Repeated dermal application of the common preservative methylisothiazolinone triggers local inflammation, T cell influx, and prolonged mast cell-dependent tactile sensitivity in mice.

Jaclyn M Kline,Devavani Chatterjea,Hayley Zacheis,Dogukan Pasha,Sayira Silverio,Marietta Saldías-Montivero,Hanna Mengistu,Nefeli Neamonitaki,Brian T Fife,Beebie Boo,Tenzin Yangdon,Tijana Martinov,Erica Arriaga-Gomez,Jasmine Landry,Praveen Thumbikat

doi:10.1371/journal.pone.0241218

Jaclyn M Kline, Devavani Chatterjea + Show 13 more

Open Access

https://doi.org/10.1371/journal.pone.0241218

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Abstract

Occupational exposure to toxic chemicals increases the risk of developing localized provoked vulvodynia-a prevalent, yet poorly understood, chronic condition characterized by sensitivity to touch and pressure, and accumulation of mast cells in painful tissues. Here, we topically sensitized female ND4 Swiss mice to the common household and industrial preservative methylisothiazolinone (MI) and subsequently challenged them daily with MI or acetone and olive oil vehicle on the labiar skin. MI-challenged mice developed significant, persistent tactile sensitivity and long-lasting local accumulation of mast cells alongside early, transient increases in CD4+ and CD8+ T cells, eosinophils, neutrophils, and increases in pro-inflammatory cytokines. Therapeutic administration of imatinib, a c-Kit inhibitor known to inhibit mast cell survival, led to reduced mast cell accumulation and alleviated tactile genital pain. We provide the first pre-clinical evidence of dermal MI-induced mast-cell dependent pain and lay the groundwork for detailed understanding of these intersections between MI-driven immunomodulation and chronic pain.

Highlights

Methylisothiazolinone or 2-Methyl-1,2-thiazol-3-one (MI) is a ubiquitous biocide preservative found in a wide range of household and commercial cleaning products, paints and hand and body soaps [1, 2]
We sensitized ND4 Swiss female mice with 1% and 0.5% MI dissolved in 4:1 acetone:olive oil (AOO) on the back and followed with 10 daily challenges of 0.5% MI or vehicle (AOO) on the Repeated dermal exposure to methylisothiazolinone provokes mast cell-dependent tactile sensitivity in mice labiar skin
In addition to increased eosinophil activity, we found significantly increased tissue myeloperoxidase (MPO) levels, a marker for heightened neutrophil activity, in the labiar skin of MI-treated mice compared to AOO-treated mice 1 day after 10th challenge (Fig 1G)

Summary

Introduction

Methylisothiazolinone or 2-Methyl-1,2-thiazol-3-one (MI) is a ubiquitous biocide preservative found in a wide range of household and commercial cleaning products, paints and hand and body soaps [1, 2]. Localized provoked vulvodynia is diagnosed by heightened sensitivity to pressure and touch and, in certain cases, accompanies increases in mast cells [11, 12], CD4+ T cells [13], and inflammatory cytokines in the vulvar tissue [14, 15] It is relatively common, affecting an estimated 8% of individuals identified as women in studies of prevalence [16, 17]. Reed and colleagues identified occupational exposures (via salon work, housecleaning, yard maintenance etc.) as risk factors for developing vulvar pain [10] In these jobs, and other household hygiene practices, it is more likely that longterm repeated exposure to MI frequently, and most significantly, occurs via the skin. These findings are the first evidence for the role of dermal MI exposures in inducing long-lasting, provoked pain

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44. European Commission Consumers