The role of tungsten in modulating DNA double-strand break repair and class switch recombination

Abstract

Tungsten, a transition metal with widespread applications, is increasingly recognized as an environmental contaminant with potential health impacts. While tungsten exposure has been previously associated with increased DNA damage, its specific effects on DNA repair mechanisms remain poorly understood. Here, we found that tungsten alone did not induce DNA damage in vitro, as assessed by γ-H2AX phosphorylation. However, tungsten exacerbated DNA double-strand breaks induced by genotoxic agents, delayed γ-H2AX resolution, and induced cell cycle arrest. Mechanistically, GFP-based reporter assays revealed that tungsten impairs both homologous recombination (HR) and non-homologous end joining (NHEJ), which coincided with reduced recruitment of critical repair proteins, including BRCA1, 53BP1, and ATM at DSB sites. To assess functional consequences of impaired DNA repair due to tungsten exposure, we examined immunoglobulin (Ig) class switch recombination (CSR), a critical antibody diversification process reliant on the repair of DSBs. Using the CH12F3 B cell line, we showed that tungsten significantly impaired cytokine stimulated-CSR from IgM to IgA without affecting cell proliferation or activation-induced cytidine deaminase (Aicda) expression. Furthermore, ex vivo activation of splenic B cells confirmed that tungsten exposure inhibits CSR from IgM to IgG1, independent of cell proliferation. Together, these data indicate that tungsten exposure impairs canonical DSB repair pathways and CSR, highlighting the potential consequences for immune function upon environmental or occupational exposure to tungsten.