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Androgen receptor mediated compensation of estradiol in response to aromatase inhibition: a mathematical model
Citation:
Mayo, M., E. Perkins, N. Garcia-Reyero, Dan Villeneuve, AND G. Ankley. Androgen receptor mediated compensation of estradiol in response to aromatase inhibition: a mathematical model. Presented at Society for Environmental Toxicology and Chemistry.
Impact/Purpose:
not applicable
Description:
Chemicals in the environment have the potential to cause reproductive toxicity by acting on the hypothalamus-pituitary-gonadal (HPG) axis. We have developed a mathematical model to predict chemical impacts on reproductive hormone production in the highly conserved HPG axis using the fathead minnow (Pimephales promelas). The HPG axis controls the supply of reproductive hormones available to the body through feedbacks between local hormone levels and enzymes produced in response to changes in gene expression. This behavior has been recently observed in studies of fathead minnow exposed to the highly selective aromatase inhibitor fadrozole. In these studies, the enzyme-mediated transformation of testosterone into estradiol, strongly correlated with egg production (oogenesis), is initially inhibited by fadrozole. However, over time direct inhibition of aromatase by fadrozole is offset, by induction of several central steroidogenic (cytochrome p450) enzymes critical to estradiol biosynthesis. The biochemical mechanisms mediating this apparent compensatory gene expression have not been fully characterized. However, microarray-based gene expression studies conducted by our group suggest the androgen receptor mediates may mediate these compensation pathways. Here we develop a mechanistic mathematical model, grounded in experimental data, to test these compensation hypotheses. Parameterized using data primarily from qPCR and literature sources, this model reproduces gene-based induction events that drive de novo aromatase production and associated increases in estradiol production at lower fadrozole doses (3 ug/L), but predicts decreased reduced capacity for compensation at higher doses (30 ug/L) despite further gene expression increases, consistent with current experiments,. Extensions of this predictive model to other less selective aromatase inhibitors (e.g., ketoconazole) will be discussed.