A transcriptomics-based biological framework for studying mechanisms of endocrine disruption in small fish species.
This study sought to construct a transcriptomics-based framework of signal transduction pathways, transcriptional regulatory networks, and the hypothalamic-pituitary gonadal (HPG) axis in zebrafish (Danio rerio) to facilitate formulation of specific, testable hypotheses regarding the mechanisms of endocrine disruption in fish. For the analyses involved, we used data from a total of more than 300 microarrays representing 58 conditions, which encompassed 4 tissue types from zebrafish of both genders exposed for 1 of 3 durations to 10 different test chemicals (17alpha-ethynyl estradiol, fadrozole, 17beta-trenbolone, fipronil, prochloraz, flutamide, muscimol, ketoconazole, trilostane, and vinclozolin). Differentially expressed genes were identified by one class t-tests for each condition, and those with false discovery rates of less than 40% and treatment/control ratios > or =1.3-fold were mapped to orthologous human, mouse, and rat pathways by Ingenuity Pathway Analysis to look for overrepresentation of known biological pathways. To complement the analysis of known biological pathways, the genes regulated by approximately 1800 transcription factors were inferred using the ARACNE mutual information-based algorithm. The resulting gene sets for all transcriptional factors, along with a group of compiled HPG-axis genes and approximately 130 publicly available biological pathways, were analyzed for their responses to the 58 treatment conditions by Gene Set Enrichment Analysis (GSEA) and its variant, Extended-GSEA. The biological pathways and transcription factors associated with multiple distinct treatments showed substantial interactions among the HPG-axis, TGF-beta, p53, and several of their cross-talking partners. These candidate networks/pathways have a variety of profound impacts on such cellular functions as stress response, cell cycle, and apoptosis.
Wang
Rong-Lin
RL
USEPA, Ecological Exposure Research Division, National Exposure Research Laboratory, 26 W Martin Luther King Dr., Cincinnati, OH 45268, USA. Electronic address: wang.rong-lin@epa.gov.
Bencic
David
D
USEPA, Ecological Exposure Research Division, National Exposure Research Laboratory, 26 W Martin Luther King Dr., Cincinnati, OH 45268, USA.
Villeneuve
Daniel L
DL
USEPA, Mid-Continent Ecology Division, National Health and Environmental Effects Research Laboratory, 6201 Congdon Boulevard, Duluth, MN 55804, USA.
Ankley
Gerald T
GT
USEPA, Mid-Continent Ecology Division, National Health and Environmental Effects Research Laboratory, 6201 Congdon Boulevard, Duluth, MN 55804, USA.
Lazorchak
Jim
J
USEPA, Ecological Exposure Research Division, National Exposure Research Laboratory, 26 W Martin Luther King Dr., Cincinnati, OH 45268, USA.
Edwards
Stephen
S
USEPA, National Health and Environmental Effects Research Laboratory, 109 TW Alexander Drive, Research Triangle Park, NC 27711, USA.
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D052244:Endocrine Disruptors / Q000145:classification / Q000633:toxicity*; D005260:Female; D005399:Fishes / Q000145:classification / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D020869:Gene Expression Profiling; D053263:Gene Regulatory Networks / Q000187:drug effects; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D010053:Ovary / Q000187:drug effects / Q000378:metabolism; D013737:Testis / Q000187:drug effects / Q000378:metabolism; D014874:Water Pollutants, Chemical / Q000633:toxicity*; D015027:Zebrafish / Q000235:genetics / Q000378:metabolism / Q000502:physiology
D052244:Endocrine Disruptors; D014874:Water Pollutants, Chemical