Windows of Susceptibility
Partnerships for Environmental Public Health (PEPH)
March 8, 2017
Before Conception: Impact of Exposure on the Methylome(2MB) - Susan Murphy, Ph.D.
The environment impacts health and behavior, but we are only beginning to understand molecular mechanisms underlying these effects. We are studying how environmental exposures can alter DNA methylation preconceptionally, in male gametes. As a first step toward understanding the potential implications of preconceptional exposure, we sought to determine whether exposures can alter the sperm methylome and, if so, to identify the target genes and magnitude of the effect. Sperm DNA from Sprague Dawley rats and zebrafish exposed for two weeks to tobacco smoke extract or vehicle via osmotic mini pumps or in tank water were used, along with mature human sperm DNA from volunteers with divergent body mass index (BMI). DNA methylation was quantified using reduced representation bisulfite sequencing (rats and zebrafish) or the HumanMethylation450 beadchip (human). The results show that there are very pronounced differences in methylation in sperm from tobacco smoke extract-exposed zebrafish and rats. Higher BMI in human males was associated with relatively smaller magnitude methylation changes in sperm relative to men with normal BMI. Genes showing some of the most dramatic changes in methylation in exposed versus unexposed zebrafish include irxb3, foxj3, and znf281a; in rat sperm, Macrod1, Igf2bp3, and Zbtb21; and in human sperm, PHLDB1, MAPK8IP3, and imprinted DLK1. Our results support the ability of the preconceptional environment to alter DNA methylation in male gametes. Intergenerational transmission of such changes may help explain non-genetic influences on offspring phenotype.
Normal Breast Tissue Biomarkers of Environmental Exposure(2MB) - Melissa Troester, Ph.D.
Normal breast tissue changes with age. A process called involution causes tissue to shrink as women get older, and some studies have shown that this process is important for breast cancer risk. However, involution occurs more slowly in some people based on hormone levels and other breast cancer risk factor exposures. In this talk, we discuss methods for measuring changes in breast tissue. The need for and advantages of biomarkers of breast cancer susceptibility is discussed. Getting "under the skin" to see the impact of exposure on breast cancer risk is an important direction for environmental breast cancer research.
ExpertsSusan Murphy, Ph.D., is an Associate Professor in the Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, at Duke University Medical Center, where her research focuses on the developmental origins of disease as well as on the epigenetics and novel diagnostic and therapeutic approaches in gynecologic malignancies. She leads the Duke Epigenetics Research Laboratory and is Director of the NICHES Children’s Environmental Health and Disease Prevention Research Center. She also leads the molecular biology studies for the Duke-based Newborn Epigenetics STudy, or NEST. NEST is a longitudinal birth cohort study from which new insights have come regarding the in utero environment’s effects on the epigenome. She is also studying the impact of preconceptional exposures on the methylation profile in sperm and the potential transmission of induced changes to the offspring. Her long-term research goals are to identify and utilize epigenetic changes that occur as a result of early-life exposures to improve diagnostics and to develop new intervention and prevention strategies based on these findings.
Melissa Troester, Ph.D., is an Associate Professor of Epidemiology and a Research Associate Professor of Pathology and Laboratory Medicine at the University of North Carolina at Chapel Hill. She studies how normal breast tissue is altered by breast cancer risk factors, such as age and reproductive history, and by interaction with breast cancers. Her research shows that from early in carcinogenesis, the normal tissue adjacent to the tumor shows gene expression changes consistent with activation of wound responses. These changes may have important translational implications, if they prove to be targetable in chemoprevention or chemotherapy or if they are shown to predict recurrence. By combining observational studies using normal breast tissue with experimental studies using cell line models of breast cancer, her lab aims to contribute to a better understanding of normal breast tissue biology and the alterations that are induced during carcinogenesis.
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