Thymic Stromal Lymphopoietin (TSLP) 在過敏免疫機制中可促進TH2細胞功能，而Runt Related Transcription Factor 3 (RUNX3) 影響FOXP3合成進而促進調節性T細胞增加。鄰苯二甲酸酯類 (Phthalate esters, PAEs) 廣泛存在於塑膠製品中以增加其彈性與柔軟度，研究已指出該暴露與孩童過敏及氣喘的發生有關。過去研究顯示PAEs之一DBP暴露會增加小鼠之TSLP蛋白，且輔助 (adjuvant) 氣喘及過敏的疾病表現。除此外，DNA甲基化被認為是環境與基因交互作用的一種關鍵性表現，而研究亦顯示PAEs代謝物可改變DNA甲基化程度。因此，本研究擬探討孩童PAEs暴露、TSLP及RUNX3之DNA甲基化程度、以及過敏性疾病/症狀表現三者之間的關係，以嘗試瞭解暴露PAEs導致過敏性疾病之內在分子生物機制。
研究對象來自研究團對前期於大臺南地區學齡前孩童過敏及呼吸道疾病之普查研究，共90位孩童具完整之血液樣本、健康診斷資訊、住家環境樣本及尿液中PAEs代謝物濃度調查。本研究萃取mRNA以瞭解基因表現量。DNA甲基化的分析，TSLP部分以pyrosequencing進行啟動子上五個位點的甲基化程度測定，而RUNX3則是以qMSP進行啟動子-308到-288 CpG島上位點之甲基化程度量測。最後以GLM考量其他影響因子進行統計分析。
TSLP啟動子-809、-775位點及RUNX3之甲基化程度皆與mRNA表現呈現負相關；考量個人因素及其他環境暴露後，ln-BBzP及ln-MEP濃度皆對TSLP-775位點之甲基化程度具影響 (β= -0.84, p=0.018；β= 1.02, p=0.004)，且甲基化每上升1%，孩童在清晨出現呼吸道症狀之風險減少13% (OR=0.87, 95%CI = 0.771-0.991)。RUNX3之結果在校正干擾因子後，發現尿液中MEP濃度越高，DNA甲基化程度越低，且Ln轉換的甲基化每上升1個單位，氣喘及過敏性疾病之風險會增加66% (OR=1.66, 95%CI=1.13-2.427)。
本研究結果指出暴露於沉降灰塵中BBzP將減少TSLP之甲基化程度，增加呼吸道症狀出現的風險。這項研究之結果有助於了解與PAEs有關的早期生物效應的病因學，並可作為早期預防或治療介入策略擬訂的重要參考。

Dysregulated expressions of Thymic Stromal Lymphopoietin (TSLP) have been linked to the presence of asthma and allergic disease. Runt Related Transcription Factor 3 (RUNX3) protein is related to direct the differentiation of naive CD4+T cells into different subsets of helper and regulatory T cells. Research has shown that exposure to the phthalate esters (PAEs), one widely used plasticizer, are associated with the development of respiratory and allergic morbidities. Previous study showed that DBP, a kind of phthalates, is sufficient for TSLP upregulation in the skin. In addition, it has been shown that phthalate exposures are associated with the changes of environmentally-induced DNA methylation, which might cause phenotypic heterogeneity. Thus, this study aimed to examine the DNA methylation of RNX3 and TSLP to verify the potential mechanism between the phthalate exposure and outcomes of interest. A total 90 subjects were randomly recruited from the previous population follow-up study in southern Taiwan. Each of them had detailed health examination and the exposure profile in household. Their serum samples were used to analyse methylation levels on the promoters of RUNX3 and TSLP (five sites) via the quantitative methylation-specific PCR (qMSP) and pyrosequencing, respectively. The results showed that every increase of ln-BBzP in settle dusts was associated with the decrease of 0.84% methylation level on the TSLP promoter -775 (β= -0.84, p=0.018) after considering potential confounders. At the same time, 13% decrease of the risk for the presence of children’ respiratory symptom in the morning for every percentage increase of methylation level (OR=0.87, 95%CI = 0.771-0.991). On the other hand, the RUNX3 met% was found to associate with the Ln-MEP levels after adjusting for confounder factors. Significantly increased level of ln-RUNX3 met% was associated with test case subjects (allergic or asthmatic children) (OR=1.66, 95%CI=1.13-2.427). In conclusion, exposure to phthalate in settled dust might increase the allergic symptom mediated through the decrease of TSLP methylation. Metabolites of phthalate in urine might decrease RUNX3 methylation level. The results of this study could contribute to the understanding of the etiology of phthalate-related biomarker and may initiate new strategies for an early prevention or a therapeutic intervention.

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