We recently used EPA databases to identify that isocyanates, most notably toluene diisocyanate (TDI), were the pollutant class with the strongest spatiotemporal and epidemiologic association with atopic dermatitis (AD). Our findings demonstrated that isocyanates like TDI disrupted lipid homeostasis and modeled benefit in commensal bacteria like Roseomonas mucosa through disrupting nitrogen fixation. However, TDI has also been established to activate transient receptor potential ankyrin 1 (TRPA1) in mice and thus could directly contribute to AD through induction of itch, rash, and psychological stress. Using cell culture and mouse models, we now demonstrate that TDI induced skin inflammation in mice as well as calcium influx in human neurons; each of these findings were dependent on TRPA1. Furthermore, TRPA1 blockade synergized with R. mucosa treatment in mice to improve TDI-independent models of AD. Finally, we show that the cellular effects of TRPA1 are related to shifting the balance of the tyrosine metabolites epinephrine and dopamine. This work provides added insight into the potential role, and therapeutic potential, or TRPA1 in the pathogenesis of AD.
Compared to the myriad of known triggers for rhinitis and asthma, environmental exposure research for atopic dermatitis (AD) is not well established. We recently reported that an untargeted search of U.S. Environmental Protection Agency (EPA) databases versus AD rates by United States (U.S.) postal codes revealed that isocyanates, such as toluene diisocyanate (TDI), are the pollutant class with the strongest spatiotemporal and epidemiologic association with AD. We further demonstrated that (di)isocyanates disrupt ceramide-family lipid production in commensal bacteria and activate the thermo-itch host receptor TRPA1. In this report, we reanalyzed regions of the U.S. with low levels of diisocyanate pollution to assess if a different chemical class may contribute. We identified antimony compounds as the top associated pollutant in such regions. Exposure to antimony compounds would be expected from brake dust in high-traffic areas, smelting plants, bottled water, and dust from aerosolized soil. Like TDI, antimony inhibited ceramide-family lipid production in Roseomonas mucosa and activated TRPA1 in human neurons. While further epidemiologic research will be needed to directly evaluate antimony exposure with surrounding AD prevalence and severity, these data suggest that compounds which are epidemiologically associated with AD, inhibit commensal lipid production, and activate TRPA1 may be causally related to AD pathogenesis.
BackgroundDespite the recent expansion of treatment options in atopic dermatitis (AD), most management responsibilities fall on the patient and/or caregivers. Disease control often requires vigilance about and avoidance of common exposures, however the concerns for patients and caregivers living with AD have not been well enumerated.MethodsAn IRB approved survey was distributed to the public to evaluate the patient and caregiver concerns for topical exposures and potential triggers.Results323 people accessed the link to the survey with 259 providing response to at least one section of questions (response rate 80.2%). Results indicated that temperature and other weather related changes were the most common trigger. Nearly all respondents avoided at least one topical ingredient, with fragrances being the most common. Steroid exposure was common, however respondents expressed concerns about overall steroid exposure.ConclusionsOur results attempt to enumerate the daily topical exposure concerns for patients and caregivers living with AD. While our online survey is both limited and without mechanistic insights, our results provide insight to providers by highlighting the role of temperature in AD symptoms; identifying commonly perceived triggers; indicating the value of provider insight for topical product selection; and indicating that no specific aspect of topical corticosteroid exposure may alleviate the general steroid concerns for patients or caregivers.
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