Projects / Programmes
Endocrine disrupting and genotoxic potential of protein kinase inhibitors: relevance for
environmental hazard in zdravje ljudi
| Code |
Science |
Field |
Subfield |
| 1.03.00 |
Natural sciences and mathematics |
Biology |
|
| Code |
Science |
Field |
| B200 |
Biomedical sciences |
Cytology, oncology, cancerology |
| Code |
Science |
Field |
| 1.06 |
Natural Sciences |
Biological sciences |
anticancer drugs; toxicity; endocrine disruptors, genotoxic; QSAR, pharmaceuticals; risk
assessment; toxicogenomics; zebrafish;
Researchers (21)
Organisations (3)
Abstract
Potential risks associated with release of pharmaceuticals into the environment are an important issue for environmental regulators and for the pharmaceutical industry. Anticancer drugs, due to their mechanism of action, belong to highly hazardous compounds. Their presence in the environment may lead to systemic environmental effects, while in exposed humans increased cancer incidence and reproductive defects may occur. Protein tyrosine kinase inhibitors (TKIs) are a group of anticancer drugs that are designed for targeted therapy of specific types of human cancers. During the last 15 years their consumption is rapidly increasing; however, there is insufficient data on their occurrence, ecotoxicity and potential effects to humans to allow for adequate risk assessment. In the frame of the EU FP7 project CytoThreat we discovered that the TKI imatinib mesilate exerts genotoxic and endocrine disrupting activity that has been not known before. The aims of the proposed project are to evaluate the consumption and predict environmental occurrence of TKIs that are currently registered for cancer therapy in Slovenia and to explore their genotoxic and endocrine disrupting potential. In the first step we will predict genotoxic and endocrine disrupting activity using the state of the art computational methods (QSAR and read across). In the next step in vitro test system with zebrafish liver cell line will be used to elucidate the mechanisms of genotoxicity and E-screen, MDA-kb2 and GH3.TRE–Luc assays to explore the mechanisms of endocrine disrupting activity. The (eco)toxicity of selected TKIs will be finally studied using an experimental model with zebrafish (Danio rerio) embryos, which is increasingly used model also for prediction of toxic effects in humans. In zebrafish embryos we will determine lethal and sublethal effects of the selected TKIs to obtain parameters (lethal concentration (LC)50, no adverse effect concentration (NOAEC)) needed for environmental and human health risk assessment. In zebrafish embryo model also transcriptomic analysis of the changes in the expression of genes involved in the pathways of DNA damage response, hormone metabolism, cell proliferation, apoptosis, sexual development and function, hypothalamic-pituitary-gonadal axis, growth and developmental neurotoxicity will be performed. The aims are to identify linkages between the transcriptomic profiles, concentrations, and adverse outcomes, and to identify molecular biomarkers of exposure and effects of specific group TKIs that will serve as diagnostic markers for these types of pharmaceutical exposure.
The project is expected to generate new knowledge on potential environmental and health risk of TKIs in the environment, providing objective arguments for recommendations and regulations concerning environmental and human health protection. To accomplish the complex tasks, the project consortium comprises partners with complementary expertise in the fields of aquatic and genetic toxicology, and genomics with bioinformatics (NIB), toxicology, pharmacology and in silico predictive models (FFA) and environmental occurrence predictions based on consumption and use of these drugs (IO).
Significance for science
Recent studies (Besse et al., 2012, Kummerer et al., 2016) and reports (CytoThreat report) pointed out that TKIs, due to increasing use in cancer therapy as well as the therapy of several other severe chronic diseases such as autoimmune disease, may be a group of pharmaceuticals that should be taken into consideration and assessed for occurrence, ecotoxicity and potential threat for aquatic organisms and human health. In addition increased occurrence of TKIs in the environment is expected also because for certain TKIs, i.e. imatinib mesilate, the pantent protection expired and are already on the market as generics, which are cheaper and therefore accessible to more patients. The project will focus not only on the intrinsic genotoxic and endocrine disrupting properties of these contaminants but also on their effects at concentrations relevant for environmental exposure that may in longterm lead to decline of susceptible populations of aquatic organisms, whereas indirect human exposure to these compounds may lead to severe health disorders particularly in more susceptible populations such as pregnant women and children. In addition the information on the intrinsic genotoxic and endocrine disrupting activities, which has not been systematically studied for TKIs so far will relevant for predicting and understanding potential side effects in treated patients. Through the aim of identifying the endocrine disrupting and genotoxic potency of PKIs and identification of multiple molecular biomarkers for these effects, based on toxicogenomic approaches, which has not been in use or reported so far, the project has the potential to provide diagnostic tools for predicting potential endocrine disrupting and genotoxic effects of such contaminants on ecosystems and human health. The results will contribute to improved risk assessment for human health and ecosystems for TKI pharmaceuticals by providing data on their PEC and toxicological properties and data on key toxicological parameters (LC , NOEC) required in science based risk assessment procedures.
Significance for the country
As residues of pharmaceuticals are currently very “hot” scientific topic it is expected that the results will have significant impact on stakeholders including national and EU regulatory bodies, pharmaceutical industry as well as public. The project contributes to national and EU policies and strategies related to human health and environment protection, i.e. to The European Action Plan on Environment and Health and to Environment and Health Strategy.
In Slovenia and EU protection of water resources is of major concern and is supported by Water Framework Directive (2000/60/EC). The implementation of this directive depends on the availability and quality of information available to those in charge for water quality management. The project will support implementation of WFD by providing data on the potential occurrence and effects of TKIs in the aquatic environment. The information from the project will be relevant also to the requirements of Directive on human medicine (2004/27/EC) and may contribute to their eventual revision in the face of improved knowledge.
Within the REACH legislation the main contribution of the project results will be to the "development of alternative methods for the assessment of hazards of different (chemical) substances” through identification, evaluation and confirmation of predictive potential of in vitro test systems for long term in vivo effects based on early biological and molecular markers.
Most important scientific results
Final report
Most important socioeconomically and culturally relevant results
Final report
