This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Arsenic is a known human carcinogen, but it has been difficult to produce tumors in adult animals by arsenic alone in bioassays. We have developed an animal model of transplacental arsenic carcinogenesis. In this model, pregnant mice was given inorganic arsenic through the drinking water from gestation day 8 to 18, and the offspring developed liver tumors and tumors in other sites in adulthood. Indeed, transplacental or earlylife exposure to inorganic arsenic induces a spectrum of tumors and other diseases in humans. The basis of the """"""""developmental origins"""""""" paradigm of arsenic carcinogenesis is not fully defined, and accumulating evidence suggests an epigenetic basis. The objective of this pilot grant proposal is to utilize genome-wide approaches to elucidate the regulatory mechanisms of arsenic-induced early-life reprogramming. Our central hypothesis is that developmental plasticity responding to in utero arsenic exposure is a sequential event regulated by epigenetic mechanisms, which would be critical for genetic reprogramming for tumor development much later in life.
Aim 1 will determine the in utero arsenic-induced changes in DNA methylation. The monoclonal antibody against 5-methylated cytosine will be used to perform chromatinimmunoprecipitation (ChiP) coupled with the Next-Generation Sequencing to determine the genome-wide methylation alterations as a result of in utero arsenic exposure.
Aim 2 will determine the in utero arsenicinduced expression changes in microRNAs and their binding to 3'-UTR genes of interest. The proposed study is novel, because it will use a genome-wide approach to elucidate how inorganic arsenic exposure in utero regulates epigenetic machinery during development. The proposed study is significant, because very little is known about epigenetic regulation of arsenic carcinogenesis during early-life exposure in vivo. The successful completion of arsenic-induced epigenetic changes in the fetus will generate critical knowledge leading to a NIH grant application to go into depth to elucidate the fetal basis of transplacental arsenic carcinogenesis.
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