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Biochemical and molecular basis of thimerosal-induced apoptosis in T cells: a major role of mitochondrial pathway

Abstract

The major source of thimerosal (ethyl mercury thiosalicylate) exposure is childhood vaccines. It is believed that the children are exposed to significant accumulative dosage of thimerosal during the first 2 years of life via immunization. Because of health-related concerns for exposure to mercury, we examined the effects of thimerosal on the biochemical and molecular steps of mitochondrial pathway of apoptosis in Jurkat T cells. Thimerosal and not thiosalcylic acid (non-mercury component of thimerosal), in a concentration-dependent manner, induced apoptosis in T cells as determined by TUNEL and propidium iodide assays, suggesting a role of mercury in T cell apoptosis. Apoptosis was associated with depolarization of mitochondrial membrane, release of cytochrome c and apoptosis inducing factor (AIF) from the mitochondria, and activation of caspase-9 and caspase-3, but not of caspase-8. In addition, thimerosal in a concentration-dependent manner inhibited the expression of XIAP, cIAP-1 but did not influence cIAP-2 expression. Furthermore, thimerosal enhanced intracellular reactive oxygen species and reduced intracellular glutathione (GSH). Finally, exogenous glutathione protected T cells from thimerosal-induced apoptosis by upregulation of XIAP and cIAP1 and by inhibiting activation of both caspase-9 and caspase-3. These data suggest that thimerosal induces apoptosis in T cells via mitochondrial pathway by inducing oxidative stress and depletion of GSH.

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Correspondence to S Gupta.

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This work was supported in part by a gift from Aida and Richard Demirjian.

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Makani, S., Gollapudi, S., Yel, L. et al. Biochemical and molecular basis of thimerosal-induced apoptosis in T cells: a major role of mitochondrial pathway. Genes Immun 3, 270–278 (2002). https://doi.org/10.1038/sj.gene.6363854

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  • DOI: https://doi.org/10.1038/sj.gene.6363854

Keywords

  • mitochondria
  • glutathione
  • caspases
  • cytochrome c
  • apoptosis-inducing factor
  • oxidative stress

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