Epigenetic dysregulation of the IGF system in placenta of newborns exposed to maternal impaired glucose tolerance

Abstract

Aims: To determine whether placental IGF1R, IGFBP3, INSR and IGF1 DNA methylation and mRNA levels were dysregulated when exposed to maternal impaired glucose tolerance (IGT) and investigate whether the epigenetic profile is associated with feto-placental developmental markers. Patients & methods: The IGT diagnosis was made according to the WHO criteria (IGT: n = 34; normal glucose tolerance [NGT]: n = 106). DNA methylation and mRNA levels were quantified using bisulfite pyrosequencing and qRT-PCR, respectively. Results:IGF1R and IGFBP3 DNA methylation levels were lower in placentas exposed to IGT compared with NGT (-4.3%; p = 0.021 and -2.5%; p = 0.006 respectively) and correlated with 2-h post-oral glucose tolerance test (OGTT) glycemia (r = -0.23; p = 0.010 and r = -0.20; p = 0.028, respectively). IGF1R mRNA levels were associated with newborns’ growth markers (e.g., birth weight; r = 0.20; p = 0.032). Conclusion: These results support the growth-promoting role of the IGF system in placental/fetal development and suggest that the IGF1R and IGFBP3 DNA methylation profiles are dysregulated in IGT, potentially affecting the fetal metabolic programming.

Keywords::

• DNA methylation
• gestational diabetes
• IGF
• mRNA
• placenta

Acknowledgements

We express our gratitude to Céline Bélanger, Chicoutimi Hospital, for her thoughtful revision of the manuscript. The authors also acknowledge the contribution of Sébastien Claveau, MSc, ECOGENE-21 Laboratory; Nadia Mior, ECOGENE-21 Laboratory; Denise Morin, ECOGENE-21 Laboratory; Jeanine Landry, RN, ECOGENE-21 Clinical Research Center; and Chantale Aubut, RN, ECOGENE-21 Clinical Research Center for their dedicated work in this study

Financial & competing interests disclosure

This study was supported by the ECOGENE-21 Clinical research center (principal investigator: D Gaudet, Université de Montréal), the Canadian Institutes of Health Research (CIHR), the Fonds de Recherche du Québec en Santé (FRQS) and Diabète Québec. V Desgagné was supported by Diabète Québec and by the Faculté de médecine et des sciences de la santé (FMSS) of Université de Sherbrooke. L Bouchard and M-F Hivert are junior research scholars from the FRQS. M-F Hivert. is also supported by a Canadian Diabetes Association clinical scientist award. L Bouchard and M-F Hivert are members of the FRQS-funded Centre de recherche clinique Étienne-Le Bel (affiliated with Centre Hospitalier de l’Université de Sherbrooke). During this research, S-P Guay was recipient of a doctoral research award from the CIHR. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Additional information

Funding

This study was supported by the ECOGENE-21 Clinical research center (principal investigator: D Gaudet, Université de Montréal), the Canadian Institutes of Health Research (CIHR), the Fonds de Recherche du Québec en Santé (FRQS) and Diabète Québec. V Desgagné was supported by Diabète Québec and by the Faculté de médecine et des sciences de la santé (FMSS) of Université de Sherbrooke. L Bouchard and M-F Hivert are junior research scholars from the FRQS. M-F Hivert. is also supported by a Canadian Diabetes Association clinical scientist award. L Bouchard and M-F Hivert are members of the FRQS-funded Centre de recherche clinique Étienne-Le Bel (affiliated with Centre Hospitalier de l’Université de Sherbrooke). During this research, S-P Guay was recipient of a doctoral research award from the CIHR. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.