Environmental toxins and stem cell epigenetic remodeling

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DESCRIPTION (provided by applicant): Epidemiological studies have long suggested a critical, but poorly understood, link between toxic environmental exposures early in life and the development of human disease(s) later in life. Environmental toxins produce oxidative stress in cells, and a link between oxidative stress and epigenetic changes in a cell has implications for a variety of human diseases including cancer, infertility, and multiple neurodegenerative disorders. Though limited data exists, it has also been suggested that environmental toxins may disrupt both DNA methylation patterns and chromatin structure, which can confer not only heritable changes in gene expression, but also affect overall genomic stability. However, a direct link between environmental toxins, oxidative damage and epigenetic changes has not yet been established and is the primary focus of this proposal. It is proposed that exposure to common environmental contaminants during development or during key windows of susceptibility (WOS) throughout a lifetime may induce abnormal epigenetic, pre-malignant changes in developing/differentiating cells. It is expected that this window of susceptibility coincides with the normal epigenetic remodeling required for lineage commitment during development or periods of cellular repair/regeneration. To test this idea the following three specific aims are proposed: Specific Aim 1: Determine the in vitro WOS during which the environmental toxin paraquat induces DNA methylation changes in differentiating stem cells. It is hypothesized that stem cells are vulnerable to errors in epigenetic remodeling when they receive a signal to actively remodel their chromatin, i.e. during development and tissue regeneration; Specific Aim 2: Investigate whether paraquat exposure disrupts the composition and/or functional recruitment of stem cell transcriptional repressive complexes to tumor suppressor gene promoters. It is postulated that the introduction of DNA damaging agents and prolonged exposure of cells to environmental toxins during a window of active epigenetic remodeling may cause disruption and/or abnormal recruitment of polycomb repressive complexes (PRC), the stress response protein SIRT1, and/or DNA methyltransferases to gene promoter regions with abnormal DNA methylation changes; and Specific Aim 3: Determine whether low-dose, chronic, in utero paraquat exposure induces DNA methylation changes in the developing mouse brain, disrupts neural cell plasticity, and/or enhances the malignant potential of neural stem cells in the F1 generation. It is also hypothesized that the dynamic nature of epigenetic remodeling during embryonic development may leave cells particularly vulnerable to the effects of environmental toxins. Prolonged exposure may result in the accumulation of abnormal, promoter associated DNA methylation, inhibit the ability of neuronal stem cells to properly differentiate, and may induce pre-malignant changes including abnormally high mitotic rates, nuclear atypia, or focal necrosis in these cells.