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Diethylstilbestrol Stimulates Persistent Phosphatidylinositol Lipid Turnover by an Estrogen Receptor-Mediated Mechanism in Immature Mouse Uterus

DIANE M. IGNAR-TROWBRIDGE^*, ARLENE R. HUGHES, JAMES W. PUTNEY, JR., JOHN A. McLACHLAN and KENNETH S. KORACH

Laboratory of Reproductive and Developmental Toxicology (D.M.I.-T., J.A.M., K.S.K.) and Laboratory of Cellular and Molecular Pharmacology (A.R.H., J. W.P.), National Institute of Environmental Health Sciences, National Institutes of Health Research Triangle Park, North Carolina 27709

Address all correspondence and requests for reprints to: Dr. John A McLachlan, M.D. 17-02, National Institute of Environmental Health Sciences, P.O. Box 12233, Research Triangle Park, North Carolina 27709.

Abstract

The effect of estrogen on phosphoinositide (PI) metabolism was evaluated in the immature mouse uterus, a tissue which undergoes estrogen-induced proliferation. Uteri isolated from untreated mice or from mice injected ip with diethylstilbestrol (DES) were incubated with [₃H]myo-inositol and assessed for incorporation of label into PI lipids or inositol phosphate generation. DES administration elicited a rapid increase in [₃H]myo-inositol incorporation, which persisted until at least 18 h post treatment. This effect could not be duplicated by incubation of uteri with DES in vitro, although [₃H]myo-inositol incorporation in uteri removed from DES-treated mice remained elevated for 3 h of in vitro incubation. Stimulation of PI lipid metabolism by DES was blocked by ICI 164,384, a specific estrogen receptor antagonist. The effect of DES on PI metabolism consisted of a time-dependent increase in the specific activity of both phosphatidylinositol-4-phosphate and phosphatidylinositol-4,5-bisphosphate and a significant increase of inositol (l,4,5)-trisphosphate mass by 12 h post treatment. These changes occur before the onset of estrogen-induced DNA synthesis. The results indicate that estrogens rapidly modulate PI lipid turnover through an estrogen receptor-mediated mechanism. Since the metabolic products of PI lipids are important for signal transduction and cellular proliferation, altered metabolism of these lipids may play an integral role in estrogeninduced mitogenesis. (Endocrinology 129: 2423–2430,1991)

Footnotes

^* Supported by a PRAT fellowship from the National Institute of General Medical Sciences.

Present address: Department of Clinical Neurosciences, Burroughs Wellcome Company, Research Triangle Park, North Carolina 27709.

Received July 8, 1991.

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