The European Chemical Industry Council (CEFIC) - Interference of hepatotoxicity with endocrine activity in fish

Projekter: ProjektForskning



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 medaka1). 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. Within the scope of recent OECD test protocols for screening for endocrine activity in fish, vitellogenin has been established as a major marker for the diagnosis of endocrine disruption in fish. A reduction of vitellogenin production in female fish may be associated with, e.g., an interference of steroidogenesis, whereas an increase of vitellogenin production in males is regarded indicative of the presence of estrogen-receptor agonists. However, the production of vitellogenin may not only be modified by typical endocrine-related pathways, but also through non-endocrine-mediated processes. In particular, liver toxicity, i.e. the toxicant-induced impairment of liver structure and function, can influence the VTG biomarker. A false VTG result in the endocrine disruptor screening assays would trigger very labour-, time- and costintensive higher tier-testing, as it would increase the number of fish used in animal experiments. Therefore, an intimate understanding of the interplay between primary endocrine-related and non-endocrine-related pathways is crucial for the avoidance of false-positive diagnoses.

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:

(1) Prove of principle that chemicals can modulate the endocrine endpoint “VTG” through a non-endocrine MOA ;

(2) a diagnostic toolbox which enables the discrimination between endocrine- and non-endocrine-mediated changes of the VTG biomarker in fish;

(3) AoPs for VTG-modulating chemicals with non-endocrine MOA.

Effektiv start/slut dato14/06/201631/10/2018