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PLoS One. 2015 Aug 10;10(8):e0134654. doi: 10.1371/journal.pone.0134654. eCollection 2015.

Kidney Dysfunction in Adult Offspring Exposed In Utero to Type 1 Diabetes Is Associated with Alterations in Genome-Wide DNA Methylation.

Author information

1
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.
2
Department of Biostatistics and Medical Computing, Saint-Louis University Hospital, Assistance Publique-Hôpitaux de Paris, University Paris-Diderot Paris-7, Paris, France.
3
Department of Diabetes, Groupe Hospitalier Bichat-Claude Bernard, Assistance Publique-Hôpitaux de Paris, DHU FIRE, University Paris-Diderot Paris-7, Paris, France.
4
INSERM UMRS 1138, Cordeliers Research Center, University Pierre et Marie Curie Paris-6, Paris, France.
5
Department of Diabetes and Endocrinology, Assistance Publique-Hôpitaux de Paris, DHU FIRE, Lariboisière Hospital, University Paris-Diderot Paris-7, Paris, France.
6
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.
7
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.
8
Department of Endocrinology and Diabetes, Centre Hospitalier Universitaire, Poitiers, France.
9
Department of Diabetes, Hôtel-Dieu Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.
10
Unit of Transfer in Molecular Oncology and Hormonology, Saint-Louis University Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.
11
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.
12
Penington Biomedical Research Center, Baton Rouge, LA, United States of America.
13
Department of Nuclear Medicine, Groupe Hospitalier Bichat-Claude Bernard, Assistance Publique-Hôpitaux de Paris, University Paris-Diderot Paris-7, Paris, France.
14
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.

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.

DESIGN:

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.

CONCLUSION:

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.

PMID:
26258530
PMCID:
PMC4530883
DOI:
10.1371/journal.pone.0134654
[Indexed for MEDLINE]
Free PMC Article

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