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Lisa Baumann

Contact:

Centre for Organismal Studies

Abteilung Tierphysiologie / Entwicklungsbiologie

Im Neuenheimer Feld 504

Tel: +49-(0)6221/54-5629

Fax:: +49-(0)6221/54-6162

e-Mail: lisa.baumann@uni-heidelberg.de

 
 
 
 
 

Cefic LRI-ECO35 project: Interference of hepatotoxicity with endocrine activity in fish

Vitellogenin (VTG) has been established as key biomarker for the diagnosis of endocrine disruption in fish, which is used in the OECD test guidelines 229, 230 and 234. A reduction of VTG production is usually associated with androgenic or anti-estrogenic activity, whereas an increase of VTG production is regarded indicative for the presence of estrogenic compounds. However, the production of VTG may not only be modified by typical endocrine-related pathways, but also through non-endocrine-mediated processes. In particular, hepatotoxicity, i.e. toxicant-induced impairment of liver structure and function, can influence the VTG biomarker, as it is synthesized in the liver. A false VTG result in a screening assay would unnecessarily trigger very labour-, time- and cost- intensive higher tier-testing, as it would increase the number of fish used in experiments. Therefore, an intimate understanding of the interplay between primary endocrine-related and non-endocrine-related pathways influencing VTG production is crucial for the avoidance of false-positive diagnoses. The present project is driven by the hypothesis that hepatotoxicity may positively or negatively interfere with VTG production, which is used as biomarker of endocrine activity in current OECD test guidelines. Consequently, the project has been designed to:

1. identify scenarios, where liver toxicity may affect the induction, synthesis and secretion of VTG from hepatocytes in small fish models;

2. develop a set of diagnostic tools to distinguish liver toxicity-mediated modulation of VTG production in fish from primary endocrine effects.

Zebrafish (Danio rerio), one of the most commonly used small fish model species, is used in OECD guideline 229 (“Fish Short Term Reproduction Assay”) type assays to address the above-mentioned aims. Hepatotoxicants with different modes of action, namely acetaminophen, isoniazid, valproate and dinitro-O-cresol (DNOC), are applied as model compounds to induce different effects on the liver of exposed fish. Endpoints recorded include: (1) histopathology of liver and gonads to assess liver structural toxicity, (2) measurement of VTG and hormone levels, (3) determination of serum liver toxicity markers (alanine aminotransferase) to assess liver functional toxicity, (4) transcriptomic analyses (RNA-seq) of genes involved in energy metabolism and (5) respirometric measurements of the energy budget to assess liver functional toxicity.