ECO35: Interference of hepatotoxicity with endocrine activity in fish

Description

The project proposed is driven by the hypothesis that hepatotoxicity may positively or negatively interfere with vitellogenin production, which is used as a key marker of endocrine activity in current OECD test guidelines 229, 230 and 234 and the proposed medaka extended one-generation test.

The purpose of the project is (1) to identify scenarios, where liver toxicity may affect the induction, synthesis and secretion of vitellogenin from hepatocytes in small fish models (preferentially zebrafish, but potentially also fathead minnow and medaka [1]). For this end, (2) the project will develop a set of diagnostic tools to distinguish primarily endocrine effects from secondary effects in consequence of liver toxicity. For selected modes of action, (3) Adverse Outcome Pathways (AOP) will be developed for liver toxicity-mediated modulation of the vitellogenin biomarker in fish.

[1] To be discussed with LRI representatives; all species available at Heidelberg University.

The proposal will differentiate between the following scenarios:

1. impaired vitellogenin production in consequence of generalized degenerative processes of the liver (including VTG modulation by excessive test concentrations);
2. decreased vitellogenin production as a consequence of an impairment of general liver cell functionality (e.g. via reduction of protein synthesis capacities, disturbances of equilibrated lipoprotein synthesis, or energy depletion by, e.g. uncouplers).

The final deliverables of the project are:

• Prove of principle that chemicals can modulate the endocrine endpoint “VTG” through a non-endocrine MOA ;
• a diagnostic toolbox which enables the discrimination between endocrine- and non-endocrine-mediated changes of the VTG biomarker in fish;
• AoPs for VTG-modulating chemicals with non-endocrine MOA.