Environmental Exposure History and Vulvodynia Risk: A Population-Based Study

Reed, Barbara D.; McKee, Kimberly Schmitt; Plegue, Melissa; Park, Sung Kyun; Haefner, Hope K.; Harlow, Sioḃán D.

doi:10.1089/jwh.2018.7188

Cited by 10 publications

(10 citation statements)

References 31 publications

(31 reference statements)

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“…Sensitivity to MI is clear and present in populations within North America and Europe, and adverse health outcomes related to MI are on the rise. Given that exposure to household cleaning products is a risk factor for developing vulvodynia [17], we found it important to investigate whether repeated exposure to MI provoked persistent pain in laboratory mice.…”

Section: Resultsmentioning

confidence: 99%

“…Allergic responses to MI have also been linked to vulvar dermatitis [15,16], but no connections between such dermatoses and the later development of vulvar pain have been made in the published clinical literature. Recently, Reed and colleagues identified exposures to household and workplace chemicals as a possible risk factor for the development of vulvodynia [17]. Our previously published mouse models demonstrated the biological plausibility of the epidemiological link between chemical exposures and the development of genital pain.…”

Section: Introductionmentioning

confidence: 88%

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Repeated Vaginal Exposures to the Common Cosmetic and Household Preservative Methylisothiazolinone Induce Persistent, Mast Cell-Dependent Genital Pain in ND4 Mice

Arriaga-Gomez

Kline

Emanuel

et al. 2019

IJMS

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A history of allergies doubles the risk of vulvodynia—a chronic pain condition of unknown etiology often accompanied by increases in numbers of vulvar mast cells. We previously established the biological plausibility of this relationship in mouse models where repeated exposures to the allergens oxazolone or dinitrofluorobenzene on the labiar skin or inside the vaginal canal of ND4 Swiss Webster outbred mice led to persistent tactile sensitivity and local increases in mast cells. In these models, depletion of mast cells alleviated pain. While exposure to cleaning chemicals has been connected to elevated vulvodynia risk, no single agent has been linked to adverse outcomes. We sensitized female mice to methylisothiazolinone (MI)—a biocide preservative ubiquitous in cosmetics and cleaners—dissolved in saline on their flanks, and subsequently challenged them with MI or saline for ten consecutive days in the vaginal canal. MI-challenged mice developed persistent tactile sensitivity, increased vaginal mast cells and eosinophils, and had higher serum Immunoglobulin E. Therapeutic and preventive intra-vaginal administration of Δ9-tetrahydrocannabinol reduced mast cell accumulation and tactile sensitivity. MI is known to cause skin and airway irritation in humans, and here we provide the first pre-clinical evidence that repeated MI exposures can also provoke allergy-driven genital pain.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 88%

Repeated Vaginal Exposures to the Common Cosmetic and Household Preservative Methylisothiazolinone Induce Persistent, Mast Cell-Dependent Genital Pain in ND4 Mice

Arriaga-Gomez

Kline

Emanuel

et al. 2019

IJMS

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“…Along with painful sensitivity to touch, a clinical diagnosis of vulvodynia often includes an increase in mast cells, local overgrowth of nerves [3], and altered inflammatory responses of vulvar tissue-derived fibroblasts to in vitro yeast antigen stimulation [4,5]. A history of seasonal and cutaneous allergies doubles the risk for vulvodynia [6], and its incidence is linked with exposure to household and workplace cleaning chemicals [7]. We have previously reported that repeated exposures to the hapten oxazolone on the labiar skin of ND4 (Notre Dame re-derived) Swiss Webster female mice recapitulate key clinical symptoms, i.e., painful ano-genital sensitivity to touch, increased nerve growth and an accumulation of mast cells [8,9].…”

Section: Introductionmentioning

confidence: 99%

Tetrahydrocannabinol Reduces Hapten-Driven Mast Cell Accumulation and Persistent Tactile Sensitivity in Mouse Model of Allergen-Provoked Localized Vulvodynia

Boo

Kamath

Arriaga-Gomez

et al. 2019

IJMS

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Vulvodynia is a remarkably prevalent chronic pain condition of unknown etiology. An increase in numbers of vulvar mast cells often accompanies a clinical diagnosis of vulvodynia and a history of allergies amplifies the risk of developing this condition. We previously showed that repeated exposures to oxazolone dissolved in ethanol on the labiar skin of mice led to persistent genital sensitivity to pressure and a sustained increase in labiar mast cells. Here we sensitized female mice to the hapten dinitrofluorobenzene (DNFB) dissolved in saline on their flanks, and subsequently challenged them with the same hapten or saline vehicle alone for ten consecutive days either on labiar skin or in the vaginal canal. We evaluated tactile ano-genital sensitivity, and tissue inflammation at serial timepoints. DNFB-challenged mice developed significant, persistent tactile sensitivity. Allergic sites showed mast cell accumulation, infiltration of resident memory CD8+CD103+ T cells, early, localized increases in eosinophils and neutrophils, and sustained elevation of serum Immunoglobulin E (IgE). Therapeutic intra-vaginal administration of Δ9-tetrahydrocannabinol (THC) reduced mast cell accumulation and tactile sensitivity. Mast cell-targeted therapeutic strategies may therefore provide new ways to manage and treat vulvar pain potentially instigated by repeated allergenic exposures.

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“…Vulvodynia is a poorly understood pain condition with no effective treatment. Alongside seasonal and contact allergies [ 18 ], dermal exposures to specific insecticides, herbicides, cosmetics, cleaners and solvents are also associated with a risk of developing vulvodynia [ 10 ]. Many of these products contain the biocide preservative MI.…”

Section: Discussionmentioning

confidence: 99%

“…However, Reed and colleagues particularly identified occupational exposures (via salon work, housecleaning, yard maintenance etc.) as risk factors for developing vulvar pain [ 10 ]. In these jobs, and also other household hygiene practices, it is more likely that long-term repeated exposure to MI frequently, and most significantly, occurs via the skin.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2020

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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.

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Environmental Exposure History and Vulvodynia Risk: A Population-Based Study

Cited by 10 publications

References 31 publications

Repeated Vaginal Exposures to the Common Cosmetic and Household Preservative Methylisothiazolinone Induce Persistent, Mast Cell-Dependent Genital Pain in ND4 Mice

Repeated Vaginal Exposures to the Common Cosmetic and Household Preservative Methylisothiazolinone Induce Persistent, Mast Cell-Dependent Genital Pain in ND4 Mice

Tetrahydrocannabinol Reduces Hapten-Driven Mast Cell Accumulation and Persistent Tactile Sensitivity in Mouse Model of Allergen-Provoked Localized Vulvodynia

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

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