Cell death induced by zinc and cadmium is mediated by clusterin in cultured mouse seminiferous tubules

Tehila Kaisman-Elbaz, Israel Sekler, Daniel Fishman, Nataly Karol, Michal Forberg, Nicole Kahn, Michal Hershfinkel, William F. Silverman

Research output: Contribution to journalArticlepeer-review

27 Scopus citations


Sertoli cells, lining the walls of the seminiferous tubules, are in close contact with and regulate all aspects of the development of the germ cells. Clusterin, is a glycoprotein produced abundantly by Sertoli cells, and associated with either apoptosis or cell survival. Zinc is present in high concentrations in the testis and required for sperm development by an as yet unknown mechanism. Permeation of zinc into cells via voltage-gated calcium channels (VGCCs), however, is suggested to induce cell death. We examined the possibility that Zn2+ acts via clusterin to regulate germ cell survival. Employing an ex vivo model of mouse testis, we have assessed the role of permeation of heavy metal ions on clusterin production and secretion. Up-regulation of clusterin expression and its secretion was observed after a short exposure to zinc or to cadmium under depolarizing conditions. Expression of zinc transporter-1 (ZnT-1), previously shown to regulate Zn2+ influx, increased following prolonged application of zinc or cadmium to the explants and prevented clusterin up-regulation by subsequent exposure to these ions. Inhibition of the MAPK and PI3K pathways reduced the up-regulation of clusterin following the intracellular rise of Zn2+ or Cd 2+. Neutralization of secreted clusterin by an antibody or attenuation of clusterin up-regulation by inhibition of Zn2+ permeation via the LTCC, reduced cell death in cultured seminiferous tubule cells. Taken together, our results indicate that ZnZn2+ and Cd 2+ influx induce expression and secretion of clusterin, thereby linking metal homeostasis and germ cell fate.

Original languageEnglish
Pages (from-to)222-229
Number of pages8
JournalJournal of Cellular Physiology
Issue number1
StatePublished - 1 Jul 2009

ASJC Scopus subject areas

  • Physiology
  • Clinical Biochemistry
  • Cell Biology


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