Estrogen signaling through both membrane and nuclear receptors in the liver of fathead minnow.

Estradiol is a potent sex steroid hormone that controls reproduction and other cellular pathways in fish. It is known to regulate important proteins such as vitellogenin, the egg yolk precursor protein, and zona radiata proteins that form the eggshell for fish eggs. These proteins are made in the liver and transported out into the blood from where they are taken up into the ovary during oogenesis. Estradiol can exert its influence directly through soluble nuclear receptors (there are three in fish) or indirectly through membrane receptors and a phosphorylation cascade. Often there is coordination through both genomic and non-genomic pathways. We have used a toxicogenomics approach to determine the contribution of genomic and non-genomic regulation in the liver of fathead minnows exposed to 5ng ethinylestradiol per liter or to a mixture of 5ng ethinylestradiol and 100ng ZM189,154 (ZM) per liter. ZM has previously been shown to be a "perfect" antagonist for the fish nuclear estrogen receptors but has displayed agonistic activities for membrane receptors. We find that both nuclear and membrane receptors contribute to the biosynthesis of vitellogenin 1 and estrogen receptor one (Esr1), among others. In addition, lipid metabolism pathways appear to require both activities.