Placental tissue, which is normally discarded at birth, is a molecular time capsule that captures gene by environmental interactions and dysregulated molecular and cellular pathways that can be revealed at the level of the epigenome. Identifying epigenetic biomarkers at birth that reflect in utero exposures or predict adverse neurodevelopmental outcomes is an important goal that has been limited by prior technologies or lack of relevant tissue availability. Our team of currently collaborating interdisciplinary scientists within the Children?s Center for Environmental Health plans to use existing placental samples from a prospective high-risk cohort study (MARBLES) to identify epigenetic biomarkers at birth for in utero exposure to polychlorinated biphenyls (PCBs) and neurodevelopmental outcomes at age three years. In the MARBLES cohort, we have shown that taking folic acid in the form of prenatal vitamins specifically in the first month of pregnancy was associated with a 50% reduction in the risk for autism. Our human studies and the work of others also show evidence that folic acid supplementation can counter epigenetic and neurodevelopmental effects of environmental contaminants. Furthermore, using unbiased whole genome bisulfite sequencing (WGBS), we have previously demonstrated that placental tissues retain the distinctive DNA methylation patterns of the preimplantation embryo and so can capture the molecular state in very early development, a feature that is conserved across mammalian species, including mouse. The proposed PCB Epigenomic Brain & Behavior Lasting Effects Study (PEBBLES) combines WGBS analysis of human placental samples from the high-risk MARBLES cohort with a more extensive epigenomic analysis of placenta and brain tissues and sorted cell types derived from a mouse model of perinatal exposure to the same mixture of PCB congeners detected in MARBLES mothers. The hypothesis to be tested in the parent PEBBLES grant is that perinatal PCB exposures adversely impact neurodevelopment and leave a lasting molecular signature over genes relevant to neurodevelopment that can be detected in placenta. The hypothesis to be tested in the nutritional supplement to PEBBLES is that dietary folic acid supplementation will be protective against the adverse effects of PCB exposures at the level of the epigenome in an experimental animal model and human placenta. Bioinformatic and statistical analyses will integrate the genomic data sets with behavioral and molecular outcome measures and determine whether similar epigenetic marks are observed in placenta that could be used to predict long-lasting brain and behavioral outcomes in humans. !
Neurodevelopmental disorders, including autism and attention deficit hyperactivity disorder, are estimated to affect 1 in 10 children in the US. This study seeks to investigate the use of human term placenta samples, usually discarded at birth, as a source of predictive biomarkers for combined genetic and environmental risk factors for neurodevelopmental disorders. Whole genome methylation sequencing results from human placental samples from a high-risk cohort with detectable levels of polychlorinated biphenyls (PCB) will be compared to placenta and brain samples from an experimental mouse model. !
