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

• Published in: Experimental and molecular pathology Vol. 114; p. 104410
• Main Authors: Wahler, Gabriella, Heck, Diane E., Heindel, Ned D., Laskin, Debra L., Laskin, Jeffrey D., Joseph, Laurie B.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Inc 01.06.2020
• Subjects: Alkylating Agents - pharmacology; Alkylating Agents - toxicity; Animals; Antioxidants - metabolism; Apoptosis - drug effects; Cyclooxygenase 2 - genetics; DNA damage; DNA Damage - drug effects; Epidermis - drug effects; Epidermis - metabolism; Glutathione Reductase - genetics; Heme Oxygenase-1 - genetics; HSP27 Heat-Shock Proteins - genetics; Humans; Inflammation - chemically induced; Inflammation - genetics; Inflammation - pathology; Mechlorethamine - pharmacology; Mechlorethamine - toxicity; Mice; Mouse epidermis; Oxidative stress; Oxidative Stress - drug effects; Phosphorylation - drug effects; Skin - drug effects; Skin - metabolism; Stress, Physiological - genetics; Superoxide Dismutase - genetics; Thioredoxin-Disulfide Reductase - genetics; Vesicants; Oxidative stress; Vesicants; Mouse epidermis; DNA damage
• ISSN: 0014-4800; 1096-0945
• DOI: 10.1016/j.yexmp.2020.104410

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.