Abstract
Estrogen signaling is important for vertebrate embryonic development. Here we have used zebrafish (Danio rerio) as a vertebrate model to analyze estrogen signaling during development. Zebrafish embryos were exposed to 1 µM 17β-estradiol (E2) or vehicle from 3 hours to 4 days post fertilization (dpf), harvested at 1, 2, 3 and 4 dpf, and subjected to RNA extraction for transcriptome analysis using microarrays. Differentially expressed genes by E2-treatment were analyzed with hierarchical clustering followed by biological process and tissue enrichment analysis. Markedly distinct sets of genes were up and down-regulated by E2 at the four different time points. Among these genes, only the well-known estrogenic marker vtg1 was co-regulated at all time points. Despite this, the biological functional categories targeted by E2 were relatively similar throughout zebrafish development. According to knowledge-based tissue enrichment, estrogen responsive genes were clustered mainly in the liver, pancreas and brain. This was in line with the developmental dynamics of estrogen-target tissues that were visualized using transgenic zebrafish containing estrogen responsive elements driving the expression of GFP (Tg(5xERE:GFP)). Finally, the identified embryonic estrogen-responsive genes were compared to already published estrogen-responsive genes identified in male adult zebrafish (Gene Expression Omnibus database). The expressions of a few genes were co-regulated by E2 in both embryonic and adult zebrafish. These could potentially be used as estrogenic biomarkers for exposure to estrogens or estrogenic endocrine disruptors in zebrafish. In conclusion, our data suggests that estrogen effects on early embryonic zebrafish development are stage- and tissue- specific.
Highlights
Estrogen signaling through its main components cytochrome P450 aromatase (CYP19) and the estrogen receptors (ERs), is well conserved through the evolution of vertebrates
To increase the understanding of how E2 acts on early zebrafish development, we performed transcriptomic analysis of whole embryos at different developmental time points
We identified E2-responsive genes that were regulated at 1-4 dpf during zebrafish development through transcriptomic analysis
Summary
Estrogen signaling through its main components cytochrome P450 aromatase (CYP19) and the estrogen receptors (ERs), is well conserved through the evolution of vertebrates (reviewed in 1) This conservation implies important roles for estrogenic pathways in a host of tissues and sexually dimorphic organs including the reproductive tract, brain, liver, heart, breast, skin and bone. The genome of the vertebrate zebrafish (Danio rerio) codes for three estrogen receptors, Esr, Esr2a and Esr2b (previously denoted ERα, ERβ2 and ERβ1, respectively) [4]. These receptors presumably mediate the genomic responses to estrogen signaling through their function as DNA-binding transcription factors. A fourth estrogen targeted receptor, the membrane localized G protein-coupled estrogen receptor 1 (Gper), induces activation of the so called non-genomic response, including phosphorylation of the mitogen-activated protein kinases MAPK3/MAPK1 [5], which eventually results in downstream transcriptional changes
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