Silver Nanoparticles Compromise Female Embryonic Stem Cell Differentiation through Disturbing X Chromosome Inactivation

The widespread use of silver nanoparticles (AgNPs) has raised substantial health risks to human beings. Despite a wealth of progress on toxicity studies, the understanding of the adverse effects on fetuses, embryos, and early stage cells is still rather limited, particularly under low-dose exposure settings. Moreover, nearly all previous studies ascribed AgNP-induced toxic effects to oxidative stress. Differently, we here unearthed a mechanism, namely, interruption of X chromosome inactivation (XCI) in female mouse embryonic stem cells (mESCs). Albeit with no observable cytotoxicity, significant differentiation retardation was found in female mESCs upon low-dose AgNP exposure. Mechanistic investigations uncovered expedited inactivation for the inactive X chromosome (Xi) and attenuated maintenance of the active X chromosome (Xa) state during mESC differentiation upon the challenge of low-dose AgNPs, indicative of disordered XCI. Thereby, a few X-linked genes (which are closely involved in orchestrating ESC differentiation) were found to be repressed, partially attributable to reinforced enrichment of histone modification (e.g., histone 3 lysine 27 trimethylation, H3K27me3) on their promoter regions, as the result of disordered XCI. In stark contrast to female mESCs, no impairment of differentiation was observed in male mESCs under low-dose AgNP exposure. All considered, our data unearthed that AgNPs at low concentrations compromised the differentiation program of female mESCs through disturbing XCI. Thus, this work would provide a model for the type of studies necessary to advance the understandings on AgNP-induced developmental toxicity.