Phosphoinositide metabolism in the developing conceptus. Effects of hyperglycemia and scyllo-inositol in rat embryo culture.
Culture of the postimplantation rat conceptus in hyperglycemic medium causes developmental abnormalities and is associated with a diminished water-soluble myo-inositol content. We investigated the effect myo-inositol depletion has on lipid-soluble phosphoinositides, precursors, and water-soluble inositol phosphates. Rat conceptuses were cultured from gestational day 9.5 (presomite, early head fold) to day 10.5 (7-15 somites) in 6.7-73.3 mM D-glucose. Significant decreases in the phosphoinositides of the embryo were observed with increased culture D-glucose concentrations. PI was reduced 15-34%, PIP 18-46%, and PIP2 26-46%. Yolk sac phosphoinositides also were reduced but to a lesser degree. Culture in hyperglycemic media also mediated significant reductions of conceptus inositol phosphates. To investigate whether effects similar to those induced by D-glucose could be mediated by another agent capable of decreasing myo-inositol content, we used scyllo-inositol, a transported but nonmetabolized isomer of myo-inositol. Conceptuses cultured in medium containing scyllo-inositol (0.06-16.7 mM) had dose-dependent decreases of myo-[3H]inositol in water-soluble and lipid-soluble fractions. Incorporation of myo-[3H]inositol into phosphoinositides and inositol phosphates was decreased concomitantly. Developmental effects of D-glucose and scyllo-inositol were assessed in rat conceptuses cultured from day 9.5 (presomite, early head fold) to day 11.5 (22-28 somites). Culture in 40.0-73.3 mM glucose and 0.06-33.3 mM scyllo-inositol impaired growth while increasing dysmorphogenesis in a dose-dependent manner. The results suggest that decreases in conceptus myo-inositol and associated diminution of phosphoinositides, which are the inositol/lipid cycle precursors, are dysmorphogenic and may contribute to the etiology of diabetic embryopathy.
Strieleman
P J
PJ
Department of Medicine, Northwestern University Medical School, Chicago, Illinois.
Connors
M A
MA
Metzger
B E
BE
D000704:Analysis of Variance; D000818:Animals; D003470:Culture Media; D046508:Culture Techniques; D004305:Dose-Response Relationship, Drug; D004622:Embryo, Mammalian / Q000187:drug effects* / Q000378:metabolism*; D005260:Female; D005947:Glucose / Q000494:pharmacology*; D007294:Inositol / Q000378:metabolism / Q000494:pharmacology*; D007295:Inositol Phosphates / Q000378:metabolism; D010716:Phosphatidylinositols / Q000378:metabolism*; D051381:Rats; D013237:Stereoisomerism; D015017:Yolk Sac / Q000187:drug effects / Q000378:metabolism
D003470:Culture Media; D007295:Inositol Phosphates; D010716:Phosphatidylinositols; C009217:scyllitol; D007294:Inositol; D005947:Glucose