title: Peroxisome proliferator-activated receptor alpha 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) alpha 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 alpha-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 alpha deficiency resulted in an increase in abortion rate, i.e. 0% in WT mice vs. 20% in PPAR alpha-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 alpha-null mice (OR = 4.28; P = 0.011). In the pups born to diabetic dams, the offspring mortality, due to the absence of PPAR alpha, was enhanced, i.e. 27.7% in WT mice vs. 78.9% in PPAR alpha-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 alpha-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 alpha-null dams were hypoinsulinemic and hyperglycemic, and they showed down-regulated profile of Th2 cytokines. However, IFN-gamma, a Th1 cytokine, was up-regulated in the offspring of both diabetic WT and PPAR alpha-null dams. Altogether, our results suggest that PPAR alpha deficiency in mice may be implicated in the increase in maternal abortion, neonatal mortality, and T cell differentiation.
authors.affiliation: Department of Physiology, University of Burgundy, Unité Propre de Recherche de l'Enseignement Supérieur Lipids and Nutrition, Faculty of Life Sciences, 21000 Dijon, France.
authors.forename: Akadiri
authors.initials: A
authors.lastname: Yessoufou
authors.forename: Aziz
authors.initials: A
authors.lastname: Hichami
authors.forename: Philippe
authors.initials: P
authors.lastname: Besnard
authors.forename: Kabirou
authors.initials: K
authors.lastname: Moutairou
authors.forename: Naim A
authors.initials: NA
authors.lastname: Khan
mesh_terms: D000022:Abortion, Spontaneous / Q000453:epidemiology / Q000209:etiology*; D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D002454:Cell Differentiation; D016207:Cytokines / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000150:complications*; D005260:Female; D005313:Fetal Death / Q000453:epidemiology / Q000209:etiology*; D007328:Insulin / Q000097:blood; D007371:Interferon-gamma / Q000097:blood / Q000235:genetics; D016753:Interleukin-10 / Q000097:blood / Q000235:genetics; D007376:Interleukin-2 / Q000097:blood / Q000235:genetics; D015847:Interleukin-4 / Q000097:blood / Q000235:genetics; D008055:Lipids / Q000097:blood; D018655:Lymphocyte Count; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D047493:PPAR alpha / Q000172:deficiency* / Q000502:physiology; D011247:Pregnancy; D011248:Pregnancy Complications; D012333:RNA, Messenger / Q000032:analysis; D013154:Spleen / Q000737:chemistry; D013601:T-Lymphocytes / Q000166:cytology*; D018417:Th1 Cells / Q000166:cytology / Q000378:metabolism; D018418:Th2 Cells / Q000166:cytology / Q000378:metabolism
chemical_list: D001786:Blood Glucose; D016207:Cytokines; D007328:Insulin; D007376:Interleukin-2; D008055:Lipids; D047493:PPAR alpha; D012333:RNA, Messenger; D016753:Interleukin-10; D015847:Interleukin-4; D007371:Interferon-gamma