AIMS

Our overarching aim is to determine the role of metabolomic and epigenomic mechanisms in the relationships between maternal risk factors for developmental overnutrition and offspring adiposity and related metabolic outcomes. We will also determine the effects of these intrauterine mechanisms on greater adiposity and associated metabolic risk into the next generation. Three related aims with specific objectives are detailed below and illustrated in figure 1 of the research strategy.

Aim 1: To determine the role of metabolomic mechanisms in developmental overnutrition, by identifying:

1.1: The associations of established maternal developmental overnutrition risk factors (adiposity in early pregnancy, gestational adipose gain, gestational diabetes (GDM) and continuous measures of fasting and postload glucose and fasting insulin) with maternal pregnancy metabolome, quantified in serum by nuclear magnetic resonance (NMR) spectroscopy.

1.2: The associations of established maternal developmental overnutrition risk factors and pregnancy metabolome with fetal metabolome, quantified in cord serum by NMR spectroscopy.

1.3: The associations of maternal pregnancy and fetal metabolome with offspring adiposity (BMI, waist, skinfolds, fat mass) from birth through to early adulthood, and with metabolic outcomes (fasting glucose, insulin and lipids from mid-childhood to early adulthood; metabolome in infancy and in adolescence).

1.4: The extent to which maternal pregnancy and/or fetal metabolome mediate the associations of established developmental overnutrition risk factors with offspring adiposity and metabolic outcomes.

Aim 2: To determine the role of epigenetic mechanisms in developmental overnutrition, by identifying:

2.1: The associations of established developmental overnutrition risk factors with fetal genome-wide DNA methylation, analysed on cord blood white cell DNA, with the Illumina 450K HumanMethylation array.

2.2: The associations of pregnancy and fetal metabolome with cord blood white cell DNA methylation.

2.3: The associations of cord blood white cell DNA methylation with offspring adiposity and metabolic outcomes.

2.4: The extent to which cord white blood cell DNA methylation differences mediate the associations of established maternal developmental overnutrition risk factors with postnatal offspring adiposity and metabolic outcomes.

Aim 3: To explore the role of developmental overnutrition, including metabolomic and epigenomic mechanisms, on risk of greater adiposity and metabolic outcomes in two generations.

[Note. we have used the following notation in objectives 3.1-3.3: G0=index pregnant women on whom developmental overnutrition risk factors were measured; G1= offspring of G0; G2 = offspring of G1 and their partners]

3.1: We will determine whether the G1 females who have been exposed to higher levels of intrauterine developmental overnutrition, determined by a weighted score of G0 developmental overnutrition risk factors, enter their pregnancies with greater adiposity and more adverse metabolic outcomes than G1 females who are less exposed to developmental overnutrition by their G0 mothers.

3.2: We will determine the associations of G1 female exposure to developmental overnutrition with G2 cord serum metabolome, cord blood white cell DNA methylation, birth weight and infant adiposity.

3.3: We will compare the associations examined in 3.2 to equivalent associations with exposure to different levels of intrauterine developmental overnutrition in G1 males.