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

Abstract

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 upregulated 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.