title: Tacrolimus in the prevention of adverse pregnancy outcomes and diabetes-associated embryopathies in obese and diabetic mice.
abstract: T2DM is a high-risk pregnancy with adverse fetal and maternal outcomes including repeated miscarriages and fetal malformations. Despite the established association between placental insufficiency and poor maternal Th1-adaptability to the development of pregnancy complications in T2DM, there have been no established data to assess benefits of pre-pregnancy immunosuppression relative to gestational outcomes in T2DM. We hypothesized that pre-pregnancy macrolide immune suppression can re-establish normal placental development and uterine vascular adaptation in a mouse model of obesity-associated T2DM.
  
  
  
  Fetal live birth rate, postnatal variability, mid-gestational uterine and umbilical flow dynamics and certain morphological features of spiral artery modification were examined in the New Zealand Obese (NONcNZO10/Ltj) female mice (n = 56) weaned to ages of 32 weeks on a 60% calories/g high-fat diet (also referred to as HFD-dNONcNZO), and which received either tacrolimus (0.1 mg/kg s.c. q2d) , its vehicle (castor oil and ethanol) or metformin (in drinking water 200 mg/dL p.o. ad libitum). HFD-BALBc-Rag2/IL2-gc female mice (n = 24) were used as HFD-immunodeficient controls.
  
  
  
  Treatment of the HFD-dNONcNZO female mice with tacrolimus improved live birth rates and postnatal viability scores (p < 0.01), normalized OGTT (p < 0.001), inhibited fetal malformation rates, restored morphology of spiral arterial modification; and improved uterine arterial and umbilical blood flow (p < 0.01). Placental production of TNFαand IL16 in the tacrolimus-treated HFD-dNONcNZO dams were restored to non-diabetic levels and the treatment resulted in the inhibition of aberrant monocyte/macrophage activation during pregnancy in the HFD-dNONcNZO dams.
  
  
  
  Our present data suggest a casual association between chronic maternal overnutrition and aberrancy in the maternal Th1-immune maladaptation to pregnancy and defective spiral artery modification, placental insufficiency and adverse fetal outcomes in the T2DM subjects. Further safety studies into the use of tacrolimus in the pre-pregnancy glycemic control may be beneficial.
authors.affiliation: Department of Biomedical and Molecular Sciences, Faculty of Health Sciences, Queen's University, Kingston, ON, K7L3N6, Canada.
authors.forename: Ahmad J H
authors.initials: AJ
authors.lastname: Albaghdadi
authors.affiliation: Department of Biomedical and Molecular Sciences, Faculty of Health Sciences, Queen's University, Kingston, ON, K7L3N6, Canada.
authors.forename: Melanie A
authors.initials: MA
authors.lastname: Hewitt
authors.affiliation: Department of Biomedical and Molecular Sciences, Faculty of Health Sciences, Queen's University, Kingston, ON, K7L3N6, Canada.
authors.forename: Samantha M
authors.initials: SM
authors.lastname: Putos
authors.affiliation: PARTEQ Innovations, Queen's University, Kingston, ON, K7L 0E9, Canada.
authors.forename: Michael
authors.initials: M
authors.lastname: Wells
authors.affiliation: Department of Biomedical and Molecular Sciences, Faculty of Health Sciences, Queen's University, Kingston, ON, K7L3N6, Canada.
authors.forename: Terence R S
authors.initials: TR
authors.lastname: Ozolinš
authors.affiliation: Department of Biomedical and Molecular Sciences, Faculty of Health Sciences, Queen's University, Kingston, ON, K7L3N6, Canada. kanfwk@queensu.ca.
authors.forename: Frederick W K
authors.identifier: 0000-0003-0026-9061
authors.initials: FW
authors.lastname: Kan
mesh_terms: D000818:Animals; D001842:Bone and Bones / Q000002:abnormalities / Q000187:drug effects / Q000196:embryology / Q000473:pathology; D003921:Diabetes Mellitus, Experimental / Q000150:complications* / Q000188:drug therapy; D059305:Diet, High-Fat; D005260:Female; D005315:Fetal Diseases / Q000188:drug therapy / Q000209:etiology* / Q000517:prevention & control*; D005951:Glucose Tolerance Test; D008687:Metformin / Q000494:pharmacology / Q000627:therapeutic use; D008807:Mice, Inbred BALB C; D008820:Mice, Obese; D011247:Pregnancy; D011256:Pregnancy Outcome; D013131:Spine / Q000098:blood supply / Q000187:drug effects / Q000503:physiopathology; D016559:Tacrolimus / Q000494:pharmacology / Q000627:therapeutic use*; D014470:Umbilical Cord / Q000098:blood supply; D055988:Uterine Artery / Q000503:physiopathology; D066253:Vascular Remodeling / Q000187:drug effects
chemical_list: D008687:Metformin; D016559:Tacrolimus
keywords: Adverse pregnancy outcomes (APO); Diabetes; Embryopathies; Immunosuppression; Metformin; Tacrolimus