Evidence is building that even brief exposure of mammalian eggs, before or around the time of fertilization, to poor maternal nutrition and other adverse conditions, including some assisted reproduction procedures, can lead to long-term effects in offspring derived from these eggs. These long-term effects include preterm birth, low birth weight, hypertension, abnormal organ growth, and abnormal behavior of adult animals. In view of the increasing incidence of early obesity and early onset of diabetes in the United States as well as the increasing use of assisted reproductive technologies, it is essential that new research be done on human egg quality. For this reason, the NICHD Reproductive Sciences Branch, established the National Cooperative Program on Female Health and Egg Quality in which the eggs and early embryos of several animal models, as well as human eggs, will be studied within the current ethical guidelines of the federal government.

Leading scientists concentrate their basic and pre-clinical research experiments on the time preceding, around, and shortly after fertilization (the pre- and peri-conceptual period), during which time damage to the immature or mature egg or very early embryo can occur and then study a wide range of long-term outcomes in embryos, fetuses, and offspring. Long-term effects of poor nutrition and reproductive technologies on genomic imprinting in eggs and early embryos will be vigorously pursued. With the improved understanding of the causes and mechanisms that lead to adverse effects, it is anticipated that the group will be able to propose preventive measures, for use even prior to conception, that are practical and efficacious to avoid or minimize these effects.

Dr. Richard Tasca, Ph.D., Reproductive Sciences Branch, Center for Population Research, NICHD, serves as the Research Coordinator for the program. Dr. John J. Eppig, Jackson Laboratory, serves as Chair of the group meetings.

Awardees in the program are:

• Mayo Clinic, Rochester, Minnesota, Departments of Obstetrics and Gynecology and Internal Medicine (Daniel Dumesic, M.D., Principal Investigator) - This project will test the hypothesis that hyperinsulinemia is a central feature in the impaired oocyte competence in polycystic ovarian syndrome (PCOS) patients and, perhaps, also in obesity and type 1 diabetes. Thus, weight loss through dietary restriction will be used to try to improve oocyte competence in a monkey model of PCOS. Molecular markers of oocyte competence in monkeys and in human eggs will also be established.
• University of Southampton, United Kingdom, School of Biological Sciences (Tom Fleming, Ph.D., Principal Investigator) - This project will study the reaction of mouse eggs and early embryos to maternal low-protein diets that result in long-term abnormalities in fetal and postnatal growth and development. This application, from the founding home of the Fetal Origins of Adult Disease hypothesis, will conduct long-term follow-ups, including fetal gene microarray analysis, fetal/neonatal endocrine status, postnatal studies of vascular function, and behavioral analysis of offspring.
• Washington University, St. Louis, Missouri, Department of Obstetrics and Gynecology (Kelle Moley, M.D., Principal Investigator) - Spontaneous miscarriages and congenital malformations found in diabetic patients may be linked to hyperglycemic effects on the quality of eggs or early embryos. Thus, these mouse and monkey studies will explore the possibility that abnormal carbohydrate metabolism is a risk factor for poor oocyte quality in diabetics, PCOS patients, and obese patients.
• University of Pennsylvania, Philadelphia, Pennsylvania, Department of Biology (Richard Schultz, Ph.D., Principal Investigator) - This project will determine the molecular basis of egg quality and the effects of low-quality mouse eggs on behavior in offspring derived from these eggs. Studies will also be done on the effect of assisted reproductive technologies on gene expression and behavior.
• University of Nottingham, United Kingdom, Division of Agricultural Sciences (Kevin Sinclair, Ph.D., Principal Investigator) - Maternal nutrition and assisted reproduction procedures are thought to influence fetal development and adult health through nongenetic changes in DNA methylation of specific genes in oocytes and preimplantation embryos. Female sheep and rats will experience specific dietary regimens and/or be subjected to assisted reproduction procedures and then fetuses, newborns, and postnatal animals will be evaluated for growth and development, as well as for insulin resistance, blood pressure, and immune function.
• University of Adelaide, Australia, Department of Obstetrics and Gynecology (Jeremy Thompson, Ph.D., Principal Investigator) - This project will investigate the impact of cellular stress, including oxidative stress, on gene expression in eggs and early embryos of sheep and mice. Followed-up will reveal subtle fetal and neonatal abnormalities. These abnormalities, may, in turn, lead to the adult onset of diabetes and cardiovascular problems.
• Monash University, Clayton, Australia, Monash Institute of Reproduction and Development (Alan Trounson, Ph.D., Principal Investigator) - Molecular markers of high-quality human, monkey, and mouse eggs and embryos will be established that can then be used to evaluate the egg quality and competence of normal and abnormal human eggs. Using monkey models, eggs from females that experience diabetes, obesity, and aging will be compared with eggs determined to be of high quality.