Maternal Obesity and Cardiac Development in the Offspring: Study in Human Neonates and Minipigs.

OBJECTIVES: The aim of this study was to investigate the consequences of maternal overweight on cardiac development in offspring in infants (short term) and minipigs (short and longer term). BACKGROUND: The epidemic of overweight involves pregnant women. The uterine environment affects organ development, modulating disease susceptibility. Offspring of obese mothers have higher rates of cardiovascular events and mortality. METHODS: Echocardiography was performed in infants born to lean and overweight mothers at birth and at 3, 6, and 12 months of age. In minipigs born to mothers fed a high-fat diet or a normal diet, cardiac development (echocardiography, histology), glucose metabolism and perfusion (positron emission tomography), triglyceride and glycogen content, and myocardial enzymes regulating metabolism (mass spectrometry) were determined from birth to adulthood. RESULTS: In neonates, maternal overweight, especially in the last trimester, predicted a thicker left ventricular posterior wall at birth (4.1 ± 0.3 vs. 3.3 ± 0.2 mm; p < 0.05) and larger end-diastolic and stroke volumes at 1 year. Minipigs born to mothers fed a high-fat diet showed greater left ventricular mass (p = 0.0001), chambers (+100%; p < 0.001), stroke volume (+75%; p = 0.001), cardiomyocyte nuclei (+28%; p = 0.02), glucose uptake, and glycogen accumulation at birth (+100%; p < 0.005), with lower levels of oxidative enzymes, compared with those born to mothers fed a normal diet. Subsequently, they developed myocardial insulin resistance and glycogen depletion. Late adulthood showed elevated heart rate (111 ± 5 vs. 84 ± 8 beats/min; p < 0.05) and ejection fraction and deficient fatty acid oxidative enzymes. CONCLUSIONS: Neonatal changes in cardiac morphology were explained by late-trimester maternal body mass index; myocardial glucose overexposure seen in minipigs can justify early human findings. Longer term effects in minipigs consisted of myocardial insulin resistance, enzymatic alterations, and hyperdynamic systolic function.

Elevated glycemia and brain glucose utilization predict BDNF lowering since early life.

Obesity and diabetes associate with neurodegeneration. Brain glucose and BDNF are fundamental in perinatal development. BDNF is related to brain health, food intake and glucose metabolism. We characterized the relationship between glycemia and/or brain glucose utilization (by 18FDG-PET during fasting and glucose loading), obesity and BDNF in 4-weeks old (pre-obese) and 12-weeks old (obese) Zucker fa/fa rats, and their age-matched fa/+ controls. In 75 human infants, we assessed cord blood BDNF and glucose levels, appetite regulating hormones, body weight and maternal factors. Young and adult fa/fa rats showed glucose intolerance and brain hyper-utilization compared to controls. Glycemia and age were positively related to brain glucose utilization, and were negative predictors of BDNF levels. In humans, fetal glycemia was dependent on maternal glycemia at term, and negatively predicted BDNF levels. Leptin levels were associated with higher body weight and lower BDNF levels. Glucose intolerance and elevated brain glucose utilization already occur in young, pre-obese rats, suggesting that they precede obesity onset in Zucker fatty rats. Glycemic elevation and brain glucose overexposure predict circulating BDNF deficiency since perinatal and early life. Future studies should evaluate whether the control of maternal and fetal glycemia during late intrauterine development can prevent these unfavorable interactions.

Maternal environmental exposure, infant GSTP1 polymorphism, and risk of isolated congenital heart disease.

The GSTP1 gene, highly expressed early in fetal life, is the most abundant phase 2 xenobiotic metabolism enzyme in a human placenta. Fetal inherited GSTP1 Ile105Val polymorphism may modify the metabolism and excretion of xenobiotics from fetal tissue and increase the risk of congenital heart disease (CHD). This study aimed to analyze the joint effects of GSTP1 genetic polymorphism (Ile105Val) and maternal environmental exposure on CHD risk. Within a case-control design, a total of 190 children with CHD (104 boys age 4 ± 5.6 years) and 190 healthy children (114 newborn boys) were genotyped for the GSTP1 Ile105Val polymorphism. Mothers completed a structured questionnaire on the demographics as well as the preconceptional and lifestyle exposures. A higher frequency of mothers of children with CHD (38 %) reported a positive history of exposure to toxicants (occupational and environmental) than mothers of healthy children (23 %) (p = 0.0013). Logistic regression analysis showed that maternal occupational and environmental exposures increased the risk of CHD (odds ratio, 2.6; 95 % confidence interval, 1.6-4.2; p < 0.0001). No significant differences in Ile105Val genotype frequencies were observed between the children with CHD and the healthy children (p = 0.9). Furthermore, case-control analysis showed no evidence of significant interaction between the maternal exposures and GSTP1 polymorphism. Maternal exposure to toxicants increased the risk of children with CHD. However, fetal GSTP1 Ile105Val polymorphism did not increase the risk of CHD.