Kidney dysfunction in adult offspring exposed in utero to type 1 diabetes is associated with alterations in genome-wide DNA methylation

Jean François Gautier, Raphaël Porcher, Charbel Abi Khalil, Naima Bellili-Munoz, Lila Sabrina Fetita, Florence Travert, Simeon Pierre Choukem, Jean Pierre Riveline, Samy Hadjadj, Etienne Larger, Philippe Boudou, Bertrand Blondeau, Ronan Roussel, Pascal Ferré, Eric Ravussin, François Rouzet, Michel Marre

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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 inmethylation 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.

Original languageEnglish
Article numbere0134654
JournalPLoS One
Volume10
Issue number8
DOIs
Publication statusPublished - 10 Aug 2015
Externally publishedYes

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ASJC Scopus subject areas

  • Medicine(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Gautier, J. F., Porcher, R., Abi Khalil, C., Bellili-Munoz, N., Fetita, L. S., Travert, F., Choukem, S. P., Riveline, J. P., Hadjadj, S., Larger, E., Boudou, P., Blondeau, B., Roussel, R., Ferré, P., Ravussin, E., Rouzet, F., & Marre, M. (2015). Kidney dysfunction in adult offspring exposed in utero to type 1 diabetes is associated with alterations in genome-wide DNA methylation. PLoS One, 10(8), [e0134654]. https://doi.org/10.1371/journal.pone.0134654