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Molecular and Morphological Changes in Placenta and Embryo Development Associated with the Inhibition of Polyamine Synthesis during Midpregnancy in Mice

Departments of Biochemistry and Molecular Biology B and Immunology (C.L.-G., A.J.L.-C., R.P.), Pharmacology (A.C.), Cell Biology (M.T.C.), and Human Anatomy and Psychcobiology (F.M.), Faculty of Medicine, University of Murcia, 30100 Murcia, Spain; and Team 15 (FS), Microbial Pathogenesis, Wellcome Trust Sanger Institute, Cambridge CB10 1SA, United Kingdom

Address all correspondence and requests for reprints to: Dr. Rafael Peñafiel, Department of Biochemistry and Molecular Biology B and Immunology, Faculty of Medicine, University of Murcia, Campus de Espinardo, 30100 Murcia, Spain. E-mail: rapegar{at}um.es.

Polyamines play an essential role in murine development, as demonstrated by both gene ablation in ornithine decarboxylase (ODC)-deficient embryos and pharmacological treatments of pregnant mice. However, the molecular and cellular mechanisms by which ODC inhibition affects embryonic development during critical periods of pregnancy are mostly unknown. Our present results demonstrate that the contragestational effect of -difluoromethylornithine (DFMO), a suicide inhibitor of ODC, when given at d 7–9 of pregnancy, is associated with embryo growth arrest and marked alterations in the development of yolk sac and placenta. Blood island formation as well as the transcript levels of embryonary globins -like x chain and β-like y-chain was markedly decreased in the yolk sac. At the placental level, abnormal chorioallantoic attachment, absence of the spongiotrophoblast layer and a deficient development of the labyrinthine zone were evident. Real-time RT-PCR analysis showed that transcript levels of the steroidogenic genes steroidogenic acute regulatory protein, 3β-hydroxysteroid dehydrogenase VI, and 17-hydroxylase were markedly decreased by DFMO treatment in the developing placenta at d 9 and 10 of pregnancy. Plasma values of progesterone and androstenedione were also decreased by DFMO treatment. Transcriptomic analysis also detected changes in the expression of several genes involved in placentation and the differentiation of trophoblastic lineages. In conclusion, our results indicate that ODC inhibition at d 8 of pregnancy is related to alterations in yolk sac formation and trophoblast differentiation, affecting processes such as vasculogenesis and steroidogenesis.