Respiratory Sensitization Research Articles

Peculiarities of the etiological spectrum of household allergens

The aim of the study was to study the range of substances that cause respiratory sensitization in adults and children living in Dnipro as of 2019.
 Materials and research methods. Enzyme-linked immunosorbent assay was used to study the serum of venous blood, which determined the specific IgE of up to 9 allergens that are most common in the home. Kits for quantification of allergen-specific IgE from Vitrotest Specific-IgE, Ukraine were used. Conducted allergy diagnosis for 380 people with certain features of allergy history of various types of allergies, who went to the laboratory to specify the etiological root cause of their disease.
 Research results. As a result of the analysis of the received data the distribution of allergens on their prevalence among the population of Dnipro was established. The degree of hypersensitivity to each specific allergen and their ability to cross-react with each other was determined. Among the allergens of the household panel, the most dangerous were allergens of molds, which caused a sensitization reaction in 292 people, which was 76.8 % of all surveyed. The top three (in prevalence) of household allergens included: cat epithelium, which caused sensitization in 125 people (32.9 %) and Derm mite. Farinae, sensitivity to which was found in 117 patients (30.7 %). The share of inadequately strong allergopathological reactions is one third of all examined and prevails in people with sensitization to allergic agents of the household panel such as cat epithelium, Derm mite. Farinae and Derm. Pteronyssinus. Hyperractivity to fungi of the genus Candida and mold has been found in 9–12 % of people. The lowest severity of sensitization was observed in the epithelium of the dog and house dust, and low sensitivity in the reactivity structure of allergopathological reactions was observed for allergens of the epidermal group (down and feathers of poultry) and cockroaches. The development of cross-reactions took place between allergens of epidermal origin: there was a hypersensitivity to the hair and epithelium of dogs and cats (r=0.94, P˂0.01), poultry feathers and cockroaches (r=0.99, P˂0.01). This association of cross-reactions is possible, given the theory of minor and major proteins, and is due to their similarity: the similarity of the inclusion in the allergen structures of specific forms of molecules inherent in both allergic agents that may have allergy-stimulating effects.
 Conclusions. Cross-linking between several types of related allergens is the best way to further investigate this issue. It makes sense to include in the laboratory study a molecular method for the determination of major and minor proteins in the case of the greatest relationship to determine not only a specific allergen as an etiological factor, but also a specific sensitizing protein that is part of them. This is of great importance for subsequent immunotherapy when the removal of only one (major) protein agent can reduce the risk of susceptibility reactions to several types of allergens

Assessment of the feed additive consisting of naringin for all animal species for the renewal of its authorisation (HealthTech Bio Actives, S.L.U. (HTBA)).

Following a request from the European Commission, the EFSA Panel on Additives and Products or Substances used in Animal Feed (FEEDAP) was asked to deliver a scientific opinion on the assessment of the application for the renewal of authorisation of naringin as a sensory additive for all animal species. The applicant provided data demonstrating that the additive currently in the market complies with the conditions of authorisation. The FEEDAP Panel confirms that the use of naringin under the current authorised conditions of use is safe for the target species, the consumers and the environment. Naringin does not cause severe irritation or corrosion to eyes, is not irritant to the skin and is not classified as a dermal sensitiser. The FEEDAP Panel cannot conclude on the possible respiratory sensitisation of the additive, due to the lack of data. There was no need for assessing the efficacy of the additive in the context of the renewal of the authorisation.

Evaluation of animal toxicity studies with diisocyanates regarding presence of thresholds for induction and elicitation of respiratory allergy by quantitative weight of evidence.

Animal toxicity studies on diisocyanates were evaluated using quantitative weight of evidence (QWoE) to test the hypothesis that the dose-response curve shows a threshold for the induction and/or elicitation of respiratory sensitization. A literature search identified 59 references that included at least two concentration groups of the diisocyanate and a vehicle-exposed concurrent control in the study design. These studies were subjected to a QWoE-assessment applying scoring criteria for quality and relevance/strength of effects relevant to the selected endpoint of respiratory sensitization. Overall, the studies assessing dose/concentration-response for diisocyanates with the endpoint, respiratory sensitization, were heterogenous regarding study design, animal models used, endpoints assessed, and quality. Only a limited number of the studies subjected to the QWoE-assessment allowed drawing conclusions about possible thresholds for respiratory sensitization. Highest quality and relevance/strength of effects scores were obtained by a series of studies specifically designed to investigate a potential threshold for elicitation of respiratory sensitization in the Brown Norway (BN) rat. These studies applied an elaborate study design to optimize induction of respiratory sensitization and reduce interference by respiratory tract irritation. In summary, the available studies provided moderate to good support for the existence of a threshold for elicitation and limited to moderate support for a threshold regarding induction of respiratory allergy by diisocyanates in experimental animals. However, a quantitative extrapolation of threshold values established in rodents to humans remains complex.

The effects of secondhand smoke on respiratory pathology, sensitization and development of allergic diseases in young children (literature review)

The prevalence of active smoking in Ukraine significantly exceeds the worldwide average, which is certainly a risk factor for children to be exposed to secondhand smoke. The article provides literature data and presents a modern view on the problem of secondhand tobacco smoke impact on the child population. In pediatric practice, the pathological impact of secondhand smoke on the child’s health is significant at the stage of its fetal development. Historical data convincingly prove the connection between the antenatal effect of secondhand smoke and the increased risk of perinatal losses and risks of pregnancy — miscarriage, stillbirth, and premature birth. As early as the 1960s and 1970s, scientific evidence was obtained for an association between the effects of tobacco smoke and the risk of sudden infant death syndrome. Children are most vulnerable to the negative effects of tobacco smoke at an early age because they have closer and longer contact with their parents, especially their mothers. Many studies have found an association between the effects of secondhand smoke and airway pathology (bronchitis, pneumonia), as well as an increase in the severity of respiratory syncytial viral infection (bronchiolitis). Numerous literature data indicate an association between the effect of passive smoking and the frequency and severity of oral cavity (dental caries) and middle ear (recurrent and chronic otitis, middle ear effusion) pathology. Many studies have shown the effects of secondhand smoke on the development and severity of bronchial asthma in children, but scientific data on the causal relationship of tobacco smoke with other allergic diseases (atopic dermatitis, allergic rhinitis, and food allergies), which are common in young children and preceded bronchial asthma in the "atopic march, are more limited and contradictory. The literature was searched using the PubMed database.

A novel coculture system for assessing respiratory sensitizing potential by IL-4 in T cells.

Although several in vitro assays that predict the sensitizing potential of chemicals have been developed, none can distinguish between chemical respiratory and skin sensitizers. Recently, we established a new three-dimensional dendritic cell (DC) coculture system consisting of a human airway epithelial cell line, immature DCs derived from human peripheral monocytes, and a human lung fibroblast cell line. In this coculture system, compared to skin sensitizers, respiratory sensitizers showed enhanced mRNA expression in DCs of the key costimulatory molecule OX40 ligand (OX40L), which is important for T helper 2 (Th2) cell differentiation. Herein, we established a new two-step DC/T cell coculture system by adding peripheral allogeneic naïve CD4+ T cells to the DCs stimulated in the DC coculture system. In this DC/T cell coculture system, model respiratory sensitizers, but not skin sensitizers, enhanced mRNA expression of the predominant Th2 marker interleukin-4 (IL-4). To improve the versatility, in place of peripheral monocytes, monocyte-derived proliferating cells called CD14-ML were used in the DC coculture system. As in peripheral monocytes, enhanced mRNA expression of OX40L was induced in CD14-ML by respiratory sensitizers compared to skin sensitizers. When these cell lines were applied to the DC/T cell coculture system with peripheral allogeneic naïve CD4+ T cells, respiratory sensitizers but not skin sensitizers enhanced the mRNA expression of IL-4. Thus, this DC/T cell coculture system may be useful for discriminating between respiratory and skin sensitizers by differential mRNA upregulation of IL-4 in T cells.

Evaluation of proteins in natural rubber latex gloves and pulmonary function amongst female nurses in two tertiary hospitals in southern, Thailand.

Inhaled natural rubber latex (NRL) allergens in a healthcare environment can cause NRL sensitization and reduce pulmonary functions. To determine the amount of proteins and the effects of NRL gloves on the pulmonary functions of female nurses in two hospitals in the southern Thailand. The study included 340 female nurses from two hospitals in which self-reported information and a blood sample were collected. NRL sensitization was determined by using a solid-phase enzyme-labeled fluoroenzyme-immunoassay for anti-NRLIgE antibodies. Proteins in NRL gloves were measured by a modified Lowry method. Pulmonary function was measured by a spirometer. The prevalences of respiratory effects self-attributed to NRL glove use and of NRL sensitization were 6.5 and 4.7%, respectively. Four of the 16 sensitized nurses reported respiratory symptoms. NRL sensitized nurses had lower forced expiratory flow (FEF25-75% predicted value) than those who were non-sensitized (Adj. difference = -12.56, 95% CI = -24.41 to -0.70). Furthermore, examination gloves contained protein levels in the range of 111-250 mg/dm2. Difference types of NRL glove contained with different amount of proteins.NRL sensitization was more prevalent in nurses with high concentrations of proteins in NRL gloves (p = 0.04). Sensitization to NRL was associated with a decrease in FEF25-75% predicted value, indicating narrowing of the small airways of the lung. Use of gloves with low proteins can reducing NRL allergen exposure in these hospitals, which may reduce the risk of developing respiratory problems and NRL sensitization.

Do aggravating rhinologic symptoms at work indicate occupational exposure? A cross-sectional outpatient clinic study.

Air impurities can exacerbate or cause rhinologic diseases. However, only a few studies have assessed rhinologic patients' symptoms at work. This study surveys the impact of work on rhinology clinic patients' quality of life in relation to work-related respiratory exposures. In addition, we surveyed patients' sick leave periods. We recruited adult employed rhinology patients referred to the otorhinolaryngology clinic. A total of 177 patients were included. We collected data on patients' medical history, rhinologic disease-specific and generic quality of life, current or most recent job title, a description of current work, nasal symptoms, possible worked-related symptom triggers and sick leave periods during the preceding year. In total, 101 (57.1%) patients reported exacerbated rhinologic symptoms at work and reported more severe rhinologic disease and a lower disease-specific quality of life compared to non-work-related rhinologic patients (P = 0.008). A minority, 24.3% of our patients were exposed to any specific occupational respiratory sensitizer or irritant at work. The mean sick leave period due to rhinologic disease was 7.7 days per year. Exposure to specific occupational sensitizers or irritants did not associate with increasing symptoms at work or quality of life amongst our patients. Most rhinology patients reported exacerbated symptoms at work. They appeared to be more symptomatic than the rest of the patients and, therefore, possibly hyperreactive to unspecific respiratory triggers at work. Rhinologic diseases caused our patients a marked burden with high work absenteeism.

Plant pollination calendar of the Southern Сoast of Crimea and elimination therapy at the resort

BACKGROUND: Plant pollen can influence the climatotherapy and elimination therapy results of respiratory allergic diseases. Flora diversity and the poorly studied prevalence and etiology of pollinosis on the Southern Coast of Crimea determine the need for aeropalinological studies of this region to optimize the treatment and rehabilitation of patients with respiratory sensitization. AIMS: To determine the potentially unfavorable periods for the stay of patients with pollen sensitization on the Southern Coast of the Crimea and develop a plant pollination calendar of the Yalta resort MATERIALS AND METHODS: The research was conducted in the coastal and foothill area of Yalta in 20112013. The study determined the content of pollen in plants that are passively deposited from the air onto the glasses-traps using the gravimetric method. The taxonomic belonging of the pollen was established by collecting the plant pollen of the Southern Coast of Crimea. RESULTS: A total of 19 pollen taxa have been identified in the air of Yalta, of which 10 had sensitizing properties. Cypress (49.7% of pollen of the average annual amount) and most deciduous trees with allergenic pollen (4.7% of pollen) were intensively pollinated in MarchApril, Poaceae grasses (1.6% of pollen) in May, and weed grasses (1.6% of pollen) in late August to early September. Birch and alder pollen was not detected. On average, 2.2 times less pollen was detected in the coastal area air of the resort than in the foothill area. The plant pollination calendar of the Yalta resort has been developed. CONCLUSIONS: The intensive cypress pollination period in MarchApril is least favorable for patients with pollen sensitization to stay on the Southern Coast of the Crimea. Poaceae in May and weeds in late August to early September create an insignificant pollen load. A plant pollination calendar has been developed to predict unfavorable aeropalinological periods and optimize the treatment and rehabilitation of patients with pollen sensitization in the Yalta resort. The best conditions for the treatment and rehabilitation of patients with respiratory allergies have been identified in the coastal area of the resort. The absence of birch and alder pollen in the air contributes to the elimination therapy at the Yalta resort.

A new cytometry-based method reveals an accumulation of Nrf2 in dendritic cells exposed to two respiratory sensitizers.

The mechanisms underlying chemical respiratory sensitization are incompletely understood. One of the major cell types involved in this pathology are dendritic cells. In this study, the mechanisms of the NRF2-Keap1 pathway were studied using a bone marrow-derived dendritic cell model exposed to two respiratory sensitizers: ammonium hexachloroplatinate (HCP) and ammonium tetrachloroplatinate (ATCP). Expression levels for two Nrf2-regulated genes, hmox1 and srxn1, were analyzed by real time-quantitative polymerase chain reaction. A flow cytometry-based method was also developed to measure intracellular Nrf2 accumulation in dendritic cells following exposure. Exposure to HCP and ATCP increased both hmox1 and srxn1 gene expression, and was associated with accumulation of Nrf2 protein in cells. Overall, these results show that the respiratory sensitizers, in addition to skin sensitizers, can also induced markers associated with NRF2-Keap1 pathway activation in dendritic cells. This study contributes to a better understanding of the adverse outcome of respiratory sensitization.

Safety and efficacy of feed additives consisting of expressed sweet orange peel oil and its fractions from Citrus sinensis (L.) Osbeck for use in all animal species (FEFANA asbl).

Following a request from the European Commission, the EFSA Panel on Additives and Products or Substances used in Animal Feed (FEEDAP) was asked to deliver a scientific opinion on the safety and efficacy of expressed sweet orange oil and its fractions obtained from the fruit peels of Citrus sinensis (L.) Osbeck, when used as sensory additives (flavourings) in feed and water for drinking for all animal species. The presence of perillaldehyde was identified as a source of potential concern. However, in target species fed citrus by‐products as part of daily feed, the use of the expressed orange oil and its fractions was not expected to increase the exposure to perillaldehyde to a relevant extent (< 10%). For dogs, cats, ornamental fish and ornamental birds not normally exposed to citrus by‐products, no conclusion can be drawn. For the other species, the FEEDAP Panel concluded that the additives under assessment are safe at the maximum proposed use levels in complete feed. The FEEDAP Panel considered that the use in water for drinking is safe provided that the total daily intake of the additive does not exceed the daily amount that is considered safe when consumed via feed. No concerns for consumer safety were identified following the use of the additives up to the maximum proposed use level in feed. The additives under assessment should be considered as irritants to skin and eyes, and as skin and respiratory sensitisers. The use of the additives under the proposed conditions of use in animal feed was not expected to pose a risk for the environment. Expressed orange oil and its fractions were recognised to flavour food. Since their function in feed would be essentially the same as that in food, no further demonstration of efficacy was considered necessary.

An outbreak of work-related asthma and silicosis at a US countertop manufacturing and fabrication facility.

Outbreaks of severe silicosis have affected workers who fabricate artificial stone countertops. Work-related asthma (WRA) has not been a prominent feature of those prior outbreaks. This report describes an outbreak of WRA and silicosis at a facility that manufactures and fabricates chemical-resistant countertops comprised of sand, epoxy resin, and phthalic anhydride (PA), a known respiratory sensitizer. The multi-disciplinary investigation included clinical examinations of workers, an industrial hygiene survey with qualitative and quantitative exposure assessments, and a cross-sectional questionnaire. Engineering controls and personal protective equipment were inadequate. Some workers were exposed to PA or silica above permissible exposure limits established by the Occupational Safety and Health Administration (OSHA). Clinical and epidemiologic investigations identified 16 workers with confirmed or suspected WRA. Two years later, after OSHA began to enforce its new silica standards, 12 workers received medical surveillance for silicosis. Of these 12 workers, four (33.3%) were diagnosed with silicosis based on abnormal chest computed tomography examinations. Artificial stone countertop workers can develop asthma or silicosis. Risk of asthma may be highest in workers exposed to asthmagens such as PA and epoxy resins while manufacturing the artificial stone material.

Trimellitic anhydride facilitates transepithelial permeability disrupting tight junctions in sinonasal epithelial cells

Trimellitic anhydride (TMA) is a chemical agent classified as a low molecular weight (LMW) agent causing occupational rhinitis (OR) or asthma. Although TMA is recognized as a respiratory sensitizer, the direct and non-immunologic effects of TMA remain unclear. Air- liquid interface (ALI) cultured human nasal epithelial cells (HNECs) derived from control subjects were treated with TMA, followed by measurement of the transepithelial electrical resistance (TEER), paracellular permeability of fluorescein isothiocyanate (FITC)-dextran and immunofluorescence of tight junction proteins claudin-1 and zonula occludens-1 (ZO-1). The cytotoxicity of TMA was evaluated by lactate dehydrogenase (LDH) assay. TMA at concentrations of 2 and 4 mg/mL significantly reduced the TEER within 10 min (p = 0.0177 on 2 mg/mL; p < 0.0001 on 4 mg/mL). The paracellular permeability of FITC-dextran was significantly increased upon challenge with 4 mg/mL TMA for 3 h (p = 0.0088) and 6 h (p = 0.0004). TMA treatment induced a reduction in the fluorescence intensity of claudin-1 and ZO-1 in a dose-dependent manner. LDH assay revealed 4 mg/mL TMA induced cytotoxicity only after 6 h incubation, while 1 or 2 mg/mL TMA caused no cytotoxicity. Our results suggest that TMA has a potential to penetrate the epithelial barrier by disrupting claudin-1 and ZO-1, indicating an important role for sensitization and OR development.

Fractional exhaled nitric oxide levels in relation to work-related respiratory burden and sensitization to wheat flour and multigrain in bakers.

BackgroundWork‐related lower airway symptoms (WR‐LAS), rhinitis (WRR), and asthma (WRA) are very common among bakers, due to airborne exposure to wheat flour and multigrain. Limited data is available regarding fractional exhaled nitric oxide (FeNO) in bakers in relation to respiratory burden and occupational sensitization in a real‐life situation.ObjectiveTo analyze FeNO levels in relation to WRR, WR‐LAS, and WRA with regard to allergic sensitization to occupational allergen in bakers.MethodsCross‐sectional, observational study of 174 bakers employed in traditional small bakeries in the Verona District. Subjects did FeNO measurements, spirometry, methacholine challenge, and skin prick test to common inhalant aeroallergens and bakeries occupational allergens.ResultsFeNO levels were higher in subjects sensitized to occupational allergens compared with bakers not sensitized to occupational allergens (22.8 ppb (18.9, 27.6) vs. 12.0 ppb (9.9, 14.5), p < 0.05). FeNO levels were higher in bakers with WRR and occupational sensitization (25.4 (20.6, 31.3)) than in bakers with WRR without occupational sensitization compared and bakers without respiratory burden (13.4 (9.6, 18.6) and 11.9 (9.8, 14.5), both p < 0.001). Similar findings were found for WR‐LAS with regard to the same categories (31.2 (24.1, 40.4) vs 13.3 (11.4, 15.6) and 15.3 (8.5, 27.5), p < 0.001 and p = 0.005). Bakers with WRA, with or without occupational allergic sensitization, had higher levels of FeNO than bakers without respiratory burden (both p ≤ 0.001). These findings were consistent after adjustments for gender, age, height, weight, smoking, and sensitization to common inhalant aeroallergens and lung function.ConclusionsWRR and lower airway symptoms in bakers sensitized to occupational allergens relate to increased FeNO. Our study suggests that FeNO is associated with work‐related allergic inflammation in occupational sensitized bakers, but future studies are needed to assess how FeNO should be integrated in the diagnostic work‐up of occupational disease in bakers.

The Age, Sex, and Geographical Distribution of Self-Reported Asthma Triggers on Children With Asthma in China.

Background: Asthma can be exacerbated by many triggers, and the heterogeneity of asthma triggers is clear among children with asthma. This study describes asthma triggers using a large-scale electronic dataset from the smartphone-based Chinese Children's Asthma Action Plan (CCAAP) app and aims to examine the difference in asthma triggers among different subgroups of children with asthma.Methods: Data from the smartphone-based CCAAP app between February 22, 2017, and November 23, 2020, were reviewed, and children with asthma who reported their asthma triggers were enrolled. Eight common asthma triggers were listed in the software: upper respiratory infection (URI), allergen sensitization, exercise, emotional disturbances, pungent odors, air pollution/smog, weather change, and tobacco smoke. We compared the incidence of asthma triggers among different subgroups (<6 years vs. 6–17 years; boy vs. girl; eastern region vs. central region vs. western region).Results: We enrolled 6,835 patients with self-reported asthma triggers. When compared by sex, boys had a higher proportion of exercise-triggered asthma than girls (boys vs. girls, 22.5 vs. 19.7%, p < 0.05). The proportion of patients <6 years of age with URI-triggered asthma was higher than that of patients 6–17 years of age (<6 vs. 6–17 years, 80.9 vs. 74.9%, p < 0.001). Patients 6–17 years of age were more likely than patients <6 years of age to report five of the asthma triggers: allergen sensitization (<6 vs. 6–17 years, 26.6 vs. 35.8%, p < 0.001), exercise (<6 vs. 6–17 years, 19.3 vs. 23.7%, p < 0.001), pungent odors (<6 vs. 6–17 years, 8.8 vs. 12.7%, p < 0.001), air pollution/smog (<6 vs. 6–17 years, 9.4 vs. 16.2%, p < 0.001), and tobacco smoke (<6 vs. 6–17 years, 3.5 vs. 5.3%, p < 0.001). In subgroups based on geographical distribution, asthma triggering of allergen sensitization was reported to be the most common in patients from the eastern region (eastern region vs. central region vs. western region, 35.0 vs. 24.6 vs. 28.0%, p < 0.001). Exercise-triggered asthma was found to be the most prevalent among patients from the central region (eastern region vs. central region vs. western region, 21.6 vs. 24.8 vs. 20.4%, p < 0.05). However, the proportion of patients with air pollution/smog as an asthma trigger was the lowest among those from the western region (eastern region vs. central region vs. western region, 14.1 vs. 14.1 vs. 10.8%, p < 0.05).Conclusion: Children with asthma present different types of asthma triggers, both allergenic and nonallergenic. Age, sex, and geographical distribution affect specific asthma triggers. Preventive measures can be implemented based on a patient's specific asthma trigger.

The perinatal use of probiotics, prebiotics, and synbiotics for the primary prevention of allergic diseases in children: A systematic review

Given the increasing prevalence of allergic diseases, as well as the extensive burden on society caused by these conditions, there is a need for strategies aimed at primary prevention. Probiotics, prebiotics, and synbiotics, when administered perinatally, have been shown to reduce the incidence of allergic diseases in children. However, there are many unanswered questions in terms of the optimal timing, duration, dosage, and composition of probiotics, prebiotics, or both (synbiotics). The objective of this systematic review is to audit the current medical literature on the effects of the perinatal administration of probiotics, prebiotics or synbiotics for the primary prevention of allergic disease in childhood. PubMed, Web of Science, and SCOPUS medical databases were systematically searched for relevant studies, published from the year 2000 to May 2020, assessing the effects of probiotics, prebiotics or synbiotics administered during the perinatal period on the prevention of allergy in children. A total of 38 studies met inclusion criteria for the systematic review. The use of probiotics, when administered during the third trimester of pregnancy and continued for the first three to six months of life, consistently reduced the incidence of atopic dermatitis, but not allergic respiratory disease or allergic sensitization. Mixtures of probiotics, in a dose of 109 to 1010 cfu/day, were most effective at reducing the incidence of atopic dermatitis. Prebiotics, administered in the postpartum period, with or without the perinatal administration of probiotics, did not consistently reduce the incidence of allergic diseases in children. Probiotics started during the third trimester of pregnancy and continued for the first three months of life, administered as a mixture of different species in the amount of 109 to 1010 cfu/day, reduces the incidence of atopic dermatitis in children. There is no consistent protective effect on the development of allergic respiratory diseases or allergic sensitization. The addition of prebiotics, other than those obtained from breastfeeding, do not appear to provide additional protection against the development of allergic disease in children.

A BMDC assay for studying the respiratory sensitisation mechanism: first results with platinum salts.

A BMDC assay for studying the respiratory sensitisation mechanism: first results with platinum salts.

Chemical Modifications Induced by Phthalic Anhydride, a Respiratory Sensitizer, in Reconstructed Human Epidermis: A Combined HRMAS NMR and LC-MS/MS Proteomic Approach.

Chemical skin and respiratory allergies are becoming a major health problem. To date our knowledge on the process of protein haptenation is still limited and mainly derived from studies performed in solution using model nucleophiles. In order to better understand chemical interactions between chemical allergens and the skin, we have investigated the reactivity of phthalic anhydride 1 (PA), a chemical respiratory sensitizer, toward reconstructed human epidermis (RHE). This study was performed using a new approach combining HRMAS NMR to investigate the in situ chemical reactivity and LC-MS/MS to identify modified epidermal proteins. In RHE, the reaction of PA appeared to be quite fast and the major product formed was phthalic acid. Two amide type adducts on lysine residues were observed and after 8h of incubation, we also observed the formation of an imide type cyclized adducts with lysine. In parallel, RHE samples topically exposed to phthalic anhydride (13C)-1 were analyzed using the shotgun proteomics method. Thus, 948 different proteins were extracted and identified, 135 of which being modified by PA, i.e., 14.2% of the extracted proteome. A total of 211 amino acids were modified by PA and validated by fragmentation spectra. We thus identified 154 modified lysines, 22 modified histidines, 30 modified tyrosines, and 5 modified arginines. The rate of modified residues, as a proportion of the total number of modifiable nucleophilic residues in RHE, was rather low (1%). At the protein level, modified proteins were mainly type I and type II keratins and other proteins which are abundant in the epidermis such as protein S100A, Caspase 14, annexin A2, serpin B3, fatty-acid binding protein 5, histone H2, H3, H4, etc. However, the most modified protein, mainly on histidine residues, was filaggrin, a protein that is of low abundance (0.0266 mol %) and rich in histidine.

Epigenetic Markers Are Associated With Differences in Isocyanate Biomarker Levels in Exposed Spray-Painters.

Isocyanates are respiratory and skin sensitizers that are one of the main causes of occupational asthma globally. Genetic and epigenetic markers are associated with isocyanate-induced asthma and, before asthma develops, we have shown that genetic polymorphisms are associated with variation in plasma and urine biomarker levels in exposed workers. Inter-individual epigenetic variance may also have a significant role in the observed biomarker variability following isocyanate exposure. Therefore, we determined the percent methylation for CpG islands from DNA extracted from mononuclear blood cells of 24 male spray-painters exposed to 1,6-hexamethylene diisocyanate (HDI) monomer and HDI isocyanurate. Spray-painters’ personal inhalation and skin exposure to these compounds and the respective biomarker levels of 1,6-diaminohexane (HDA) and trisaminohexyl isocyanurate (TAHI) in their plasma and urine were measured during three repeated industrial hygiene monitoring visits. We controlled for inhalation exposure, skin exposure, age, smoking status, and ethnicity as covariates and performed an epigenome-wide association study (EWAS) using likelihood-ratio statistical modeling. We identified 38 CpG markers associated with differences in isocyanate biomarker levels (Bonferroni < 0.05). Annotations for these markers included 18 genes: ALG1, ANKRD11, C16orf89, CHD7, COL27A, FUZ, FZD9, HMGN1, KRT6A, LEPR, MAPK10, MED25, NOSIP, PKD1, SNX19, UNC13A, UROS, and ZFHX3. We explored the functions of the genes that have been published in the literature and used GeneMANIA to investigate gene ontologies and predicted protein-interaction networks. The protein functions of the predicted networks include keratinocyte migration, cell–cell adhesions, calcium transport, neurotransmitter release, nitric oxide production, and apoptosis regulation. Many of the protein pathway functions overlap with previous findings on genetic markers associated with variability both in isocyanate biomarker levels and asthma susceptibility, which suggests there are overlapping protein pathways that contribute to both isocyanate toxicokinetics and toxicodynamics. These predicted protein networks can inform future research on the mechanism of allergic airway sensitization by isocyanates and aid in the development of mitigation strategies to better protect worker health.

Asthma-inducing potential of 28 substances in spray cleaning products-Assessed by quantitative structure activity relationship (QSAR) testing and literature review.

Exposure to spray cleaning products constitutes a potential risk for asthma induction. We set out to review whether substances in such products are potential inducers of asthma. We identified 101 spray cleaning products for professional use. Twenty‐eight of their chemical substances were selected. We based the selection on (a) positive prediction for respiratory sensitisation in humans based on quantitative structure activity relationship (QSAR) in the Danish (Q)SAR Database, (b) positive QSAR prediction for severe skin irritation in rabbits and (c) knowledge on the substances' physico‐chemical characteristics and toxicity. Combining the findings in the literature and QSAR predictions, we could group substances into four classes: (1) some indication in humans for asthma induction: chloramine, benzalkonium chloride; (2) some indication in animals for asthma induction: ethylenediaminetetraacetic acid (EDTA), citric acid; (3) equivocal data: hypochlorite; (4) few or lacking data: nitriloacetic acid, monoethanolamine, 2‐(2‐aminoethoxy)ethanol, 2‐diethylaminoethanol, alkyldimethylamin oxide, 1‐aminopropan‐2‐ol, methylisothiazolinone, benzisothiazolinone and chlormethylisothiazolinone; three specific sulphonates and sulfamic acid, salicylic acid and its analogue sodium benzoate, propane‐1,2‐diol, glycerol, propylidynetrimethanol, lactic acid, disodium malate, morpholine, bronopol and benzyl alcohol. In conclusion, we identified an asthma induction potential for some of the substances. In addition, we identified major knowledge gaps for most substances. Thus, more data are needed to feed into a strategy of safe‐by‐design, where substances with potential for induction of asthma are avoided in future (spray) cleaning products. Moreover, we suggest that QSAR predictions can serve to prioritise substances that need further testing in various areas of toxicology.

Atopic respiratory diseases and IgE sensitization are associated with leukocyte subset concentrations in 14,440 blood donors

Background and aimsAllergic rhinitis (AR), allergic conjunctivitis (AC), and asthma are characterized by activation of the immune system. The aim of this study was to explore the long-term association between AR, AC, asthma, and specific immunoglobulin E (IgE) and blood platelet and leukocyte differential counts. Material and methodsIn the Danish Blood Donor Study, 14,440 participants from Central Denmark Region had platelet and leukocyte differential counts available and completed a questionnaire regarding AR, AC, and asthma. Of these participants, 8485 were tested for IgE to inhalation allergens. ResultsThe prevalence of AR, AC, asthma, and IgE sensitization was 19%, 15%, 9%, and 29%, respectively. AR, AC, asthma, wheeze, and IgE sensitization was associated with increased blood eosinophil concentration even in IgE sensitized participants who did not report any allergy or asthma. The strongest associations were observed for participants with current disease. We found no differences in eosinophil concentration between months without symptoms and months with symptoms of AR and asthma. ConclusionAR, AC, asthma, wheezing, and IgE sensitization to inhalation allergens are associated with increased eosinophil concentration. This may reflect a persistent inflammation even in periods without symptomatic disease.