title: Kidney Dysfunction in Adult Offspring Exposed In Utero to Type 1 Diabetes Is Associated with Alterations in Genome-Wide DNA Methylation.
abstract: BACKGROUND
  Fetal exposure to hyperglycemia impacts negatively kidney development and function.
  
  
  OBJECTIVE
  Our objective was to determine whether fetal exposure to moderate hyperglycemia is associated with epigenetic alterations in DNA methylation in peripheral blood cells and whether those alterations are related to impaired kidney function in adult offspring.
  
  
  METHODS
  Twenty nine adult, non-diabetic offspring of mothers with type 1 diabetes (T1D) (case group) were matched with 28 offspring of T1D fathers (control group) for the study of their leukocyte genome-wide DNA methylation profile (27,578 CpG sites, Human Methylation 27 BeadChip, Illumina Infinium). In a subset of 19 cases and 18 controls, we assessed renal vascular development by measuring Glomerular Filtration Rate (GFR) and Effective Renal Plasma Flow (ERPF) at baseline and during vasodilatation produced by amino acid infusion.
  
  
  RESULTS
  Globally, DNA was under-methylated in cases vs. controls. Among the 87 CpG sites differently methylated, 74 sites were less methylated and 13 sites more methylated in cases vs. controls. None of these CpG sites were located on a gene known to be directly involved in kidney development and/or function. However, the gene encoding DNA methyltransferase 1 (DNMT1)--a key enzyme involved in gene expression during early development--was under-methylated in cases. The average methylation of the 74 under-methylated sites differently correlated with GFR in cases and controls.
  
  
  CONCLUSIONS
  Alterations in methylation profile imprinted by the hyperglycemic milieu of T1D mothers during fetal development may impact kidney function in adult offspring. The involved pathways seem to be a nonspecific imprinting process rather than specific to kidney development or function.
authors.affiliation: Department of Diabetes and Endocrinology, Assistance Publique-Hôpitaux de Paris, DHU FIRE, Lariboisière Hospital, University Paris-Diderot Paris-7, Paris, France; Clinical Investigation Center, INSERM-CIC9504, Saint-Louis University Hospital, Assistance Publique-Hôpitaux de Paris, University Paris-Diderot Paris-7, Paris, France; INSERM UMRS 1138, Cordeliers Research Center, University Pierre et Marie Curie Paris-6, Paris, France.
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Gautier
authors.affiliation: Department of Biostatistics and Medical Computing, Saint-Louis University Hospital, Assistance Publique-Hôpitaux de Paris, University Paris-Diderot Paris-7, Paris, France.
authors.forename: Raphaël
authors.initials: R
authors.lastname: Porcher
authors.affiliation: Department of Diabetes, Groupe Hospitalier Bichat-Claude Bernard, Assistance Publique-Hôpitaux de Paris, DHU FIRE, University Paris-Diderot Paris-7, Paris, France.
authors.forename: Charbel
authors.initials: C
authors.lastname: Abi Khalil
authors.affiliation: INSERM UMRS 1138, Cordeliers Research Center, University Pierre et Marie Curie Paris-6, Paris, France.
authors.forename: Naima
authors.initials: N
authors.lastname: Bellili-Munoz
authors.affiliation: Department of Diabetes and Endocrinology, Assistance Publique-Hôpitaux de Paris, DHU FIRE, Lariboisière Hospital, University Paris-Diderot Paris-7, Paris, France.
authors.forename: Lila Sabrina
authors.initials: LS
authors.lastname: Fetita
authors.affiliation: Department of Diabetes, Groupe Hospitalier Bichat-Claude Bernard, Assistance Publique-Hôpitaux de Paris, DHU FIRE, University Paris-Diderot Paris-7, Paris, France; Clinical Investigation Center, Groupe Hospitalier Bichat-Claude Bernard, Assistance Publique-Hôpitaux de Paris, University Paris-Diderot Paris-7, Paris, France.
authors.forename: Florence
authors.initials: F
authors.lastname: Travert
authors.affiliation: Department of Diabetes and Endocrinology, Assistance Publique-Hôpitaux de Paris, DHU FIRE, Lariboisière Hospital, University Paris-Diderot Paris-7, Paris, France.
authors.forename: Simeon-Pierre
authors.initials: SP
authors.lastname: Choukem
authors.affiliation: INSERM UMRS 1138, Cordeliers Research Center, University Pierre et Marie Curie Paris-6, Paris, France; Department of Diabetes and Endocrinology, Centre Hospitalier Sud Francilien, Corbeil-Essonnes, France.
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Riveline
authors.affiliation: Department of Endocrinology and Diabetes, Centre Hospitalier Universitaire, Poitiers, France.
authors.forename: Samy
authors.initials: S
authors.lastname: Hadjadj
authors.affiliation: Department of Diabetes, Hôtel-Dieu Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.
authors.forename: Etienne
authors.initials: E
authors.lastname: Larger
authors.affiliation: Unit of Transfer in Molecular Oncology and Hormonology, Saint-Louis University Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Boudou
authors.affiliation: INSERM UMRS 1138, Cordeliers Research Center, University Pierre et Marie Curie Paris-6, Paris, France.
authors.forename: Bertrand
authors.initials: B
authors.lastname: Blondeau
authors.affiliation: Department of Diabetes, Groupe Hospitalier Bichat-Claude Bernard, Assistance Publique-Hôpitaux de Paris, DHU FIRE, University Paris-Diderot Paris-7, Paris, France; INSERM U695, University Paris-Diderot Paris-7, Paris, France.
authors.forename: Ronan
authors.initials: R
authors.lastname: Roussel
authors.affiliation: INSERM UMRS 1138, Cordeliers Research Center, University Pierre et Marie Curie Paris-6, Paris, France.
authors.forename: Pascal
authors.initials: P
authors.lastname: Ferré
authors.affiliation: Penington Biomedical Research Center, Baton Rouge, LA, United States of America.
authors.forename: Eric
authors.initials: E
authors.lastname: Ravussin
authors.affiliation: Department of Nuclear Medicine, Groupe Hospitalier Bichat-Claude Bernard, Assistance Publique-Hôpitaux de Paris, University Paris-Diderot Paris-7, Paris, France.
authors.forename: François
authors.initials: F
authors.lastname: Rouzet
authors.affiliation: Department of Diabetes, Groupe Hospitalier Bichat-Claude Bernard, Assistance Publique-Hôpitaux de Paris, DHU FIRE, University Paris-Diderot Paris-7, Paris, France; Clinical Investigation Center, Groupe Hospitalier Bichat-Claude Bernard, Assistance Publique-Hôpitaux de Paris, University Paris-Diderot Paris-7, Paris, France; INSERM U695, University Paris-Diderot Paris-7, Paris, France.
authors.forename: Michel
authors.initials: M
authors.lastname: Marre
mesh_terms: D000328:Adult; D000596:Amino Acids / Q000378:metabolism; D018899:CpG Islands; D004247:DNA / Q000235:genetics; D019175:DNA Methylation; D003922:Diabetes Mellitus, Type 1 / Q000097:blood*; D005220:Fathers; D005260:Female; D016678:Genome; D015894:Genome, Human; D005919:Glomerular Filtration Rate; D006801:Humans; D006943:Hyperglycemia / Q000097:blood; D007668:Kidney / Q000098:blood supply / Q000503:physiopathology*; D007962:Leukocytes / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009035:Mothers; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D011786:Quality Control; D012039:Regional Blood Flow
chemical_list: D000596:Amino Acids; D004247:DNA