Peroxisome proliferator-activated receptor α 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) α 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 PPARα-null mice of C57BL/6J genetic background were rendered diabetic by five low doses of streptozotocin. We observed that, in the absence of diabetes, PPARα deficiency resulted in an increase in abortion rate, i.e. 0% in WT mice vs. 20% in PPARα-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 PPARα-null mice (OR = 4.28; P = 0.011). In the pups born to diabetic dams, the offspring mortality, due to the absence of PPARα, was enhanced, i.e. 27.7% in WT mice vs. 78.9% in PPARα-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 PPARα-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 PPARα-null dams were hypoinsulinemic and hyperglycemic, and they showed down-regulated profile of Th2 cytokines. However, IFN-γ, a Th1 cytokine, was up-regulated in the offspring of both diabetic WT and PPARα-null dams. Altogether, our results suggest that PPARα deficiency in mice may be implicated in the increase in maternal abortion, neonatal mortality, and T cell differentiation. Copyright © 2006 by The Endocrine Society.