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

Nickel (Ni) is a naturally occurring heavy metal whose environmental levels have been steadily rising due to industrial activities and the widespread use of Ni-containing products. Ni exposure poses significant health risks, and studies in vertebrate models and human populations link Ni to developmental toxicity. However, the mechanisms by which Ni perturbs early developmental programs remain poorly understood. Here, we examined the effects of Ni exposure on pluripotency in mouse embryonic stem cells (mESCs) maintained under pluripotency-supporting conditions. Ni exposure led to aberrant upregulation of genes associated with mesodermal and endodermal lineages, while ectodermal gene expression remained largely unaffected. However, the expression of core pluripotency factors was preserved, indicating that Ni does not induce differentiation but instead disrupts normal transcriptional control within the pluripotent state. Mechanistically, Ni exposure caused a selective loss of the repressive histone modification H3K27me3 at bivalent promoters of mesoderm-associated genes without altering global H3K27me3 levels. Pharmacological inhibition of H3K27me3 demethylases attenuated Ni-induced gene activation, suggesting that localized H3K27me3 removal contributes to this aberrant activation of developmental genes. ESCs normally exist as heterogeneous populations that dynamically fluctuate between naïve and lineage-primed pluripotent states. Our findings indicate that Ni exposure perturbs this equilibrium through aberrant activation of lineage-associated genes while core pluripotency remains preserved. Such dysregulation of early transcriptional programs may predispose cells to abnormal fate decisions. These findings suggest a mechanistic link between Ni exposure and developmental abnormalities.