Long duration exposure to cadmium leads to increased cell survival, decreased DNA repair capacity, and genomic instability in mouse testicular Leydig cells

Kamaleshwar P. Singh, Ragini Kumari, Christina Pevey, Desiree Jackson, James W. DuMond

Research output: Contribution to journalArticle

54 Scopus citations

Abstract

Epidemiological and experimental studies have shown that cadmium is carcinogenic to human and experimental animals, however, the mechanism of cadmium-induced carcinogenesis is not clear. The aberrant expression of cell cycle and DNA repair genes resulting in increased cell proliferation and genomic instability are the characteristic features of cancer cells. The purpose of this study was to determine if exposure to cadmium can perturb cell proliferation/survival and causes genomic instability in TM3 cells, a mouse testicular Leydig cell line. The results of this study revealed that short-duration exposure to lower doses of cadmium significantly increase the growth of TM3 cells, whereas, higher doses are toxic and cause cell death. The long duration exposure to higher doses of cadmium, however, results in increased cell survival and acquisition of apoptotic resistance. Gene expression analysis by real-time PCR revealed increased expression of the anti-apoptotic gene Bcl-2, whereas decreased expression of pro-apoptotic gene Bax. Decreased expression of genes for maintenance of DNA methylation, DNMT1, and DNA repair, OGG1 and MYH, was also observed in cells exposed to cadmium for 24 h. The random amplified polymorphic DNA (RAPD) assay revealed genomic instability in cells with chronic exposure to cadmium. The findings of this study indicate that mouse testicular Leydig cells adapt to chronic cadmium exposure by increasing cell survival through increased expression of Bcl-2, and decreased expression of Bax. The increased proliferation of cells with genomic instability may result in malignant transformation, and therefore, could be a viable mechanism for cadmium-induced cancers.

Original languageEnglish
Pages (from-to)84-92
Number of pages9
JournalCancer Letters
Volume279
Issue number1
DOIs
StatePublished - Jun 28 2009

Keywords

  • Cadmium exposure
  • Cell survival
  • DNA repair
  • Genomic instability

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