Nutrigenetics, epigenetics and gestational diabetes: consequences in mother and child

Figures & data

Table 1. Rodent studies related to maternal nutrition assessing the effects of epigenetic alterations and their consequences on offspring.

Author Year [Reference]	Animal Model	Maternal intervention	Offspring tissue	Method	Alterations in the offspring
Cannon 2004 [77]	C57BL/6J mouse	HFD LFD	Liver	RRBS Gene Expression BeadChips	No detectable DNA methylation differences Upregulation of genes involved in inflammation, cholesterol synthesis and RXR activation
Davison 2009 [69]	Sprague-Dawley rat	Choline-supplement/deficiency	Liver Frontal cortex	MS-PCR RT-PCR Western blot	Upregulation of DNA methylation of the G9a and Suv39h1 genes by choline-deficient diet Upregulation of H3K9Me2 and H3K27Me3 levels by choline supplementation
Tosh 2010 [70]	Sprague Dawley rat	FR	Liver Plasma	ChIP Western blot qRT-PCR	Decreased demethylation at H3K4 in the Igf1 region in the IUGR offspring Increased trimethylation of H3K4 in Igf1 region and increased of hepatic Igf1 mRNA expression in obese adult males offspring
Strakovsky 2011 [71]	Sprague-Dawley rat	HFD	Liver Plasma Serum	RT-PCR ChIP	Higher mRNA expression of gluconeogenic genes Increased plasma glucose levels Modifications of the Pck1 histone code in liver
Garbory 2012 [136]	C57BL/6J mouse	HFD	Placenta	Microarray qRT-PCR Western Blotting	Dysregulation of 7 genes due to diet, sex or both, including the Y- and X-linked histone demethylase paralogues Kdm5c and Kdm5d
Borengasser 2013 [72]	Sprague Dawley rat	Over nutrition	WAT	RRBS RT-PCR	Alterations in DNA methylation in developmentally important genes. Upregulation of lipogenic genes
Zhang 2015 [73]	Sprague-Dawley rat	HFD	Liver	MeDIP-seq MRE-seq	Hypomethylation of 12,494 DMRs Hypermethylation of 6,404 DMRs Identification of DMGs involved in critical hepatic signaling networks
Petropoulos 2015 [102]	Cohen diabetes-sensitive rat	HSD	Placenta Liver	MeDIP	Different methylation of genes in the placenta and liver with a significant overlap
Wankhade 2017 [74]	C57BL6/J mouse	HFD	Liver	RNA-seq qRT-PCR RRBS	Higher pro-fibrogenic genes expression Identification of 82 DMRs in O-MCD diet
Moody 2017 [75]	Sprague–Dawley rat	HFD	Liver	MeDIP-seq MRE-seq qRT-PCR	Identification of DMGs clustered in the T2DM and the adipocytokine signaling pathways Alteration of several genes expression involved in lipid metabolism and inflammation
Keleher 2018 [76]	SM/J mouse	HFD	Liver Heart	RNA-seq MeDIP-seq MRE-seq	Identification of tens of thousands DMRs Alteration of several genes expression in liver and heart
Jiang 2018 [93]	ICR mouse	STZ	Placenta	qRT-PCR bisulfite genomic sequencing PCR	Upregulation of 35 imprinted genes Down-regulation of 10 imprinted genes Down-regulation of Dlk1 and upregulation of Gtl2 due to their abnormal methylation status

HFD, high fat diet; LFD, low fat diet; RRBS, reduced representation bisulfite sequencing; MS-PCR, methylation specific PCR; RT-PCR, reverse transcription-PCR; FR, food restriction; ChIP, Chromatin immunoprecipitation; qRT-PCR, quantitative real-time PCR; IUGR, intrauterine growth restricted; WAT, white adipose tissue; MeDIP-seq, methylated DNA immunoprecipitation sequencing; MRE-seq, methylation-sensitive restriction enzyme sequencing; DMRs, differentially methylated regions; DMGs, Differentially methylated genes; MeDIP, Methylated DNA immunoprecipitation arrays; HSD, high sucrose, low-copper diet; O-MCD diet, methionine choline deficient diet; STZ, streptozotocin.

Table 2. Human studies investigating epigenetic alterations in pregnant women with hyperglicemia and in their offspring.

Author Year [Reference]	Study Design	Sample size	Hyperglicemia criteria	Tissue	Method	Main finding
Bouchard 2010 [95]	Case-control	48 (23 IGT)	2-h 75 g OGTT, IGT glucose ≥7.8 mmol/L at 2-h	Placenta (foetal and maternal) UCB	Bisulfite pyrosequencing	Correlation between LEP DNA methylation and 2h glucose levels in IGT women
Bouchard 2012 [96]	Cohort	98 (31 IGT)	2-h 75 g OGTT, IGT glucose ≥7.8 mmol/L at 2-h according to WHO	Placenta (foetal and maternal) UCB MBS	Bisulfite pyrosequencing	Inverse correlation between ADIPOQ DNA methylation on the foetal side and 2h glucose levels in IGT women
Houde 2013 [97]	Cohort	100 (26 IGT)	2-h 75 g OGTT, IGT glucose ≥7.8 mmol/L at 2-h according to WHO	Placenta (foetal and maternal) UCB MBS	Bisulfite pyrosequencing qRT-PCR	Positive correlation between ABCA1 DNA methylation on the maternal side and HDL-C and 2h glucose levels in IGT women correlation between DNA methylation on the fetal side and TGs in UCB Negative correlation between ABCA1 DNA methylation in UCB and 2h glucose levels
El Hajj 2013 [103]	Cohort	251 offspring (88 OD-GDM 98 OI-GDM 65 O non-GDM)	2-h 75 g OGTT, GDM glucose >180 mg/dL at 1 h and/or >155 mg/dL at 2 h	Placenta UCB	Bisulfite pyrosequencing	Decreased methylation of MEST, NR3C1, and ALUs in O-GDM
Ruchat 2013 [100]	Case-control	44 offspring (30 O-GDM)	2-h 75 g OGTT, GDM glucose ≥7.8 mmol/L at 2 h according to WHO	Placenta (foetal) UCB	Infinium HumanMethylation450 array	Number of genes potentially differentially methylated in the placenta and UCB in O-GDM
Quilter 2014 [87]	Cohort	C-HAPO cohort (n = 36) I-CBGS cohort [n = 96 (16 GDM)]	WHO criteria	UCB	Human Methylation27 BeadChip	Different methylation of some loci related to growth and diabetes
Houde 2014 [99]	Cohort	126 (27 GDM)	2-h 75 g OGTT, GDM glucose ≥7.8 mmol/L according to WHO criteria	Placenta (foetal)	Bisulfite pyrosequencing qRT-PCR	Lower LPL DNA methylation levels in GDM. Negative correlation between LPL DNA methylation levels in GDM and maternal 2h glucose levels/HDL-C
Desgagne 2014 [101]	Cohort	140 (IGT 34)	2-h 75 g OGTT, IGT glucose ≥7.8 mmol/L at 2 h according to WHO criteria	Placenta (foetal)	Bisulfite pyrosequencing qRT-PCR	Lower IGF1R and IGFBP3 DNA methylation levels and correlation with maternal 2h glucose levels Association between IGF1R mRNA levels and newborns’ growth markers
Petropoulos 2015 [102]	Case control	14 (7 mild hyperglicemia)	GCT or a OGTT (1 week after GCT)	Placenta	Infinium HumanMethylation450 array	Different methylation of some loci involved in endocrine function, metabolism, and insulin responses
Reichetzeder 2016 [94]	Cohort	1030 (56 GDM)	GDA and DGGG 2014	Placenta (maternal)	LC-MS/MS	Increased global methylation in GDM
Côté 2016 [105]	Cohort	E-21 birth cohort (n = 133, 33 GDM) Gen3G birth cohort (n = 172, all controls)	E-21: 2h OGTT, GDM glucose ≥7.8 mmol/L according to WHO criteria Gen3G: 2h OGTT according to IADPSG 2010	Placenta (foetal)	E-21: bisulfite pyrosequencing Gen3G: HumanMethylation450 array	Inverse correlation between PRDM16, BMP7 and PPARGC1A DNA methylation levels and maternal glycemia at the 2^nd and 3^rd trimester
Gagné-Ouellet 2017 [17]	Prospective birth cohort	66 offspring (24 O-GDM)	2-h 75 g OGTT, GDM glucose ≥7.8 mmol/L according to WHO criteria	Placenta (foetal) Offspring’s whole blood at 5 years	Bisulfite pyrosequencing qRT-PCR	Negative correlation between LPL DNA methylation and mRNA levels in placenta Positive correlation between LPL DNA methylation levels and anthropometric profile at 5 years of age
Chen 2017 [53]	Cohort	388 Pima Indian offspring (187 O-T2DM, 201 O-BP)	2-h 75 g OGTT, T2DM FBG≥7 mmol/L or 2-h glucose ≥11.1 mmol/L according to WHO criteria	blood samples	Illumina HumanMethylation450 K	Different methylation at multiple genomic sites
Houshmand-Oeregaard 2017 [106]	Cohort	206 adult offspring (82 O-GDM, 67 O-T1DM, 57 O-BP)	Mother = 3-h 50g OGTT in women at risk with two consecutive FBG ≥4.1 mmol/l Offspring = 2-h 75g OGTT according to WHO 2006 criteria	SAT plasma	Bisulfite pyrosequencing qRT-PCR	Increased ADIPOQ methylation levels and decreased ADIPOQ and RETN gene expression in SAT of O-GDM
Ott 2018 [107]	prospective observational cohort	55 mother-child dyads (25 GDM)	National Germany guidelines	SAT VAT UCB blood samples	Bisulfite pyrosequencing qRT-PCR	Alteration of ADIPOQ DNA methylation profiles in CB cells of O-GDM Reduction of mRNA adiponectin levels in SAT and VAT of GDM women
Ott 2019 [108]	Prospective observational	55 mother-child dyads (25 GDM)	National Germany guidelines	SAT VAT UCB blood samples	Bisulfite pyrosequencing qRT-PCR	Similar DNA methylation patterns across tissues Reduction of IR mRNA/protein expressions in SAT and VAT of GDM women

IGT, Impaired Glucose Tolerance; OGTT, oral glucose tolerance test; UCB, umbilical cord blood; MBS, Maternal blood samples; qRT-PCR, quantitative Real-Time PCR; HDL-C, high-density lipoprotein cholesterol; TGs, triglycerides; OD-GDM, offspring of mother with dietetically treated gestational diabetes, OI-GDM offspring of mother with insulin-dependent GDM; C-HAPO, children from Hyperglicemia and Adverse Pregnancy Outcome; I-CBGS, infants from Cambridge Baby Growth Study; WHO, World Health Organization; GCT, Glucose Challenge Test; GDA, German Diabetes Association; DGGG, German Association for Gynaecology and Obstetrics; LC-MS/MS, Liquid Chromatography tandem Mass Spectrometry; E-21, ECOGENE-21; Gen3G, Genetics of Glucose regulation in Gestation and Growth; IADPSG, International Association of the Diabetes and Pregnancy Study Groups; O-GDM, offspring of women with GDM; O-T2DM, offspring of women with T2DM during pregnancy, O-BP, offspring of women from the background population; FBG, fasting blood glucose; O-T1DM, offspring of women with T1DM during pregnancy; SAT, subcutaneous adipose tissue; VAT, visceral adipose tissue;

Table 3. Studies investigating miRNAs in GDM and offspring.

Author Year [Reference]	Study design	Sample size	GDM criteria	Tissue (GA wks)	Method	Main finding
Zhao 2011 [110]	Case-control	48 (24 GDM)	Two-step approach: 50 g GCT followed, if positive, by 3-h 75 g OGTT according to the ADA 2003	Maternal serum (16^th–19^th)	TLDA chip qRT-PCR	miR-132, miR-29a, miR-222 downregulation
Shi 2014 [113]	Case-control	26 (13 GDM)	ADA 2006	Maternal omental adipose tissue (cesarean delivery at 38^th–39^th)	AFFX miRNA expression chips qRT-PCR	miR-222 upregulation and negatively correlation with ERα and GLUT4 protein levels
Zhu 2015 [112]	Case-control	20 (10 GDM)	Two-step approach: 50 g GCT followed, if positive, by 3-h 75 g OGTT according to the ADA 2011	Maternal plasma (16^th–19^th)	High-throughput sequencing (Ion Torrent) qRT-PCR	hsa-miR-16-5p, hsa-miR-17-5p, hsa-miR-19a-3p, hsa-miR-19b-3p, hsa-miR-20a-5p upregulation
Cao 2016 [114]	Case-control	395 (193 GDM)	IADPSG 2010	Placenta (37^th-40^th)	qRT-PCR	miR-98 upregulation linked to the global DNA methylation via targeting MECP2
Sebastiani 2017 [109]	Case-control	31 (21 GDM)	A 2h 75 g OGTT according to the Italian guidelines (IADPSG 2010)	Maternal plasma (24^th–33^rd)	TaqMan array profiling analysis qRT- PCR	miR-330-3p upregulation
Tagoma 2018 [111]	Case-control	22 (13 GDM)	2-h 75 g OGTT according to the IADPSG 2010	Maternal plasma (23^rd-31^st)	RT-PCR	miR-195-5p upregulation
Houshmand-Oeregaard 2018 [115]	observational follow-up	206 offspring (82 O-GDM 67 O-T1D 57 O-BP)	Mother = OGTT in women at risk with two consecutive FBG ≥4.1 mmol/l Offspring = 2h 75 g OGTT according to WHO 2006 criteria	Skeletal muscle of adult offspring (26- to 35-year-old)	Taqman miRNA assays	miR-15a, miR-15b upregulation in O-GDM and O-T1D

GCT, glucose challenge test; OGTT, oral glucose tolerance test; ADA, American Diabetes Association; TLDA, TaqMan Low Density Array; qRT-PCR, quantitative reverse transcriptase polymerase chain reaction; IADPSG, International Association of the Diabetes and Pregnancy Study Groups; O-BP, offspring of women from the background population; OGDM, offspring of women with gestational diabetes; O-T1D, offspring of women with type 1 diabetes in pregnancy; FBG, fasting blood glucose; WHO, World Health Organization.

Figure 1. Epigenetic modifications induced by nutrition, hyperglycemia, smoking, radiation, psychological stress, alcohol consumption, etc. can lead to range of long-term metabolic disorders in offspring.

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