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(PH167) A systems approach to the study of endocrine disruption using teleost models.
Villeneuve, D1, Johnson, R1, Miracle, A2, Knoebl, I, Degitz, S1, Ankley, G, 1 US EPA Mid-Continent Ecology Division, Duluth, MN, USA2 US EPA Ecological Exposure Research Division, Cincinnati, OH, USA
ABSTRACT- Accurate prediction of effects associated with exposure to endocrine disrupting chemicals (EDCs) requires an understanding of the dynamic function of a multi-organ biological system involving feedback and complex regulation at multiple levels. The rapid explosion in computing power, availability of web-based biological databases, and technological advances in the area of genomics and proteomics provide unprecedented tools for the study of dynamic, complex, biological systems. In response to these advances, we developed a conceptual systems model for the function of the teleost hypothalamic-pituitary-gonadal (HPG) axis. The model consists of organ-, tissue-, and cellular-level diagrams that depict functional relationships among genes and proteins thought to be involved in the regulation of reproductive endocrine processes. It is composed of six modules representing (1) gonadotropin releasing hormone (GnRH) release from the GnRH neuronal system in the brain, (2) gonadotropin expression and secretion from the pituitary, and (3) cholesterol transport, (4) steroidogenesis, (5) spermatogenesis/spermiation, and (6) vitellogenesis/oocyte maturation in the gonads. Where adequate information was available, submodules depicting the regulation of specific genes were also included. The model is intended to guide systems-oriented EDC research over upcoming years. Specifically, the conceptual model will be used to generate predictions regarding the effects of EDCs, with known mechanisms of action, on multiple gene or protein targets. Predictions will be tested using genomic and proteomic approaches. Iterations of prediction and testing will be used to identify key regulatory nodes in the teleost HPG axis, identify missing elements in the model, and generally refine the model toward greater predictive sophistication. The conceptual model presented represents a preliminary step toward the eventual development of a computational systems model of the teleost HPG axis that can predict functional effects of EDCs based on a limited number of readily measured endpoints.
Key words: hypothalamic-pituitary-gonadal axis, systems biology, teleost, toxicogenomics
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