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Transcriptional regulatory dynamics of the hypothalamic-pituitary-gonadal axis and its peripheral pathways as impacted by the 3-beta HSD inhibitor Trilostane in zebrafish (Danio rerio)
Citation:
WANG, R., D. C. BENCIC, J. M. LAZORCHAK, DAN VILLENEUVE, AND G. T. ANKLEY. Transcriptional regulatory dynamics of the hypothalamic-pituitary-gonadal axis and its peripheral pathways as impacted by the 3-beta HSD inhibitor Trilostane in zebrafish (Danio rerio). ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY. Elsevier Science Ltd, New York, NY, 74(6):1461-1470, (2011).
Impact/Purpose:
Biological resource conservation and management programs have benefitted greatly over the last decade from advances in population genetics research. The EPA, while having very similar goals to these programs, has yet to capitalize on the rapid advances in molecular population genetic methods. This research aims to evaluate the utility of population genetic measurements for describing the current condition and vulnerabilities of biological populations exposed to anthropogenic stressors.
Description:
To identify transcription factors (TFs), members of hypothalamic-pituitary- gonadal axis (HPG-axis), TF networks and signaling pathways underlying generalized effects of 3-beta hydroxysteroid dehydrogenase (HSD3B) inhibition, reproductively mature zebrafish (Danio rerio) were exposed to trilostane at two dosages for 24, 48, or 96 hrs and their gonad RNA samples profiled with Agilent zebrafish microarrays. Trilostane had substantial impact on the transcriptional dynamics of zebrafish, as reflected by a number of differentially expressed genes (DEGs), including TFs, altered TF networks, pathways, and Gene Ontology (GO) biological processes. Changes in gene expression between a treatment and its control were mostly moderate, ranging from 1.3 to 2.0 fold. Expression of genes coding for HSD3B and many of its transcriptional regulators remained unchanged, suggesting transcriptional up-regulation is not a primary compensatory mechanism for HSD3B enzyme inhibition. While some trilostane-responsive TFs appear to share cellular functions linked to endocrine disruption, there are also many other DEGs not directly linked to steroidogenesis. Of the 65 significant TF networks, little similarity and therefore little cross-talk existed between them and a gene set for the HPG-axis. The most enriched GO biological processes are regulations of transcription, phosphorylation, and protein kinase activity. Most of the impacted TFs and TF networks are broadly involved in cellular proliferation, differentiation, migration, and apoptosis. While these functions are fairly basic, their underlying TF networks may be useful to development of generalized toxicological screening methods. These findings suggest that trilostane effects on fish endocrine functions are not confined to the HPG-axis alone. Its impact on corticosteroid synthesis could also have contributed to some system wide transcriptional changes in zebrafish observed in this study.