberty, a period in which the body undergoes many different cellular and molecular changes, alterations in DNA may have a significant impact on disease development later in life e.g. cancer, reproductive and endocrine system effects, respiratory diseases, etc. The current PhD research was part of the Flemish Policy Centre for Environment and Health, and has a twofold objective. First of all, we want to identify the impact of environmental chemicals on DNA damage in Flemish adolescents. We saw that various environmental contaminantswith known carcinogenic potential (polycyclic aromatic hydrocarbons, benzene, chromium, etc.) present in the environment of youngsters (FLEHS III) were associated with short-term DNA damage, assessed by the alkaline comet assay and urinary 8-hydroxydeoxyguanosine (8-OHdG). These associations show that the current DNA damage assays are sensitive and predictive markers for transient DNA damage in Flemish youngsters. Also chemicals with insufficient human toxicity data available, such as phthalates, correlated with systemic oxidative stress (8-OHdG) in both FLEHS II and FLEHS III adolescent cohorts. In the second part of this work associations between traditional biomarkers of DNA damage and gene expression changes were studied in two independent population studies (PAH-study and FLEHS I-study) consisting of adult members of the general Flemish population. Using multiple regression analyses, we identified genes whose expression was significantly correlated with DNA damage assessed by the micronucleus assay. Four micronuclei-related genes (CAPN12, RAC1, TP73 and VEGFA) were selected for confirmation of their differential expression in a third study population (FLEHS III), namely in 14- and 15-year old adolescents. The micronuclei-related change in RAC1 expression could be confirmed in boys. Further, RAC1 and VEGFA were significantly associated with the alkaline comet assay in the adolescent population, and CAPN12 and TP73 were significantly associated with the comet assay, but again only in boys. We suggest that the identified genes should be further explored to reveal more insights in the pathways of DNA damage caused by the Flemish environment as measured by the traditional bioassays.

Keywords:BIOMONITORING, BIOCHEMISTRY

Disciplines:Catalysis and reacting systems engineering, Chemical product design and formulation, General chemical and biochemical engineering, Process engineering, Separation and membrane technologies, Transport phenomena, Other (bio)chemical engineering