Emerging Risk: Intranasal Tin Exacerbates Allergic Rhinitis in Humans and Mice

Intranasal exposure to lead (Pb) from airborne particles worsens Japanese cedar pollinosis (JCP) [1, 2], suggesting that components of airborne particles influence the severity of allergic rhinitis (AR) symptoms. Since homologous elements share similar chemical properties [3], tin (Sn), a homolog of Pb, may also affect these symptoms. Indeed, intraperitoneal Sn exposure has been shown to increase bronchial eosinophils, IL-5, and serum IgE in a murine model of asthma, a disease closely related to AR [4]. However, the effect of airway Sn exposure under conditions simulating human exposure remains unclear, despite the fact that the airways are the key sites of allergic inflammation directly exposed to airborne Sn in individuals with AR and asthma. To clarify the role of intranasal Sn from air pollutants in AR, we performed a cross-sectional epidemiological study to assess the Sn levels in the nasal epithelial lining fluid (nELF) and serum and symptom scores of patients with JCP (n = 44) and controls (n = 57) during the pollen season (Table S1). Measurements were performed using inductively coupled plasma-mass spectrometry (ICP-MS), as previously described [1-3]. Subsequently, longitudinal studies in ovalbumin (OVA)-sensitized AR model mice were conducted to examine the causal inferences suggested by the cross-sectional human study. A laser ablation system coupled with ICP-MS (LA-ICP-MS) further enabled the first high-resolution analysis of Sn distribution in both the upper and lower airways. Univariate analysis showed that the mean Sn levels in the nELF and serum during the season were 3.4- and 1.4-fold higher, respectively, in patients than in controls (Figure 1A,B). Multivariate analysis revealed a significant positive association between the symptom scores and Sn levels in the nELF, but not in the serum (Figure 1C,D). Allergic and non-allergic mice received intranasal drops containing an estimated human-equivalent Sn dose (0.52 μg Sn), based on the maximum Sn level in patients' nELF. This Sn exposure significantly exacerbated symptoms immediately after the final nasal challenge in allergen-induced allergic mice (Figure 2A–C). These epidemiological and experimental findings suggest that elevated intranasal Sn levels exacerbate allergen-induced AR. The similar Sn levels in the nELF and serum between mice and humans suggest that allergic and non-allergic mice effectively model the Sn distribution in patients and controls. In allergen-induced allergic mice, Sn treatment increased Sn levels in the nELF, serum, and nasal mucosa by 7.9-fold (2.76/0.35), 3.5-fold (1.21/0.35), and 7.1-fold (1.07/0.15), respectively, 24 h after the final nasal challenge compared with those in untreated mice (Figure 2D–G). Such differences were not seen in non-allergic mice. These findings raise the question of why allergic individuals, both humans and mice, show higher intranasal Sn levels in both the nELF and mucosa than non-allergic individuals, despite having similar levels of intranasal Sn exposure. Mucin-secreting goblet cell density was 2.4-fold higher in Sn-treated than in untreated allergic mice. The results of the LA-ICP-MS analysis showed 67% colocalization of Sn signals with mucin in Sn-treated, but not in untreated, allergic mice (Figure 2H–J). These findings suggest that Sn-induced mucin prolongs intranasal Sn retention, raising the Sn levels in allergic individuals under comparable exposure levels. Contrary to the above hypothesis, inhaled PM2.5 containing high Sn levels reportedly bypasses the nasal cavity and deposits predominantly in the lungs in healthy individuals [4-6]. To resolve this discrepancy, a more accurate exposure model simulating human conditions is needed, as suspended particulate matter (SPM) is a major source of human Sn exposure [5, 6]. Therefore, allergic and non-allergic mice were exposed to artificial aerosols mimicking the PM2.5 properties (Figure S1) and containing an adult human-equivalent Sn dose, based on airborne Sn levels (Table S2). An estimated total exposure of 0.02–0.03 μg Sn via PM2.5-like aerosols exacerbated the symptoms immediately after the final nasal challenge in allergen-induced allergic mice (Figure S2A–C). Ten minutes after the final challenge, Sn levels in the nELF and nasal mucosa were 2.4-fold and 2.5-fold higher, respectively, in allergic mice compared with non-allergic controls, whereas Sn levels in the bronchial ELF (bELF) and lungs were 64% and 67% lower, respectively (Figure S2D–I). The results of the ICP-MS and LA-ICP-MS analyses first indicate that airway capture of Sn from PM2.5 differs between allergic and non-allergic individuals. Unlike previous findings in healthy individuals [5, 6], a greater amount of Sn from PM2.5 appears to be retained in the nasal mucosa rather than in the lungs of individuals with allergic rhinitis. In conclusion, the results of the present epidemiological and animal studies suggest that intranasally exposed Sn is effectively trapped by mucin, which is elevated in cases of AR and further enhanced by Sn exposure, leading to higher intranasal Sn levels and symptom exacerbation in allergic individuals. Delgama ASM Nishadhi: Investigation; Resources; Formal analysis; Data curation; Writing-original draft, Shogo Sumiya: Investigation; Resources; Writing-original draft, Akira Tazaki: Methodology; Data curation; Validation; Writing-review and editing, Takumi Kagawa: Methodology; Validation, Mohamed Abdelmoneim: Data curation, Masafumi Sakashita: Resources, Kazuhiro Ogi: Resources, Shigeharu Fujieda: Resources, Shinichi Iwasaki: Validation, Masashi Kato: Conceptualization; Funding acquisition; Project administration; Supervision; Writing-review and editing. All authors have read and approved the final version of the manuscript. We appreciate the contribution of Ms. Shoko Ohnuma to the measurement of elements. The authors also acknowledge the Division for Medical Research Engineering, Nagoya University Graduate School of Medicine, for their technical support. This research was partially supported by a Grant-in-Aid for Scientific Research (B) (23H03147, 23K27837) and (C) (22K10508); Challenging Exploratory Research (25K22731); Research Activity Start-up (24K23745) and the Fund for the Promotion of Joint International Research (22KK0145), all from the Japan Society for the Promotion of Science (JSPS). Additional support was provided by the THERS New Standards Program for the Next Generation Researchers (JPMJSP2125) supported by JST SPRING as well as by the Kobayashi International Scholarship Foundation, the Asahi Glass Foundation and the Tojuro Iijima Foundation for Food Science and Technology in Japan. The authors declare no conflicts of interest. The data that support the findings of this study are available from the corresponding author upon reasonable request. Data S1: Supporting Information. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. 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