| Arsenic is a toxicant commonly found in water systems around the world. Evidence from epidemiological studies indicates that chronic arsenic exposure can result in cancer, central nervous system and sensory deficits, effects on development, and neuromuscular deficits. However, the molecular mechanism of arsenic’s toxicity remains largely unclear. In this study, both C2C12 mouse myoblast cells and mouse embryonic stem cells (mESCs) were used as models of arsenic mediated developmental toxicity in humans to investigate the effects of sodium arsenite on cellular differentiation.;Results from our first and second studies indicate that exposure of 20nM sodium arsenite to C2C12 mouse myocyte cells results in delayed muscle differentiation due to a reduction myogenin expression. The repressed myogenin expression was due to a combination of abnormal DNA methylation and histone modifications on the myogenin promoter, repressed Igf-1 and Mef2 expression, and enhanced Ezh2 expression. In the third study, we examined arsenic’s effects earlier in development, using mouse P19 embryonic carcinoma cells as our model. These results indicate that arsenic inhibits myogenesis and neurogenesis due to the reduction of essential myogenic and neurogenic transcription factors, such as Pax3, Myf5, MyoD, myogenin, neurogenin 1&2, and NeuroD. The reduction of these transcription factors was, in part, due to repressed Wnt/β-catenin signaling during early embryogenesis following arsenic exposure. In conclusion, these results illustrate the mechanisms of how environmental realistic arsenic exposure impacts development. More importantly, this study gives us reasonable motivation to ask whether the drinking water standard for arsenic is protective of fetal health. |
