| Metal exposure early during development induces histone modifications resulting in pathologies often seen in adulthood through epigenetic modification of gene expression. The effects of cadmium (Cd) and aluminum maltolate (AM) exposures were monitored by measuring cell viability, total histone protein (THP) production, H3K27 mono-methylation (H3K27me1) levels and cell cycle progression in mouse embryonic stem (mES) cells. The data indicates that metals affect differentiation, DNA repair and epigenetic status in mES cells. Furthermore we tested the premise that Cd exerts differential toxicity in mES cells by targeting THP production early in stem cell development, while affecting H3K27me1 in latter stages of differentiation. The data suggests that unlike AM, Cd exerts cumulative toxicity in mES cells since the IC50 for 24-h exposures is less than that of 1-h exposure. To study the effects of AM on transcription we quantified H3K27me1 during 24-h AM exposure, H3K27me1 was lowered at 200muM but not at 100muM. Moreover, the current study reports that as a measure of chromatin stability, low dose acute Cd exposure lowers THP production where as cell cycle progression is more susceptible to AM exposure than chromatin stability. Both AM and Cd repress transcription, but H3K27me1 was lowered only at higher doses during AM exposures. Importantly, metals such as Cd induce heritable effects on cell proliferation, chromatin stability and transcription through several cell population doublings. Since the data did not indicate a change in expression EZH2 expression with either metal, we present that the net transcriptional repression following AM and Cd exposures results from altered EZH2 activity. Thus, we establish that metal exposure triggers heritable changes in cell proliferation, DNA repair, cell cycle progression, chromatin stability and transcriptional repression in mES cells. |
