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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE310598 | GEO | 2026/04/08

REPOSITORIES: GEO

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Project description:Our main objectives were: 1) to identify transcriptional signatures specific to the exposure to two metals: Ni and Cd; 2) to investigate the mechanisms of toxicity for these two metals; and 3) to develop a predictive tool to identify the sublethal effects of Ni and Cd contaminants in fish sampled from natural environments. The molecular mechanisms underlying nickel (Ni) and cadmium (Cd) toxicity and their specific effects on fish are poorly understood. Documenting gene transcription profiles offers a powerful approach towards identifying the molecular mechanisms affected by these metals and to discover biomarkers of their toxicity. However, confounding environmental factors can complicate the interpretation of the results and the detection of biomarkers for fish captured in their natural environment. In the present study, a 1000 candidate-gene microarray, developed from a previous RNA-seq study on a subset of individual fish from contrasting level of metal contamination, was used to investigate the transcriptional response to metal (Ni and Cd) and non metal (temperature, oxygen, and diet) stressors in yellow perch (Perca flavescens). Specifically, we aimed at 1) identifying transcriptional signatures specific to Ni and Cd exposure, 2) investigating the mechanisms of their toxicity, and 3) developing a predictive tool to identify the sublethal effects of Ni and Cd contaminants in fish sampled from natural environments. A total of 479 genes displayed significantly different transcription levels when temperature varied while 287 and 177 genes were differentially transcribed at different concentrations of Ni and Cd, respectively. These metals were found to mainly affect the transcription level of genes involved in iron metabolism, transcriptional and translational processes, vitamin metabolism, blood coagulation, and calcium transport. In addition, a linear discriminant analysis (LDA) made using gene transcription levels yielded 94% correctly reassigned samples regarding their level of metal contamination, which indicates the potential of the microarray to detect perch response to Cd or Ni effects.

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

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