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Caught in a Network: Recovery from Aromatase Inhibition
Citation:
REYERO, N. G., T. HABIB, DAN VILLENEUVE, D. MARTINOVIC, Y. DEN, G. T. ANKLEY, N. DENSLOW, AND E. PERKINS. Caught in a Network: Recovery from Aromatase Inhibition. Presented at 15th Annual Symposium on Pollutant Responses in Marine Organisms, Bordeaux, FRANCE, May 17 - 20, 2009.
Impact/Purpose:
To research results
Description:
Fadrozole is an inhibitor of aromatase, an enzyme critical to estrogen synthesis. We exposed female fathead minnows (Pimephales promelas, FHM) to 0 or 30 ug/L fadrozole for 8 days, and fish were then held in clean water for 8 extra days. We analyzed ex vivo steroid production, plasma steroid and vitellogenin levels. We also analyzed gene expression changes using a 15,000 probe microarray. As expected, plasma concentrations of estradiol (E2) and vitellogenin were significantly reduced within 24h of exposure to fadrozole. Our results supported previous observations that FHM can compensate for aromatase (CYP19A) inhibition by increasing transcription, presumably to increase the synthesis of the enzyme. Plasma E2 concentrations recovered rapidly once fadrozole delivery stopped. Of all the differentially expressed genes (fold change>2, p<0.01), 194 were exclusively in the exposure phase and 128 were exclusive in the recovery phase, with 23 genes including aromatase, common between the two phases. Almost 80% of the phase-unique genes and most of the common genes had high fold-changes during exposure and fold-change decreases during recovery. The time-series data was used to build a dynamic network to better understand the response to fadrozole. As exposure time increased from 1 to 8 days during exposure, an increasing number of network motifs such as feedback loops and self or auto regulated motifs were observed, as well as the involvement of an increasing number of biological pathways. Important genes from the steroidogenic pathway, such as LDL receptor and aromatase, were found to be highly connected genes, i.e. hub genes.