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Peroxisome Proliferator-Activated Receptor Deficiency Increases the Risk of Maternal Abortion and Neonatal Mortality in Murine Pregnancy with or without Diabetes Mellitus: Modulation of T Cell Differentiation

Department of Physiology (A.Y., A.H., N.A.K.), University of Burgundy, Unité Propre de Recherche de l’Enseignement Supérieur Lipids and Nutrition, Faculty of Life Sciences, 21000 Dijon, France; Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l’Alimentation (P.B.), University of Burgundy, Dijon, France; and Laboratory of Cell Biology and Physiology (A.Y., K.M.), Faculty of Sciences and Techniques, University of Abomey-Calavi, 01BP 526 Cotonou, Bénin

Address all correspondence and requests for reprints to: Prof. Naim Akhtar Khan, Head, Department of Physiology, Unité Propre de Recherche de l’Enseignement Supérieur Lipides and Nutrition, Université de Bourgogne, Faculté des Sciences de la vie, 6 Boulevard Gabriel, 21000 Dijon, France. E-mail: Naim.Khan{at}u-bourgogne.fr.

We assessed the implication of peroxisome proliferator-activated receptor (PPAR) deficiency in pregnancy outcome and neonatal survival and in the modulation of T cell differentiation in murine diabetic pregnancy and their offspring. Pregnant wild-type (WT) and PPAR-null mice of C57BL/6J genetic background were rendered diabetic by five low doses of streptozotocin. We observed that, in the absence of diabetes, PPAR deficiency resulted in an increase in abortion rate, i.e. 0% in WT mice vs. 20% in PPAR-null mice [odds ratio (OR) = 14.33; P = 0.013]. Under diabetic conditions, the abortion rate was enhanced, i.e. 8.3% in WT mice vs. 50% in PPAR-null mice (OR = 4.28; P = 0.011). In the pups born to diabetic dams, the offspring mortality, due to the absence of PPAR, was enhanced, i.e. 27.7% in WT mice vs. 78.9% in PPAR-null animals (OR = 11.48; P < 0.001). Moreover, we observed that T helper (Th) 1/Th2 balance was shifted to a pregnancy protecting Th2 phenotype in WT diabetic dams and to a noxious Th1 phenotype in PPAR-null mice with diabetic pregnancy. Furthermore, offspring born to diabetic WT dams were hyperinsulinemic and hyperglycemic, and they exhibited up-regulated profile of Th2 cytokines, whereas those born to diabetic PPAR-null dams were hypoinsulinemic and hyperglycemic, and they showed down-regulated profile of Th2 cytokines. However, IFN-, a Th1 cytokine, was up-regulated in the offspring of both diabetic WT and PPAR-null dams. Altogether, our results suggest that PPAR deficiency in mice may be implicated in the increase in maternal abortion, neonatal mortality, and T cell differentiation.

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