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Transcriptomic analysis of Cr(VI)-induced changes in C2C12 cells during myogenic differentiation

ABSTRACT: Hexavalent chromium [Cr(VI)] is an environmental toxicant extensively used in a variety of industrial processes including chrome plating, leather tanning, textile manufacturing, aircraft production, and stainless-steel production. Our previous study showed that exposure to Cr(VI) impaired C2C12 myogenic differentiation in a dose-dependent manner, yet the transcriptional mechanisms underlying Cr(VI)-induced disruption of myogenesis remains poorly understood. Here, we performed bulk RNA-sequencing on C2C12 myoblasts undergoing differentiation in the presence of 0, 2, or 5 µM of Cr(VI). Differential gene expression analysis demonstrated a dose- and time-dependent increase in transcriptional dysregulation. Fuzzy c-means clustering identified 12 distinct gene expression patterns, with Clusters 3, 10, and 12 showing significant overlap with Cr(VI)-regulated genes. Functional enrichment analyses revealed Cr(VI) disrupts genes involved in early-stage cell cycle regulation and DNA repair as well as terminal differentiation processes like sarcomere organization and muscle contraction. Specifically, Cr(VI) impaired expression of key structural and contractile genes and disrupted DNA repair and cell cycle regulatory pathways, including downregulation of p21 and upregulation of proliferative marker PCNA. Furthermore, we identified suppression of Hippo signaling through downregulation of Tead4 and its muscle-specific downstream targets, providing a mechanism for impaired differentiation. These findings highlight widespread alterations in transcriptional programs governing muscle development and maturation, offering insight into how Cr(VI) exposure affects skeletal muscle health.

ORGANISM(S): Mus musculus

PROVIDER: GSE294800 | GEO | 2025/09/03

REPOSITORIES: GEO

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Project description:Significant occupational and environmental exposures to hexavalent chromium, a metal with broad toxicity potential in humans, have been reported. In order to understand the mechanisms of dermal toxicity induced by hexavalent chromium, global gene expression profiling of human dermal fibroblasts exposed to a toxic concentration of potassium dichromate was performed. Microarray analysis of the gene expression profile in the fibroblasts treated with potassium dichromate identified significant differential expression of approximately 1,200 transcripts compared with the control cells. Hierarchical cluster analysis of the gene expression profile demonstrated a clear separation of the treated cells from the control group of cells. Functional categorization of the differentially expressed genes identified the enrichment of genes involved in several cellular processes, including apoptosis and oxidative stress, in the fibroblasts exposed to hexavalent chromium. Induction of apoptosis and generation of hydroxyl radicals indicative of oxidative stress in the dermal fibroblasts in response to their exposure to hexavalent chromium were independently confirmed by TUNEL assay and electron spin resonance (ESR) analysis, respectively. The potassium dichromate-induced cytotoxicity, differential gene expression, apoptosis, and oxidative stress were significantly blocked by the addition of ferrous sulfate, an agent known for its ability to reduce hexavalent chromium to the insoluble and therefore impermeable trivalent form, to the cell culture medium. Taken together, our data provide insights into the potential mechanisms underlying the dermal toxicity of hexavalent chromium and suggest a definite role for apoptosis and oxidative stress in Cr(VI)-induced cytotoxicity in human dermal fibroblasts. 16 samples were analyzed in this experiment. Exponentially growing human dermal fibroblasts (3x105 cells) were cultured in T25 cell culture flasks. When the cells were approximately 70% confluent, hexavalent potassium dichromate (5µM) was added to the medium with or without 40µM ferrous sulfate. Following 16 hours of culturing at 37oC, total RNA was isolated for gene expression studies. Details of the samples are: Control 4 Samples: Cr(0)-1, Cr(0)-2, Cr(0)-3, Cr(0)-4 Cr 5 µM 4 Samples: Cr(5)-5, Cr(5)-6, Cr(5)-7, Cr(5)-8 FeSO4 40 µM 4 Samples: Fe(40)-9, Fe(40)-10, Fe(40)-11, Fe(40)-12 Cr 5 µM + FeSO4 40 µM 4 Samples: Cr(5)+Fe(40)-13,Cr(5)+Fe(40)-14, Cr(5)+Fe(40)-15, Cr(5)+Fe(40)-16

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Transcriptomic analysis of Cr(VI)-induced changes in C2C12 cells during myogenic differentiation

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