Spatial modeling connecting childhood atopic dermatitis prevalence with household exposure to pollutants.

BACKGROUND: Atopic dermatitis (AD) is a chronic, inflammatory disease characterized by dry, pruritic skin. In the U.S., the prevalence of AD has increased over three-fold since the 1970s. We previously reported a geographic association between isocyanate-containing air pollution and AD as well as mechanistic data demonstrating that isocyanates induce skin dysbiosis and activate the host itch receptor TRPA1. However, non-spatial models are susceptible to spatial confounding and may overlook other meaningful associations. METHODS: We added spatial analysis to our prior model, contrasting pollution data with clinical visits. In addition, we conducted a retrospective case-control survey of childhood exposure to BTEX-related products. Finally, we assessed implicated compounds, in pure form and as part of synthetic fabric, for their effect on the growth and metabolism of skin commensal bacteria. RESULTS: Spatial analysis implicate benzene, toluene, ethylbenzene, and, most significantly, xylene (BTEX) compounds. Survey odds ratios for AD were significant for xylene-derived polyester bed sheets (OR = 9.5; CI 2.2-40.1) and diisocyanate-containing wallpaper adhesive (OR = 6.5; CI 1.5-27.8). Staphylococcus aureus lives longer on synthetic textiles compared to natural textiles. Meanwhile, synthetic fabric exposure shifts the lipid metabolism of health-associated commensals (Roseomonas mucosa and S. epidermidis) away from therapeutic pathways. CONCLUSIONS: We propose that BTEX chemicals in their raw forms and in synthetic products represent a unifying hypothesis for environmentally induced AD flares through their ability to create dysbiosis in the skin microbiota and directly activate TRPA1. Unequal distribution of these pollutants may also influence racial disparities in AD rates.

Atopic dermatitis (AD) is a chronic, inflammatory disease characterized by dry, itchy skin that has become increasingly more common since around 1970. We aimed to identify chemicals that may cause atopic dermatitis (eczema). Building on prior work, we discovered that these chemicals could prevent the good bacteria that live on the skin from making the lipids and oils needed to keep human skin healthy. In this study, we combined new research methods with patient surveys. We link eczema to the chemical xylene, which is found in numerous home products. Exposure to xylene, benzene, or isocyanate containing fabrics (polyester, nylon, or spandex) disrupted the normal functions of skin bacteria. Our results indicate exposure to synthetic fabrics and other sources of these chemicals may contribute to eczema and deepen the understanding of how the environment can drive common diseases.

Association of Fibroids, Endometriosis, and Gynecologic Surgeries with Breast Cancer Incidence and Hormone Receptor Subtypes.

BACKGROUND: Fibroids and endometriosis are sex hormone-mediated and exhibit cancer-like behavior. Breast cancer may be more common in women who have had these conditions, but the literature is conflicting and does not always address factors like hysterectomy/oophorectomy status, race/ethnicity, menopause, and hormone receptor subtypes. METHODS: Data are from the Sister Study, a cohort of 50,884 U.S. women enrolled in 2003 to 2009 and followed through 2020. Cox proportional hazards models with time-varying exposures and covariates assessed the relationship of fibroids or endometriosis with breast cancer. Logistic regression examined the association with estrogen receptor (ER) status among cases. RESULTS: Fibroids (19,932 cases) were positively associated with breast cancer [fully adjusted HR: 1.07; 95% confidence interval (CI): 1.01-1.14], notably among Black participants (HR: 1.34; 95% CI: 1.07-1.69) and women who had a hysterectomy (HR: 1.18; 95% CI: 1.05-1.31). Endometriosis (3,970 cases) was not associated with breast cancer (HR: 0.99; 95% CI: 0.91-1.08). Among 4,419 breast cancer cases, fibroids were positively associated with ER+ subtypes (OR: 1.34; 95% CI: 1.10-1.65), while endometriosis was negatively associated with ER+ subtypes (OR: 0.78; 95% CI: 0.61-1.01). CONCLUSIONS: We observed a modest positive association between fibroids and breast cancer, particularly ER+ breast cancer. No relationship with endometriosis and breast cancer incidence was found. IMPACT: Fibroids, even in those with a family history of breast cancer, might modify breast cancer risk stratification tools. Future studies should further assess this link and interrogate shared risk factors.

The circadian metabolome of atopic dermatitis.

BACKGROUND: Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by dry, pruritic skin. Several studies have described nocturnal increases in itching behavior, suggesting a role for the circadian rhythm in modulating symptom severity. However, the circadian rhythm of metabolites in the skin and serum of patients with AD is yet to be described. OBJECTIVE: We sought to assess circadian patterns of skin and serum metabolism in patients with AD. METHODS: Twelve patients with moderate to severe AD and 5 healthy volunteers were monitored for 28 hours in a controlled environment. Serum was collected every 2 hours and tape strips every 4 hours from both lesional and nonlesional skin in participants with AD and location-, sex-, and age-matched healthy skin of controls. We then performed an untargeted metabolomics analysis, examining the circadian peaks of metabolism in patients with AD. RESULTS: Distinct metabolic profiles were observed in AD versus control samples. When accounting for time of collection, the greatest differences in serum metabolic pathways were observed in arachidonic acid, steroid biosynthesis, and terpenoid backbone biosynthesis. We identified 42 circadian peaks in AD or control serum and 17 in the skin. Pathway enrichment and serum-skin metabolite correlation varied throughout the day. Differences were most evident in the late morning and immediately after sleep onset. CONCLUSIONS: Although limited by a small sample size and observational design, our findings suggest that accounting for sample collection time could improve biomarker detection studies in AD and highlight that metabolic changes may be associated with nocturnal differences in symptom severity.

Antimony Compounds Associate with Atopic Dermatitis and Influence Models of Itch and Dysbiosis.

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.

Shotgun metagenomic sequencing on skin microbiome indicates dysbiosis exists prior to the onset of atopic dermatitis.

BACKGROUND: While the microbiome is increasingly seen as a targetable contributor to atopic dermatitis (AD), questions remain as to whether the dysbiosis is secondary to diseased skin or if it predates symptom onset. Previous work has evaluated how the skin microbiome changes with age and established the influence of factors like delivery mode and breastfeeding on global microbiome diversity. However, these studies were unable to identify taxa which predict subsequent AD. METHODS: Skin swab samples were collected from the first week of life for 72 children in the neonatal intensive care unit (NICU) at a single site hospital. Participants were followed for 3 years to determine their health status. We applied shotgun metagenomic sequencing to assess the microbiome differences between 31 children who went on to develop AD and 41 controls. RESULTS: We identified that subsequent development of AD was associated with differential abundance of several bacterial and fungal taxa as well as several metabolic pathways, each of which have been previously associated with active AD. CONCLUSIONS: Our work provides evidence of reproducibility for the previously reported dysbiotic signatures predating AD onset while also expanding prior findings through the first use of metagenomic assessment prior to AD onset. While extrapolation of our findings beyond the pre-term, NICU cohort is limited, our findings add to the evidence that the dysbiosis associated with AD pre-dates disease onset rather than reflect a secondary consequence of skin inflammation.

Diisocyanates influence models of atopic dermatitis through direct activation of TRPA1.

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.

Exposure to isocyanates predicts atopic dermatitis prevalence and disrupts therapeutic pathways in commensal bacteria.

Atopic dermatitis (AD) is a chronic inflammatory skin condition increasing in industrial nations at a pace that suggests environmental drivers. We hypothesize that the dysbiosis associated with AD may signal microbial adaptations to modern pollutants. Having previously modeled the benefits of health-associated Roseomonas mucosa, we now show that R. mucosa fixes nitrogen in the production of protective glycerolipids and their ceramide by-products. Screening EPA databases against the clinical visit rates identified diisocyanates as the strongest predictor of AD. Diisocyanates disrupted the production of beneficial lipids and therapeutic modeling for isolates of R. mucosa as well as commensal Staphylococcus. Last, while topical R. mucosa failed to meet commercial end points in a placebo-controlled trial, the subgroup who completed the full protocol demonstrated sustained, clinically modest, but statistically significant clinical improvements that differed by study site diisocyanate levels. Therefore, diisocyanates show temporospatial and epidemiological association with AD while also inducing eczematous dysbiosis.

Assessing microbial manipulation and environmental pollutants in the pathogenesis of psoriasis.

The cutaneous microbiome is increasingly recognized as a contributor to skin diseases like atopic dermatitis (AD) and psoriasis. Although traditionally AD and psoriasis have been viewed as having opposing immunologic findings, recent evidence suggests an overlap in ceramide-family lipid production in the protection against symptoms. We recently identified that specific environmental pollutants may drive dysbiosis through direct suppression of ceramide-family lipids produced by health-associated skin bacteria in atopic dermatitis (AD). We further demonstrated that one such bacteria, Roseomonas mucosa, generated significant clinical improvement in AD lasting beyond active treatment via lipid-mediated modulation of tumor necrosis factor (TNF) signaling. To assess the potential preclinical benefit of R. mucosa in psoriasis we assessed for direct effects on surface TNF signaling in cell cultures and identified direct effects on the TNF axis. We also identified preclinical efficacy of R. mucosa treatment in the imiquimod mouse model of psoriasis. Finally, we expanded our previous environmental assessment for psoriasis to include more traditional markers of air quality and found a strong association between disease rates and ambient carbon monoxide (CO), nitrogen dioxide (NO2), and particulate matter (PM). At the current stage this work is speculative but does support consideration of further preclinical models and/or clinical assessments to evaluate any potential for therapeutic benefit through microbial manipulation and/or environmental mitigation.