Changes in genetic material induced by DNA-damaging substances are of major concern for human health, since they are associated with serious adverse health effects including cancer, reproductive impairment, developmental anomalies and genetic diseases. Consequently, predictive testing of the genotoxic potential (in other words the degree at which it can damage DNA or genes) of new chemical and biological compounds (e.g. pharmaceuticals, chemicals, cosmetic ingredients, food additives) is required in most regulatory settings. The GENOMARK project, a collaborative project with the VUB (IVTD unit), aimed to develop a new test method to improve existing in vitro genotoxicity testing. In vitro tests are tests that are performed on cells that are grown and treated outside the body.
At present, most strategies to investigate the genotoxic potential of compounds are based on a “standard battery” of in vitro tests. Despite the value of this test battery, the scientific community is aware of its limitations including the high number of irrelevant positive results, meaning that compounds are in vitro identified as being genotoxic whereas in vivo they are not. These so-called false positive results have a major impact on society and industry as they trigger unnecessary follow-up testing in animals and/or result in a high number of potentially safe compounds that are restricted or even rejected. One possibility to improve the predictive capacity of in vitro genotoxicity testing is to develop a tool which contributes to the understanding of the mode of action (MOA) underlying the genotoxic activity of compounds. Such a tool would not only improve the follow-up of in vitro test results, but would also provide a way forward to develop more human-relevant methodologies for risk assessment.
The GENOMARK project therefore aimed to identify a set of genes (“gene classifier”) that are activated in human, metabolically competent HepaRG cells after exposure to a genotoxic compound based on the results of transcriptomic experiments. Afterwards, the innovative and mechanistically-based gene classifier was translated into an easy-to-handle PCR array chip. Predictivity and reproducibility of the tool were further investigated by the evaluation of an additional set of well-known genotoxic and non-genotoxic compounds. The developed PCR tool will allow fast and relatively cheap follow-up of positive in vitro genotoxicity test results. Consequently, the availability of the new in vitro tool might both speed-up drug developmental processes, and at the same time improve human safety assessment of chemicals in general by providing essential mechanistic information. Furthermore, the tool can be applied in other research projects of Sciensano.
Added value at scientific level
The project aimed to improve the specificity of the in vitro test battery for genotoxicity by using a PCR tool based on toxicogenomics. The domain of toxicogenomics is still in full development and is particularly promising for the evaluation of genotoxicity. Until now, it remains however unclear how the information generated by toxicogenomic approaches can be applied for regulatory purposes. The GENOMARK project clearly showed that the newly developed PCR tool can improve human safety assessment of chemicals in general by basing predictions on mechanistic toxicogenomics information.
Added value for public health
Within the GENOMARK project, particular care was taken to ensure that the sensitivity to detect genotoxic potential, which may have human health implications, is not compromised. On the other hand, by applying the GENOMARK tool, the availability of certain new consumer products can be advanced due to the improved time- and cost-efficacy of R&D processes.