Low-Level Methylmercury Exposure Causes Human T-Cells to Undergo Apoptosis: Evidence of Mitochondrial Dysfunction

Low-Level Methylmercury Exposure Causes Human T-Cells to Undergo Apoptosis: Evidence of... There is growing evidence that heavy metals, in general, and mercurial compounds, in particular, are immunotoxic to the human immune system. The major focus of our study is to demonstrate that methylmercuric chloride (MeHgCl) kills human lymphocytes by inducing apoptosis. T-cells exposed to 0.6–5 μM MeHgCl for 24 h were analyzed by flow cytometry. Methylmercury-treated cells exhibited increased Hoechst 33258 fluorescence while maintaining their ability to exclude the vital stain 7-aminoactinomycin. Furthermore, T-cells exposed to methylmercury exhibited changes in light scatter patterns that included decreased forward light scatter and increased side light scatter. The light scatter and fluorescent changes were consistent with morphological alterations displayed by cells during apoptosis. Cell death was further evaluated by assessing annexin V binding to the plasma membrane. Methylmercury-treated cells exhibited increased annexin V binding indicative of phosphatidylserine translocation to the outer leaflet of the plasma membrane. Using the fluorescent probe DiOC 6 (3), we noted that methylmercury exposure resulted in a decrease in mitochondrial transmembrane potential (Ψ m ). Since a low Ψ m is associated with altered mitochondrial function, we also determined if exposure to methylmercury potentiated reactive oxygen species (ROS) generation. We noted that treated cells generated ROS, as evidenced by oxidation of hydroethidine and the generation of the fluorescent product, ethidium. Finally, we evaluated the effect of methylmercury on T-cell GSH content utilizing the fluorescent probe monochlorobimane; in the presence of MeHgCl, there is a marked loss in reduced cell thiols. The results of the study indicate that a key event in the induction of T-cell apoptosis by mercuric compounds is depletion in the thiol reserve which predisposes cells to ROS damage and at the same time activates death signaling pathways. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Environmental Research Elsevier

Low-Level Methylmercury Exposure Causes Human T-Cells to Undergo Apoptosis: Evidence of Mitochondrial Dysfunction

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Publisher
Elsevier
Copyright
Copyright © 1998 Academic Press
ISSN
0013-9351
eISSN
1096-0953
D.O.I.
10.1006/enrs.1997.3816
Publisher site
See Article on Publisher Site

Abstract

There is growing evidence that heavy metals, in general, and mercurial compounds, in particular, are immunotoxic to the human immune system. The major focus of our study is to demonstrate that methylmercuric chloride (MeHgCl) kills human lymphocytes by inducing apoptosis. T-cells exposed to 0.6–5 μM MeHgCl for 24 h were analyzed by flow cytometry. Methylmercury-treated cells exhibited increased Hoechst 33258 fluorescence while maintaining their ability to exclude the vital stain 7-aminoactinomycin. Furthermore, T-cells exposed to methylmercury exhibited changes in light scatter patterns that included decreased forward light scatter and increased side light scatter. The light scatter and fluorescent changes were consistent with morphological alterations displayed by cells during apoptosis. Cell death was further evaluated by assessing annexin V binding to the plasma membrane. Methylmercury-treated cells exhibited increased annexin V binding indicative of phosphatidylserine translocation to the outer leaflet of the plasma membrane. Using the fluorescent probe DiOC 6 (3), we noted that methylmercury exposure resulted in a decrease in mitochondrial transmembrane potential (Ψ m ). Since a low Ψ m is associated with altered mitochondrial function, we also determined if exposure to methylmercury potentiated reactive oxygen species (ROS) generation. We noted that treated cells generated ROS, as evidenced by oxidation of hydroethidine and the generation of the fluorescent product, ethidium. Finally, we evaluated the effect of methylmercury on T-cell GSH content utilizing the fluorescent probe monochlorobimane; in the presence of MeHgCl, there is a marked loss in reduced cell thiols. The results of the study indicate that a key event in the induction of T-cell apoptosis by mercuric compounds is depletion in the thiol reserve which predisposes cells to ROS damage and at the same time activates death signaling pathways.

Journal

Environmental ResearchElsevier

Published: May 1, 1998

References

  • Mercury inhibits Na-K–ATPase primarily at the cytoplasmic side
    Anner, B.M.; Moosmayer, M.
  • Mitochondrial perturbations define lymphocytes undergoing apoptotic depletion in vivo
    Castedo, M.; Macho, A.; Zamzami, N.; Hirsch, T.; Marchetti, P.; Uriel, J.; Kroemer, G.
  • Mercury suppression of a potassium current in human B lymphocytes
    Gallagher, J.D.; Noelle, R.J.; McCann, F.V.
  • Activation of cell membrane potassium conductance by mercury in cultured renal epitheloid (MDCK) cells
    Jungwirth, A.; Ritter, M.; Paulmichl, M.; Lang, F.
  • Sensitive method for measuring apoptosis and cell surface phenotype in human thymocytes by flow cytometry
    Schmid, I.; Uittenbogaart, C.H.; Giorgi, J.V.
  • Induction of apoptosis in human T-cells by organomercuric compounds: A flow cytometric analysis
    Shenker, B.J.; Datar, S.; Mansfield, K.; Shapiro, I.M.
  • Induction of human T cells that coexpress CD4 and CD8 by an immunomodulatory protein produced by Actinobacillus actinomycetemcomitans
    Shenker, B.J.; Vitale, L.; King, C.
  • Sequential reduction of mitochondrial transmembrane potential and generation of reactive oxygen species in early programmed cell death
    Zamzami, N.; Marchetti, P.; Castedo, M.; Decaudin, D.; Macho, A.; Hirsch, T.; Susin, S.A.; Petit, P.X.; Mignotte, B.; Kroemer, G.

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