Antioxidant/stress response in mouse epidermis following exposure to nitrogen mustard

Exp Mol Pathol. 2020 Jun;114:104410. doi: 10.1016/j.yexmp.2020.104410. Epub 2020 Feb 28.

Abstract

Nitrogen mustard (NM) is a highly reactive bifunctional alkylating agent that induces inflammation, edema and blistering in skin. An important mechanism mediating the action of NM and related mustards is oxidative stress. In these studies a modified murine patch-test model was used to analyze DNA damage and the antioxidant/stress response following NM exposure in isolated epidermis. NM (20 μmol) was applied to glass microfiber filters affixed to a shaved dorsal region of skin of CD-1 mice. NM caused structural damage to the stratum corneum as reflected by increases in transepidermal water loss and skin hydration. This was coordinate with edema, mast cell degranulation and epidermal hyperplasia. Within 3 h of NM exposure, a 4-fold increase in phosphorylated histone H2AX, a marker of DNA double-stranded breaks, and a 25-fold increase in phosphorylated p53, a DNA damage marker, were observed in the epidermis. This was associated with a 40% increase in 8-oxo-2'-deoxyguanosine modified DNA in the epidermis and a 4-fold increase in 4-hydroxynonenal modified epidermal proteins. At 12 h post NM, there was a 3-75 fold increase in epidermal expression of antioxidant/stress proteins including heme oxygenase-1, thioredoxin reductase, superoxide dismutase, glutathione reductase, heat shock protein 27 and cyclooxygenase 2. These data indicate that NM induces early oxidative epidermal injury in mouse skin leading to an antioxidant/stress response. Agents that enhance this response may be useful in mitigating mustard-induced skin injury.

Keywords: DNA damage; Mouse epidermis; Oxidative stress; Vesicants.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Alkylating Agents / pharmacology
  • Alkylating Agents / toxicity
  • Animals
  • Antioxidants / metabolism*
  • Apoptosis / drug effects
  • Cyclooxygenase 2 / genetics
  • DNA Damage / drug effects
  • Epidermis / drug effects
  • Epidermis / metabolism*
  • Glutathione Reductase / genetics
  • HSP27 Heat-Shock Proteins / genetics
  • Heme Oxygenase-1 / genetics
  • Humans
  • Inflammation / chemically induced
  • Inflammation / genetics
  • Inflammation / pathology
  • Mechlorethamine / pharmacology*
  • Mechlorethamine / toxicity
  • Mice
  • Oxidative Stress / drug effects
  • Phosphorylation / drug effects
  • Skin / drug effects
  • Skin / metabolism
  • Stress, Physiological / genetics*
  • Superoxide Dismutase / genetics
  • Thioredoxin-Disulfide Reductase / genetics

Substances

  • Alkylating Agents
  • Antioxidants
  • HSP27 Heat-Shock Proteins
  • Mechlorethamine
  • Heme Oxygenase-1
  • Cyclooxygenase 2
  • Superoxide Dismutase
  • Glutathione Reductase
  • Thioredoxin-Disulfide Reductase