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

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 μg
fadrozole/L for 7 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
their utility and limitations, graphical models can serve as
important tools for linking molecular and biochemical
changes to whole organism outcomes.