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Tissue-Specific Actions of the Ept1, Ept2, Ept6, and Ept9 Genetic Determinants of Responsiveness to Estrogens in the Female Rat

Department of Genetics, Cell Biology and Anatomy (S.G.K., K.K.H., B.S.S., K.A.G., J.D.S.), Eppley Institute for Research in Cancer (S.G.K., K.K.H., M.T.M., B.S.S., K.A.G., J.D.S.), and Departments of Internal Medicine (V.S.), of Pathology and Microbiology (R.D.M., J.D.S.), and of Biostatistics (J.L.M.), University of Nebraska Medical Center, Omaha, Nebraska 68198-5805

Address all correspondence to: Dr. James D. Shull, Department of Genetics, Cell Biology and Anatomy, 6005 Durham Research Center, 985805 Nebraska Medical Center, Omaha, Nebraska 68198-5805. E-mail: jshull{at}unmc.edu.

Ept1, Ept2, Ept6, and Ept9 are quantitative trait loci mapped in crosses between the ACI and Copenhagen (COP) rat strains as genetic determinants of responsiveness of the pituitary gland to estrogens. We have developed four congenic rat strains, each of which carries, on the genetic background of the ACI rat strain, alleles from the COP rat strain that span one of these quantitative trait loci. Relative to the female ACI rats, female ACI.COP-Ept1 rats exhibited reduced responsiveness to 17β-estradiol (E2) in the pituitary gland, as evidenced by quantification of pituitary mass and circulating prolactin, and in the mammary gland, as evidenced by reduced susceptibility to E2-induced mammary cancer. The ACI.COP-Ept2 rat strain exhibited reduced responsiveness to E2 in the pituitary gland but did not differ from the ACI strain in regard to susceptibility to E2-induced mammary cancer. Interestingly, female Ept2 congenic rats exhibited increased responsiveness to E2 in the thymus, as evidenced by enhanced thymic atrophy. The ACI.COP-Ept6 rat strain exhibited increased responsiveness to E2 in the pituitary gland, which was associated with a qualitative phenotype suggestive of enhanced pituitary vascularization. The ACI.COP-Ept9 rat strain exhibited reduced responsiveness to E2 in the anterior pituitary gland, relative to the ACI rat strain. Neither Ept6 nor Ept9 impacted responsiveness to E2 in the mammary gland or thymus. These data indicate that each of these Ept genetic determinants of estrogen action is unique in regard to the tissues in which it exerts its effects and/or the direction of its effect on estrogen responsiveness.