Exposures and the Impacts on the Epigenome that Persist from Youth to Adulthood and Intergenerationally

Abstract

Environmental exposures have an impact on the epigenome that persists throughout a lifetime and can be transmitted intergenerationally. While a plethora of exposures exist, the mechanisms of epigenetic destruction are unique with each exposure. My research explores two exposures, arsenic and the chemotherapeutic drug 5-aza-2'-deoxycytidine (Decitabine), both of which disrupt different elements of the DNA methylation pathway resulting in persistent epigenetic changes. I first share my findings on the impacts of maternal arsenic exposure, which disrupts the 1-carbon metabolism pathway. I provide evidence that in utero arsenic exposure in mice disrupts epigenetic reprogramming in the developing embryo and primordial germ cells, causing dysregulated methylation and the onset of diseases into adulthood. This work is the first of its kind to show the intergenerational effects of in utero arsenic exposure on adulthood disease phenotypes and the inherited DNA methylation damage in offspring. In my second study I examine the epigenetic damage caused by decitabine exposure, which disrupts the maintenance of DNA methylation in replicating cells. I identify site specific and global methylation damage within the reproductive tracts of mice as a response to a curated chemotherapeutic exposure paradigm. This data highlights the persistent changes of the epigenome in healthy non-target tissues. My findings promote the cautionary application of decitabine as a hypomethylating agent, as it paradoxically alters DNA methylation where the long-term effects on non-target tissues remain unknown. Together my research contributes to the long-term goal of understanding how environmental exposures disrupt the methylation pathway and the lasting consequences of disrupted DNA methylation.