Citrinin-generated reactive oxygen species cause cell cycle arrest leading to apoptosis via the intrinsic mitochondrial pathway in mouse skin

Toxicol Sci. 2011 Aug;122(2):557-66. doi: 10.1093/toxsci/kfr143. Epub 2011 May 27.


The mycotoxin, citrinin (CTN), is a contaminant of various food and feed materials. Several in vivo and in vitro studies have demonstrated that CTN has broad toxicity spectra; however, dermal toxicity is not known. In the present investigation, dermal exposure to CTN was undertaken to study oxidative stress, DNA damage, cell cycle arrest, and apoptosis in mouse skin. A single topical application of CTN caused significant change in oxidative stress markers, such as lipid peroxidation, protein carbonyl content, glutathione (GSH) content, and antioxidant enzymes in a dose-dependent (25-100 μg/mouse) and time-dependent (12-72 h) manner. Single topical application of CTN (50 μg/mouse) for 12-72 h caused significant enhancement in (1) reactive oxygen species (ROS); (2) cell cycle arrest at the G0/G1 phase (30-71%) and G2/M phase (56-65%) along with the induction of apoptosis (3.6-27%); (3) expression of p53, p21/waf1; (4) Bax/Bcl₂ ratio and cytochome c release; and (5) activities of caspase 9 (22-46%) and 3 (42-54%) as well as increased poly(ADP-ribose) polymerase cleavage. It was also observed that pretreatment with bio-antioxidants viz butylated hydroxyanisole (55 μmol/100 μl), quercetin (10 μmol/100 μl), or α-tocopherol (40 μmol/100 μl) resulted in decreases of ROS generation, arrest in the G0/G1 phase of the cell cycle, and apoptosis. These data confirm the involvement of ROS in apoptosis and suggest that these bio-antioxidants may be useful in the prevention of CTN-induced dermal toxicity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antioxidants / pharmacology
  • Apoptosis / drug effects*
  • Biomarkers
  • Butylated Hydroxyanisole / pharmacology
  • Caspase 9 / metabolism
  • Cell Division / drug effects
  • Citrinin / toxicity*
  • DNA Damage / drug effects
  • Dose-Response Relationship, Drug
  • Female
  • G1 Phase / drug effects
  • M Phase Cell Cycle Checkpoints / drug effects
  • Mice
  • Mitochondria / metabolism*
  • Oxidative Stress / drug effects
  • Poly(ADP-ribose) Polymerases / metabolism
  • Quercetin / pharmacology
  • Reactive Oxygen Species / metabolism*
  • Skin / metabolism*
  • alpha-Tocopherol / pharmacology
  • bcl-2-Associated X Protein / metabolism


  • Antioxidants
  • Bax protein, mouse
  • Biomarkers
  • Reactive Oxygen Species
  • bcl-2-Associated X Protein
  • Butylated Hydroxyanisole
  • Citrinin
  • Quercetin
  • Poly(ADP-ribose) Polymerases
  • Casp9 protein, mouse
  • Caspase 9
  • alpha-Tocopherol