Nickel exposure disrupts epigenetic repression of developmental genes in mouse embryonic stem cells

Nickel (Ni) is a naturally occurring heavy metal widely found in the environment, but anthropogenic activities such as industrial processes and the widespread use of Ni-containing products have elevated its environmental levels. Ni exposure poses significant health risks, and both vertebrate models and epidemiological studies link it to developmental toxicity. However, the mechanisms underlying Ni-induced developmental toxicity remain poorly understood. In this study, we investigated how Ni exposure affects pluripotency in mouse embryonic stem cells (mESCs). Ni exposure led to aberrant activation of genes associated with mesodermal and endodermal lineages, while ectodermal genes remained largely unaffected. Despite this induction of lineage-associated genes, key pluripotency genes were not downregulated, suggesting a metastable or incomplete differentiation state. Examination of the underlying mechanisms revealed that Ni exposure induced a loss of the repressive histone modification H3K27me3 at bivalent mesodermal gene promoters, without altering its global levels. Pharmacological inhibition of H3K27me3 demethylases attenuated Ni-induced gene activation, confirming that H3K27me3 loss contributes to this process. ESCs are known to naturally exist as heterogeneous populations that fluctuate between naïve and lineage-primed pluripotent states. Maintaining this balance is essential for proper differentiation. Our findings suggest that Ni exposure disrupts this equilibrium by prematurely inducing mesodermal and endodermal programs. Such dysregulation of early pluripotent states may bias cell-fate decisions and contribute to Ni-induced developmental toxicity, providing a mechanistic link between Ni exposure and developmental toxicity.