A Graphical Systems Model to Facilitate Hypothesis-Driven Ecotoxicogenomics Research on the Teleost Brain−Pituitary−Gonadal Axis

Abstract

Graphical systems models are powerful tools that can help facilitate hypothesis-driven ecotoxicogenomic research and aid in mechanistic interpretation of results. This paper describes a novel graphical model of the teleost brain-pituitary-gonadal (BPG) axis designed for ecotoxicogenomics research on endocrine-disrupting chemicals using small fish models. The model incorporates six compartments representing the major organs involved in the fish reproductive axis and depicts the interactions of over 105 proteins and 40 simple molecules, transcriptional regulation of 25 genes, and over 300 different reactions/ processes. Application of the model is illustrated in the context of a study examining effects of the competitive aromatase inhibitor, fadrozole, on gene expression in gonad, brain, and liver tissue of fathead minnows. Changes in mRNA transcript abundance were measured using a fathead minnow oligonucleotide microarray and quantitative real-time polymerase chain reaction. Gene expression changes observed in the ovaries of females exposed to 6.3 microg fadrozole/L for7 d were functionally consistent with fadrozole's mechanism of action, and expected compensatory responses of the BPG axis to fadrozole's effects. Furthermore, microarray results helped identify additional elements (genes/ proteins) that could be included in the model to potentially increase its predictive capacity. With proper recognition of