There is strong evidence that the environment experienced in utero can contribute to the development of cardiovascular, metabolic, and mental health and disease in childhood and adulthood. Understanding the mechanisms that account for these relationships can impact the development of novel treatment and prevention efforts to reduce long-term health risks. Emerging published evidence, from our own laboratory and others, is suggesting that the placenta, as a master regulator of the intrauterine environment and of fetal development plays a critical role in the developmental origins of health and disease, and thus is an ideal tissue in which to study mechanisms underlying the effect of the environment on newborn and child health. Work from our group has linked altered expression of specific microRNA in the placenta, which can impact tens to hundreds of genes, to newborn outcomes including growth and neurobehavioral development. We propose the hypothesis that variation in expression of miRNA in the placenta acts as a mediator of the impact of common environmental exposures, specifically trace metals on neurobehavioral and growth outcomes. Further, we hypothesize that variation in miRNA expression in the placenta is linked mechanistically to these outcomes by (1) impacting placental gene and protein expression thereby altering placental function and potentially altering levels of serum neuropeptides and hormones regulated by the placenta, and/or (2) acting to signal to the mother or developing fetus by being packaged as exosomes and released into maternal or fetal circulation where they can impact various tissues of the mother or developing child thereby altering development. We will employ the existing resources of the ongoing New Hampshire Birth Cohort Study and the Rhode Island Child Health Study, which have similar study designs and exposure assessment tools and which represent populations of infants exceeding 2,000 newborns. These cohorts have established biorepositories of placental tissues to allow sensitive and robust assessment of genomic and epigenomic features including microRNA expression as well as infant and maternal toenail samples for sensitive detection of trace metals representing chronic long-term exposures.
We aim to comprehensively profile the expression of microRNAs to examine their association with newborn outcomes including growth and newborn neurobehavior, assessed using the validated, prospectively predictive NICU Network Neurobehavioral Scales. We will also examine the effect of altered miRNA expression on target mRNA and protein in placental tissue and in circulation. These examinations will provide critical insight into the mechanisms of the developmental origins of lifelong health, will highlight novel pathways affected by exposures and driving children's health that can be targeted for prevention and treatment, and will identify novel biomarkers which can be used to identify, children at-risk so that necessary interventions can be employed early enough to prevent future disease.
This research aims to identify the mechanistic role of microRNA, which can effect the function of the placenta, in mediating the impact of environmental exposures on children's growth neurodevelopment. Such findings may have significant clinical and public health impact, providing an opportunity for early interventions for at-risk children, and potentially identifying novel paths for prevention and treatment.
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|Thompson, Jeffrey A; Marsit, Carmen J (2017) A METHYLATION-TO-EXPRESSION FEATURE MODEL FOR GENERATING ACCURATE PROGNOSTIC RISK SCORES AND IDENTIFYING DISEASE TARGETS IN CLEAR CELL KIDNEY CANCER. Pac Symp Biocomput 22:509-520|
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