Effect of Chronic Topical Exposure to Low-Dose Noxious Chemicals and Stress on Skin Sensitivity in Mice

It has been suggested that the recent increase in inflammatory diseases is related to an increase in environmental chemicals and psychiatric stress. To investigate the effect of chronic topical exposure to chemicals and isolation stress, low-dose formalin (a mild contact sensitizer and an irritant), 2, 4, 6-trinitrochlorobenzene (TNCB; a potent contact sensitizer) and sodium lauryl sulphate (SLS; an irritant) were applied to mouse ears at 7-d intervals under no-stress or stress conditions. Skin reactions (ear swelling) elicited by formalin and TNCB increased time dependently. At the chronic stage, a significant skin reaction peaking at 1h after application was elicited on the formalin-treated sites, while a shift from a delayed-type hypersensitivity to an immediate-type response was observed on the TNCB-treated sites. At the formalin-treated sites, genes related to neurogenic inflammation, i.e., bradykinin (BK) B2 receptor, IL-6, and membrane metallo endopeptidase (NEP) mRNA were upregulated. In the TNCB-treated sites, marked upregulation of IFN-γ, IL-1β, IL-4, and IL-6 mRNA was observed in addition to B2 receptor mRNA. Pretreatment with HOE140, the B2 receptor antagonist suppressed these skin reactions. Increased skin sensitivity to an unrelated chemical, ethanol, and thermal stimuli were elicited in formalin and TNCB-treated mice. Cortisol levels in formalin-treated mice and IgE levels in TNCB-treated mice were elevated respectively. Stress markedly amplified the skin reactions and gene expression related to neurogenic inflammation. SLS did not induce any changes. It was concluded that chronic topical exposure to low-dose noxious chemicals and stress could easily induce skin sensitivity relating to the BK-B2 pathway and nociceptive sensitization reflecting neural sensitization.