Maternal One Carbon Metabolism and Low Birth Weight Infant


Principal Investigator: Satish C Kalhan
Abstract: DESCRIPTION (provided by applicant): Low birth weight (LBW) in infants, due to intrauterine growth retardation (IUGR), defined as weight <2500gms at term gestation, remains a critical problem in the developing countries and is a major contributor to the morbidity and mortality. It is estimated that almost 30% of all live births in developing countries are LBW. A strong association has been shown in adulthood between LBW and non-communicable diseases, such as type 2 diabetes, hypertension and coronary heart disease. Indirect evidence from intervention studies of micronutrient or protein/energy supplement suggests that no single nutrient is itself responsible for the IUGR. Studies with humans and experimental animals have shown that perturbation in the methionine and one carbon metabolism in the mother and possibly in the fetus, impacts fetal growth and "programming" of the metabolism of the infant and ultimately causes the observed phenotype. We have reported specific gestational-related changes in methionine metabolism in healthy women and in the human newborn infant. Isocaloric protein restriction in rodents during pregnancy, results in IUGR, metabolic re-programming, and long term morbidity in the off spring. In humans, a significant correlation between maternal B12 and folate status and insulin resistance in their children at age 6 years has been observed. We hypothesize that marginal protein intake and altered micronutrient status, insufficient to cause "classical" deficiency syndrome, will impact one carbon metabolism and methyl transfers in the mother and the fetus and thereby alter fetal growth. The specific aims are to longitudinally document maternal methionine, homocysteine metabolism, relate it to nutrient (protein) intake, folate, B12, pyridoxine status, and measures of insulin resistance. Methionine metabolism, transmethylation and transsulfuration, will be measured using a novel and innovative stable isotope labeled methionine loading test early and late in gestation. These data will be related to the macro and micronutrient status of the mother estimated by dietary recall, plasma B12, methylmalonic acid, pyridoxine and red blood cell folate levels. The physiological measurements of methionine metabolism will allow us to identify the effect of subclinical changes in nutrient status on the one carbon metabolism of the mother. These physiological data will be related to fetal growth as assessed by birth weight and body composition, and metabolic and hormonal assessments in the cord blood. These studies will identify the mechanism of IUGR and lead to the development of strategic recommendations at the identified critical periods in pregnancy using various methyl donors with the goal of preventing both immediate neonatal and long term "programming" consequences in the baby. There are major public health and economic implications for this study, when one considers the enormous magnitude of the LBW, the associated clinical problems and the economic burden to the society.
Funding Period: 2013-08-01 - 2015-07-31
more information: NIH RePORT

Detail Information

Research Grants30

  1. Lifecourse Exposures &Diet: Epigenetics, Maturation &Metabolic Syndrome
    KAREN EILEEN PETERSON; Fiscal Year: 2013
    ..Career development and training activities will draw upon extensive institutional resources and will be fully integrated with the Center's Research Projects and Cores. ..
  2. Stanford University Center for Reproductive and Stem Cell biology
    Margaret T Fuller; Fiscal Year: 2013
    ..abstract_text> ..
  3. Southern California Children's Enviromental Health Center (SC-CEHC)
    Rob S McConnell; Fiscal Year: 2013
  4. The UCSF Pregnancy Exposures to Environmental Chemicals (PEEC) Children's Center
    Tracey J Woodruff; Fiscal Year: 2013
    ..Finally, the Administrative Core will work closely with a program evaluator, to monitor the progress of the PEEC Children's Center and ensure the achievement of its goals. ..
  5. The Conte Center for Schizophrenia Research
    Daniel C Javitt; Fiscal Year: 2013
    ..The overall goal of the Center is to develop new assessment and intervention approaches for schizophrenia based upon glutamatergic models. ..
  6. COBRE Center for Central Nervous System Function
    Jerome N Sanes; Fiscal Year: 2013
    ..The COBRE Center will leverage the administrative resources available through the Brown Institute for Brain Science to ensure efficient operation and coordinate with other brain science research activities at Brown. ..
  7. Maternal nutrient restriction: Effects on offspring immune function
    Mark J Nijland; Fiscal Year: 2013
  8. Stable isotope evaluation of the methionine cycle in undernourished pregnancy
    Peter W Nathanielsz; Fiscal Year: 2013
    ..Information will translate to human pregnancy aiding diagnostic, preventative and therapeutic strategies. B12 has been ignored in comparison to folic acid. ..
  9. Semi-volatile PCBs: Sources, Exposures, Toxicities
    Larry W Robertson; Fiscal Year: 2013
    ..These data and dietary studies in the last Aim will provide a scientific basis for risk assessment and advice for stakeholders with the ultimate goal to protect highly-exposed individuals and populations. ..
  10. Hopkins Center for Eliminate Cardiovascular Health Disparities
    Lisa A Cooper; Fiscal Year: 2013
    ..abstract_text> ..
  11. Exploring Interactions between Folate and Environmental Risk Factors for Autism
    REBECCA JEAN SCHMIDT; Fiscal Year: 2013
    ..As such, it is likely to have a measurable impact on the scientific community, potentially on nutritional and environmental policies, and could potentially identify strategies for ASD prevention. ..
  12. Revolutionizing Biomedical and Clinical Research through Innovative Technology
    Michael N Mindrinos; Fiscal Year: 2013
  13. Alberta Pregnancy Outcomes and Nutrition (APrON) - Toxicant-Diet Interactions on
    JONATHAN WAYNE MARTIN; Fiscal Year: 2013
    ..It is anticipated that the results of this unique study will inform preventio strategies to help mitigate the harmful effects of classic and emerging environmental developmental neurotoxicants. ..
  14. Human Capital Interventions Across Childhood and Adolescence
    GREG JOHN DUNCAN; Fiscal Year: 2013
    ..Taken together, the group's involvement with multiple projects as well as seminars, jointly-authored papers and other core activities will constitute a research network - the Irvine Network on Interventions in Development. ..
  15. Prenatal stress biology, infant body composition and obesity risk
    Sonja Entringer; Fiscal Year: 2013
    ..abstract_text> ..
  16. Vitamin B6 Effects on One-Carbon Metabolism
    Jesse F Gregory; Fiscal Year: 2013
    ..These studies will expand our understanding of the functional impact of vitamin B6 inadequacy in OC users and will provide a metabolically validated supplementation strategy to alleviate low B6 status and promote health in OC users. ..
  17. Genetic Risk for Orofacial Clefts in the Folate/Homocysteine Pathway
    NICHOLAS MARINI; Fiscal Year: 2013
    ..This research plan capitalizes on an ongoing and successful collaboration that unites a unique combination of expertise for its execution. ..