Developmental Susceptibility Research Core
Research Accomplishments - 2006
The Developmental Susceptibility Research Core (DSRC) has continued utilizing diverse approaches to promote interdisciplinary research on how environmental exposures at particular stages of the life cycle affect susceptibility to disease and to deficits in development. The Core sponsored the CEHS Enrichment Seminar, “Long-term child health effects of prolonged and exclusive breastfeeding: Lessons from Belarus” by Dr. Michael Kramer, Departments of Epidemiology, Biostatistics and Pediatrics, McGill University in April 2006. To facilitate interdisciplinary communication and collaboration the Developmental Susceptibility Research Core has continued to utilize “focus groups”. In the past year we have had meetings related to reproductive and perinatal, neurodevelopment, and pediatric health. These meetings included both epidemiologists and laboratory scientists and helped to plan seminars, special meetings, and encourage collaborative efforts. In addition, Dr. Olshan has met with other Core directors, for example, meeting with Dr. Kaufmann, to develop new synergies in approaches to studying genetic susceptibility and developmental outcomes. Collaborative research highlights are presented by focus group.
Reproductive and Perinatal
Members of this focus group include, Olshan, Darney, Herring, Siega-Riz, and Mendola. Multiple members (Herring, Olshan, Mendola, Darney) are working on collaborative multidisciplinary studies of drinking water disinfection by-products as potential influences on both miscarriage and male reproductive health. Drs. Savitz and Hartmann left the University of North Carolina for new positions, however, both continue to collaborate on multiple studies. The potential adverse effects of disinfection by-products (DBPs) on female and male reproduction are of particular public health concern. A large multisite prospective cohort study of DBPs and miscarriage (Right from the Start, RFTS) was conducted by Core members (Savitz, Herring, Hartmann). The five-year study, funded by the American Water Works Research Foundation, enrolled nearly 3,132 women across three study sites chosen to reflect differing levels or forms of DBP exposures (Savitz et al., 2005). The primary study results did not indicate a pattern of association between elevated DBP levels and an increased risk of miscarriage (Savitz, 2005). Dr. Mendola, an affiliate member, and Dr. Olshan, have recently begun working with an epidemiology doctoral student on the impact of disinfection byproducts in drinking water on preterm delivery and fetal growth using RFTS data. Drs. Herring and Olshan are also collaborating with a postdoctoral researcher, Dr. Tom Luben, who is interested in drinking water exposure assessment and reproductive outcomes. Dr. Luben has just submitted an application for a CEHS grant to link detailed drinking water exposure data from the RFTS study to pregnancy outcome data from vital records. These collaborations have led to an NICHD R03 grant awarded to Dr. Herring which will address complex issues of exposure assessment and multifactorial outcomes through newly developed statistical methods. Her collaboration on the Right from the Start study has also led to another funded proposal, "Bayesian Modeling of Complex Environmental Exposures", funded by EPA with Dr. Herring as PI. Multiple publications have been submitted based on this work. These collaborations and a CEHS pilot grant has led to Dr. Hartmann being funded with two R01s to establish a prospective cohort study of 4,500 pregnant women to identify women with fibroids, examine risk factors for fibroid growth, and evaluate their risk of spontaneous abortion or preterm birth. Dr. Olshan is now the local PI for these projects. These ongoing cohort studies will serve as an important resource for new projects involving environmental exposures and an array of reproductive outcomes.
A cooperative agreement with the US EPA has continued (since October, 2001) to conduct a study to evaluate the relationship between DBP exposure and male reproductive health factors (Healthy Men Study, HMS) such as sperm count, sperm abnormalities, and sperm DNA damage as measured by the sperm chromatin structure assay (Olshan and S. Darney co-principal investigators, with Savitz, Herring). Animal studies have suggested that certain DBPs are strong male reproductive hazards and this study will be the first to evaluate the potential association in humans. Data collection for the male study has been completed with semen samples obtained from 228 men. A paper describing the study design and conduct is in press (Olshan et al., 2007). The main analyses have been completed by Dr. Luben and a manuscript is undergoing review at the EPA. Additional funding from the EPA has been obtained to recontact the men and obtain a mouthrinse sample for DNA extraction and genotyping of enzyme polymorphisms involved in DBP metabolism. The preliminary analyses have been completed.
The investigation of genetic susceptibility factors and the interaction of genetic factors and environmental exposures in determining the risk of adverse pregnancy outcomes is the focus of several collaborative Core efforts involving multiple core members (Siega-Riz, Herring, Olshan). Three projects using specimens and interview data from the Pregnancy, Infection, and Nutrition Study (PIN, D. Savitz, PI) of over 4,000 pregnancies have been completed. Analyses have been completed for 5 folate metabolizing enzyme polymorphisms and the risk of preterm birth and small-for-gestational age birth and an increased risk for a SHMT SNP was found; a paper on this project has just appeared (Engel, 2006). Dr. Herring has also has worked with Dr. David B. Dunson (BEMFC member) on a new statistical methodology applied to an analysis of the relationship between presumed pro- and anti-inflammatory SNPs and pregnancy outcome using data from the CEHS pilot grant awarded to Dr. Olshan. A new analysis of CYP1A1 polymorphisms and risk of preterm birth is in progress.
Neurodevelopment
The neurodevelopmental focus group includes Drs. Lauder (co-leader), Daniels (co-leader), Deshmukh, Longnecker, Piven, Siega-Riz, and Zeisel. This Core research has involved environmental exposures and effects on the neurodevelopment of offspring. Dr. Daniels has been involved in a number of childhood neurodevelopment projects. Dr. Daniels and Siega-Riz were funded by a Center Pilot Project to examine the association between maternal prenatal dietary exposures and the child’s neurodevelopment. The pilot study collected breast milk samples and proved the feasibility of following the children of an ongoing pregnancy cohort (the Pregnancy Infection and Nutrition (PIN) Study for future research, which supported a successful application for funding from the EPA. The EPA grant funds the evaluation of polybrominated diphenyl ethers (PBDEs) in maternal milk and environmental samples in relation to the neurodevelopment of children at age 3 years. These brominated flame retardants are rising in the environment and little is known of their consequences for human health. In addition, CDC recently renewed the Center for Autism and Developmental Disabilities Research and Epidemiology (PI is J. Daniels). The Center is one of six who will conduct a multi-site investigation of genetic and environmental correlates of autism. Dr. Deshmukh’s laboratory is interested in understanding the fundamental mechanism by which mammalian cells activate the programmed cell death pathway and undergo apoptosis. His group has identified endogenous XIAP as a critical inhibitor of cytochrome c-mediated caspase activation in postmitotic but not in mitotic cells. Knowledge of how apoptosis is regulated in neurons and cardiomyocytes has important therapeutic implications for the development of novel strategies that may prevent environment-induced toxicity.
Dr. Lauder’s lab, as part of a CEHS pilot project, has conducted a study of the behavioral phenotype in young adult (2.5 months postnatal) 129/SVEV mice, following prenatal exposure to chlorpyrifos (cpf) during two critical periods (GD 7-9 or GD 17-19), and performed behavioral testing. They found evidence of increased anxiety and hyperactivity in animals treated during the early period. Dr. Zeisel’s research team, in studies funded by the NIEHS (ES012997), showed that diethanolamine (DEA), a common component of shampoo and sunscreen, makes mice choline deficient (1,2) and that DEA applied to the skin of pregnant mice results in diminished proliferation and increased apoptosis in neural progenitor cells in fetal mouse brain (3). Higher doses of diethanolamine cause fetal resorption at about the time the neural tube is closing (3). This observation arises from a larger body of research investigating the effects of choline and folic acid in the diet during pregnancy and the neurodevelopmental status of offspring. Dr. Zeisel’s group recently reported that the signal and receptor in fetal brain responsible for guiding neuron migration in the developing brain (netrin and DCC) are directly influenced by maternal choline intake. Dr Zeisel is also conducting a study of choline supplementation during pregnancy in humans and correlation with tests of memory, language ability, and general intelligence among their infants. Dr. Zeisel’s group is also identifying common genetic variations that increase choline requirements in humans.
Pediatric Health
Dr. Mendola, an DSRC affiliate member at the Environmental Protection Agency, has recently completed two major projects working with DSRC members and UNC epidemiology graduate students. Dr. Sharon Sagiv completed her dissertation on ambient air pollution and preterm delivery. The results from this time-series analysis, which provides evidence of an increase in preterm birth risk with exposure to PM10 and SO2, are consistent with prior investigations of spatial contrasts (Sagiv) . Drs. Loomis, Herring, and Poole were coauthors and collaborators in this research. Dr. Suzanne Gilboa completed her dissertation on air quality and birth defects risk under the guidance of Drs. Mendola and Olshan. Evidence that air pollution exposure influences the risk of oral clefts was limited. Suggestive results support a previously reported finding of an association between ozone exposure and pulmonary artery and valve defects (Gilboa). Two other papers have resulted from this project. Other DSRC members collaborating on this project are Drs. Savitz, Loomis, and Herring.
In conjunction with the Genetic Susceptibility Research Core, an expanded project has been initiated to examine possible relationships between gene polymorphisms and the risk of birth defects. Using data and samples from the National Birth Defects Prevention Study (NBDPS) Dr. Olshan will evaluate DNA repair SNPs in relation to the risk of congenital cardiac anomalies; this will be the first study to ever investigate this pathway and cardiac defects. Dr. Kaufmann of the GSRC is consulting on the candidate gene selection using a systems biology approach. There has been a national trend of increasing incidence of gastroscisis, especially among young mothers. Dr Siega-Riz and Olshan have recently completed an analysis of dietary fat and gastroschisis using NBDPS data (Siega-Riz). They found higher maternal intake of certain fats during pregnancy increased the risk of gastroschisis. They have also recently completed an analysis of low BMI and young maternal age and have found that both factors interact to increase risk.
