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Altered Gene Expression in the Brain and Ovaries of Zebrafish Exposed to the Aromatase Inhibitor Fadrozole: Microarray analysis and Hypothesis Generation
Citation:
VILLENEUVE, D. L., R. WANG, D. C. BENCIC, A. D. BIALES, D. MARTINOVIC, J. M. LAZORCHAK, G. P. TOTH, AND G. T. ANKLEY. Altered Gene Expression in the Brain and Ovaries of Zebrafish Exposed to the Aromatase Inhibitor Fadrozole: Microarray analysis and Hypothesis Generation. ENVIRONMENTAL TOXICOLOGY AND CHEMISTRY. Society of Environmental Toxicology and Chemistry, Pensacola, FL, 28(8):1767-1782, (2009).
Impact/Purpose:
We hypothesize that gene expression changes in the ovary of fadrozole-exposed zebrafish reflect disruption of oocyte maturation and ovulation due to impaired vitellogenesis. These hypotheses and others derived from the microarray results provide a foundation for future studies aimed at understanding responses of the HPG axis to EACs and other chemical stressors.
Description:
As part of a research effort examining system-wide responses of the hypothalamic-pituitary-gonadal (HPG) axis in fish to endocrine active chemicals (EACs) with different modes of action, we exposed zebrafish (Danio rerio) to 25 or 100 ìg/L of the aromatase inhibitor fadrozole for 24, 48, or 96 h. Global transcriptional response in brain and ovary tissue of fish exposed to 25 ìg fadrozole/L was compared to that in control fish using a commercially available 22,000 gene oligonucleotide microarray. Transcripts altered in brain were functionally linked to differentiation, development, DNA replication, and cell cycle. Additionally, multiple genes associated with the one carbon pool by folate pathway (KEGG 00670) were significantly up-regulated. Transcripts altered in ovary were functionally linked to cell-cell adhesion, extracellular matrix, vasculogenesis, and development. Promoter motif analysis identified GATA-binding factor 2, Ikaros 2, alcohol dehydrogenase gene regulator 1, myoblast determining factor, and several heat shock factors as being associated with co-expressed gene clusters that were differentially-expressed following fadrozole exposure. Based on the transcriptional changes observed, we hypothesize that fadrozole elicits neurodegenerative stress in brain tissue and that fish cope with that stress through proliferation of radial glial cells. Additionally, we hypothesize that gene expression changes in the ovary of fadrozole-exposed zebrafish reflect disruption of oocyte maturation and ovulation due to impaired vitellogenesis. These hypotheses and others derived from the microarray results provide a foundation for future studies aimed at understanding responses of the HPG axis to EACs and other chemical stressors.