Toxic effects of cadmium on flatworm stem cell dynamics: A transcriptomic and ultrastructural elucidation of underlying mechanisms

Environ Toxicol. 2016 Oct;31(10):1217-28. doi: 10.1002/tox.22129. Epub 2015 Apr 6.


Stem cells or undifferentiated cells can cope more easily with external stresses. To evaluate the impact of toxic compounds on stem cell dynamics in vivo, in relation to other biological responses, we use the carcinogenic element cadmium and the regenerating model organism Macrostomum lignano. Through both BrdU and anti-histone H3 immunostainings, cadmium-induced effects were investigated at different stages of the stem cell cycle. A 24-h exposure to 100 and 250 μM CdCl2 significantly decreased the number of stem cells (neoblasts) in mitosis, whereas the number of cells in the S phase remained unchanged. After this short-term exposure, the ultrastructure of the neoblasts was minimally affected in contrast to the epidermal tissues. These results were supported by gene expression data: transcripts of cdc2 and pig3 were significantly upregulated during all treatments. Both genes are involved in the cell cycle progression and are transcribed in the gonadal region, where stem cells are highly represented. Based on a substantial increase in gene expression of heat shock proteins (HSP) and their high activity in the gonadal region, we hypothesize that these proteins are key players in the protection of stem cells against external stresses. Apart from the strong HSP induction, other protective processes including cell division, apoptosis and anti-oxidative defence, were also activated. We, therefore, conclude that the protection of stem cells against external stressors may be based on the interplay between stem cell maintenance, i.e. repair and recovery through division, on one hand and apoptosis on the other hand. © 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 1217-1228, 2016.

Keywords: Macrostomum lignano; cadmium; stem cell; stress; toxicology.

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • CDC2 Protein Kinase / metabolism
  • Cadmium Chloride / toxicity*
  • Epidermis / drug effects
  • Epidermis / ultrastructure
  • Gonads / drug effects
  • Gonads / metabolism
  • Heat-Shock Proteins / metabolism
  • Histones / metabolism
  • In Situ Hybridization
  • Microscopy, Electron
  • Mitosis / drug effects
  • Platyhelminths / cytology
  • Proto-Oncogene Proteins / metabolism
  • Reactive Oxygen Species / metabolism
  • S Phase
  • Stem Cells / cytology
  • Stem Cells / drug effects
  • Stem Cells / metabolism
  • Transcriptome / drug effects*
  • Up-Regulation / drug effects


  • Heat-Shock Proteins
  • Histones
  • Proto-Oncogene Proteins
  • Reactive Oxygen Species
  • CDC2 Protein Kinase
  • Cadmium Chloride