Proteomics as an alternative approach for hazard characterization and the identification of specific chemical targets : elucidation of potential biomarkers for differentiating endocrine disruption from hepatotoxicity [thesis]

Steve Uwa Ayobahan, Andreas Schäffer, Christoph Schäfers, Henner Hollert
2020
Ecotoxicological testing of the chemical impact on reproductive endocrine function for regulatory purposes is currently focused on the characterization of apical endpoints rather than identifying the molecular mechanisms accountable for the observed adverse effects. Specifically, alterations in endpoints and biomarkers related to reproduction such as vitellogenin (VTG) content, gonadal morphology and fecundity may also be affected by disruption being unconnected to a perturbed endocrine system.
more » ... d endocrine system. As the liver is the site of VTG production, also hepatotoxicants can induce similar changes on this biomarker. Since regulation of chemicals is different when they are identified as endocrine disruptors, there is a growing demand for the development of novel endpoints to be included in testing strategies. This dissertation aimed at demonstrating the sensitivity and the applicability of integrating proteomics into the conventional fish short term reproduction assay (FSTRA, OECD 229), not only for linking changes in apical endpoints with the corresponding underlying molecular alterations but also to detect candidate makers for discriminating hepatotoxicity from endocrine mediated toxicity. In order to ensure consistency in substance evaluation and to avert further extensive testing, the development of an additional weight-of-evidence approach to differentiate between effects caused by hepatotoxicity and endocrine modulated actions is of significant importance for industry and regulatory authorities. To this end, an FSTRA according to OECD TG 229 was performed with one known hepatotoxic substance (acetaminophen, APAP) and an endocrine disrupting chemical (EDC, fadrozole). Fadrozole is an anti-breast cancer drug, which acts as a non-steroidal aromatase inhibitor that specifically inhibits estrogen synthesis. APAP, a non-steroidal anti-inflammatory drug, is one of the commonly used over the counter medication for pain and fever when taken at the recommended therapeutic dose. At high concentrations, the substance has been identi [...]
doi:10.18154/rwth-2020-09981 fatcat:v4ptojllzzeonos4lbz7mw26fa