近年來，孩童氣喘、過敏性鼻炎、濕疹等過敏性疾病在世界各地之盛行率皆有逐年攀升的現象，過去已有充分之研究指出，基因遺傳以及室內外環境中各式的生物性污染物，如塵蟎、真菌孢子等，皆成為促使孩童過敏性疾病發展或增加其嚴重度的風險因子，然而，這些因子卻不能完全地解釋過敏性疾病盛行率攀升之現象。因此，在工業發展潮流之下，環境中各式新興化學物質的使用，已逐漸被視為可能的重要因素。其中，鄰苯二甲酸酯類（phthalate esters，簡稱PAEs），為一廣泛被運用在塑膠產品中來增加延展性之化學物質，在前期流行病學研究中已指出與孩童氣喘及過敏性疾病的發生有關。然而在動物實驗上，PAEs之暴露與過敏/氣喘間的機制尚未完全被確認；是否PAEs具有免疫上輔助 (adjuvant)之角色，讓人體免疫機制偏向與TH2有關之過敏反應？且其中是否透過發炎之反應來導致可能的危害？尚需進一步地釐清。因此，本研究為透過評估學齡前孩童實際PAEs的暴露量，並同時考量其他室內環境中可能的危險因子，以瞭解PAEs暴露對於血清中過敏及發炎反應相關細胞激素的影響。
研究對象篩選自前期台南地區學齡前孩童的大規模問卷普查研究。依一定的標準進行樣本的排除及納入篩選出980位具有過敏症狀與803位健康之孩童，經電話訪問後約有27%的過敏孩童與11%的健康孩童之家長同意後續的追蹤研究，因此進一步邀請至醫院由小兒專科醫師進行疾病/症狀之確診以及收集血清樣本進行相關指標的測定，此外，亦前往孩童的家裡進行居家環境調查，透過完整之問卷訪視、代表性灰塵樣本收集、空氣中生物性與化學性汙染物的採集，以瞭解孩童對於各項汙染物之暴露程度，同時亦取得孩童採樣當天的尿液樣本以評估對於各式PAEs包含DMP （代謝物MMP）、DEP（代謝物MEP）、DBP（代謝物MBP）、BBzP（代謝物MBzP）與DEHP（代謝物MEHP、MEHHP與MEOHP）的暴露程度，主要是以HPLC-MS/MS進行分析。血清之細胞激素則是以流式細胞儀分析共八種，包含與TH1 （IL-12與IFN-γ）、TH2 （IL-4、IL-5與IL-13）及發炎 （IL-6、IL-8與TNF-α）路徑有關之細胞激素濃度。最後，共有101位孩童擁有完整之暴露與健康資訊者納入後續之分析討論，首先，本研究先將所有孩童尿液中鄰苯二甲酸酯類代謝物濃度加總後分為高低暴露兩組進行比較，爾後再令孩童PAEs代謝物濃度高於中位數者 (MMP: 4.87, MEP: 12.83, MBP: 57.93, MBzP: 4.78, MEHP: 8.66, MEHHP: 42.34, MEOHP: 40.55 ng/ml )為高暴露組，反之為低暴露組，來探討在不同PAEs的暴露程度下，對於血清中細胞激素的影響。
整體研究對象的分析結果來看，代謝物總濃度為高暴露組之孩童血清中會有較高之IL-5 (高暴露組total: 1.30 vs. 低暴露組total: 0.55 pg/ml, p=0.04)與TNF-α濃度 (高暴露組total: 1.12 vs. 低暴露組total: 0.90 pg/ml, p=0.03)。而由各別PAEs之種類發現，孩童MBP與MEHP屬高暴露者，有較高IFN-γ濃度 (高暴露組MBP: 1.15 vs. 低暴露組MBP: 0.35 pg/ml, p=0.03; 高暴露組MEHP: 1.13 vs. 低暴露組MEHP: 0.35 pg/ml, p=0.04)，而屬MEHHP與MEOHP高暴露者，其IL-5 (高暴露組MEHHP: 1.30 vs. 低暴露組MEHHP: 0.55 pg/ml, p=0.02; 高暴露組MEOHP: 11.30 vs. 低暴露組MEOHP: 0.55 pg/ml, p=0.02)、IL-8 (高暴露組MEHHP: 2.15 vs. 低暴露組MEHHP: 1.96 pg/ml, p=0.02; 高暴露組MEOHP: 2.15 vs. 低暴露組MEOHP: 1.96 pg/ml, p=0.05)與TNF-α (高暴露組MEHHP: 1.25 vs. 低暴露組MEHHP: 0.90 pg/ml, p=0.01; 高暴露組MEOHP: 1.12 vs. 低暴露組MEOHP: 0.90 pg/ml, p=0.01)濃度亦顯著較高。進一步探討高、低暴露組中過敏孩童與一般孩童細胞激素濃度之差異，高暴露組的過敏孩童在MBP的代謝物分組下，血清中IL-5 (過敏組MBP: 1.36 vs. 健康組MBP: 0.55 pg/ml, p=0.01)與TNF-α (過敏組MBP: 1.40 vs. 健康組MBP: 0.35 pg/ml, p=0.001)濃度顯著的高於健康孩童，而低暴露組別中之過敏孩童在MEHP的暴露下，IL-5 (過敏組MEHP: 1.23 vs. 健康組MEHP: 0.55 pg/ml, p=0.04)濃度會較高，在MEHHP與MEOHP組別上，過敏孩童TNF-α 第75百分位濃度同樣的也會高於健康孩童 (過敏組MEHHP: 1.47 vs. 健康組MEHHP: 0.35 pg/ml, p=0.01; 過敏組MEOHP: 1.51 vs. 健康組MEOHP: 0.35 pg/ml, p=0.03)，此外，不論是在過敏孩童還是健康孩童比較上，PAEs暴露程度較高的孩童，血清中IL-8以及TNF-α濃度也會較高。顯示PAEs的暴露會引起孩童體內過敏以及發炎免疫反應的發生。透過PAEs與孩童細胞激素濃度相關性研究發現，MEHHP與MEOHP暴露濃度則是和過敏反應相關的IL-5激素 (r=0.30, p =0.03; r=0.30, p=0.03)，以及與發炎反應相關之TNF-α濃度 (r=0.31, p=0.002 ; r=0.30, p=0.002)有中度的正相關。利用回歸模式探討PAEs暴露對於細胞激素的影響，並在校正其他的環境因子後仍然發現，MEHHP會顯著影響血清中IL-5 (aOR=2.84, 95%CI: 1.05-7.70)、IFN-γ (aOR=4.18, 95%CI: 1.18-14.79)與IL-8 (aOR=2.83, 95%CI: 1.01-7.91)之分佈。
綜合上述之結果，本研究發現PAEs特別是DBP與DEHP的暴露，對於健康之孩童來說，會增加與發炎相關之細胞激素如TNF-α之濃度，而對具過敏性體質者，除了發炎細胞激素上升外，與過敏反應有關的激素濃度亦會升高。因此，本研究認為PAEs暴露除了會誘發體內的發炎反應產生之外，並會同時會對孩童體內TH1/TH2路徑的免疫反應產生輔助效應，即鄰苯二甲酸酯類暴露濃度會與血清中IL-5與IFN-γ濃度有關。

Rising prevalence and morbidity of childhood asthma and allergic diseases has been evident throughout the world in recent years. Studies have shown that, both the genetics and biological pollutants, such as dust mites, and fungal spores in indoor and outdoor environment, are major risk factors for the development and exacerbation of allergic diseases. However, as a multi-factorial disease, the rising prevalence mentioned can’t be completely justified only by those factors. Consequently, the increasing presence of emerging chemical pollutants in overall environment since the industrial era is considered one important risk factor in modern society. Phthalate esters (PAEs), a kind of chemical materials used wildly in the PVC products have been reported in previous epidemiology studies that phthalates exposure might have adverse effects on respiratory symptoms and cause allergic diseases in children. However, the mechanism between phthalates exposure and allergy/asthma were not confirmed clearly in the animal studies, and there were not sure that phthalates exposure could trigger an adjuvant effect of TH2 immune response or induce allergic reaction by inflammation mechanism. This study is therefore aimed to investigate the underlying mechanism by assessing the associations between phthalates exposure, using urinary metabolites levels, and also consider other environmental factors to try to understand clearly about the effect of allergic-related and inflammatory-related cytokines in children.
Study subjects of pre-school children were selected from our previous questionnaires survey. According the standardized inclusion and exclusion criteria to select subjects and then divided into 980 cases and 801controls. All the selected subjects were asked by telephone for participating in the follow-up study, and then about 27% cases and 11% control subjects agreed. To further invited participators to the medical center of the great metropolitan for clinic visit to confirm their health status and collected the serum samples to analyze the levels of biomarkers. Moreover, we investigated the environmental exposure by standardized questionnaires, house dust and other biological and chemical sample collection to understand the levels about children exposure, and the children’s urine samples also collected during households’ visits. We measured the levels of children’s phthalates exposure about DMP (metabolite: MMP), DEP (metabolite: MEP), DBP (metabolite: MBP), BBzP (metabolite: MBzP), DEHP (metabolite: MEHP, MEHHP and MEOHP) in children’s urine by HPLC-MS/MS, and the levels of eight cytokines including TH1 pathway-related cytokines (IL-12 and IFN-γ), the TH2 pathway-related cytokines (IL-4, IL-5 and IL-13) and inflammatory-related cytokines (IL-6, IL-8 and TNF-α) in serum were also measured by flow cytometry. Finally, total of 101 children had completely information about healthy states and exposure profiles, and the data would analyze by statistics methods. We first divided the children into high or low exposure group based on the median of total PAEs’ metabolites levels in children’s urine estimated by the summary of individual PAE. Relationship between each PAE and the levels of cytokines was further also assessed by defining the subject group with high phthalates exposure was those having the phthalates’ metabolites levels above the median of all phthalates’ metabolites levels measured in urine (MMP: 4.87, MEP: 12.83, MBP: 57.93, MBzP: 4.78, MEHP: 8.66, MEHHP: 42.34, MEOHP: 40.55 ng/ml). On the contrary, the levels of phthalates’ metabolites below the median of phthalates’ metabolites levels in urine were defined the low exposure groups.
In general, children with higher levels of total PAEs in urine were found to have higher level of IL-5 (Hightotal: 1.30 vs. Lowtotal: 0.55 pg/ml, p=0.04) and TNF-α (Hightotal: 1.12 vs. Lowtotal: 0.90 pg/ml, p=0.03) in serum. For each PAE, children with higher levels of MBP and MEHP in urine, who had higher level of IFN-γ in serum (HighMBP: 1.15 vs. LowMBP: 0.35 pg/ml, p=0.03; HighMEHP: 1.13 vs. LowMEHP: 0.35 pg/ml, p=0.04), and higher levels of IL-5 (HighMEHHP: 1.30 vs. LowMEHHP: 0.55 pg/ml, p=0.02; HighMEOHP: 11.30 vs. LowMEOHP: 0.55 pg/ml, p=0.02), IL-8 (HighMEHHP: 2.15 vs. LowMEHHP: 1.96 pg/ml, p=0.02; HighMEOHP: 2.15 vs. LowMEOHP: 1.96 pg/ml, p=0.05) and TNF-α (HighMEHHP: 1.25 vs. LowMEHHP: 0.90 pg/ml, p=0.01; HighMEOHP: 1.12 vs. LowMEOHP: 0.90 pg/ml, p=0.01) in serum were also showed in higher levels of MEHHP and MEOHP’s exposure group children. To further estimate the cytokines’ level in serum between allergic and healthy children in high and low exposure groups, respectively. In higher group, allergic children with higher levels of MBP in urine, who had higher level of IL-5 (CaseMBP: 1.36 vs. ControlMBP: 0.55 pg/ml, p=0.01) and TNF-α (CaseMBP: 1.40 vs. ControlMBP: 0.35 pg/ml, p=0.001) when compared to healthy children. On the contrary, allergic children compared with healthy in low exposure group, data were showed that the level of IL-5 (CaseMEHP: 1.23 vs. ControlMEHP: 0.55 pg/ml, p=0.04) were higher in allergic children in MEHP exposure, and then levels of TNF-α on 75 percentile (CaseMEHHP: 1.47 vs. ControlMEHHP: 0.35 pg/ml, p=0.01; CaseMEOHP: 1.51 vs. ControlMEOHP: 0.35 pg/ml, p=0.03) also present the allergic children had higher level than health children in MEHHP and MEOHP. Moreover, we also found that phthalate exposures were associated with the levels of IL-8 and TNF-α no matter in allergic children or healthy children’s serum. Therefore, our results were showed that phthalates exposure may cause allergy-related and inflammatory reactions happened. According to the Spearman's rank correlation coefficient to estimate the relationship between phthalate exposure and children’s cytokines profiles in serum, data were showed that levels of MEHHP and MEOHP in urine were associated with TH2 pathway-related cytokines IL-5 (r=0.30, p =0.03; r=0.30, p=0.03) and inflammation-related cytokine TNF-α (r=0.31, p=0.002 ; r=0.30, p=0.002). We also used the logistic regression model to evaluate the odds ratio for phthalates exposure and cytokines profiles (IL-5, IL-8, IFN-γ and TNF-α), and then adjusted by other environmental risk factors. Results were showed that the DEHP’s metabolite MEHHP still play a risk factor to IL-5 (aOR=2.84, 95%CI: 1.05-7.70), IFN-γ (aOR=4.18, 95%CI: 1.18-14.79) and IL-8 (aOR=2.83, 95%CI: 1.01-7.91) in serum.
In conclusions, our study showed that phthalates exposure, especially DBP and DEHP exposure, would induce the inflammatory-related cytokines, such as TNF-α secretion. On the other hand, allergic children would also have higher inflammatory-related and allergic-related cytokines, while they exposed to phthalates. We therefore propose, with quantitative evidence from field study, that phthalates exposure may be more likely to be linked to inflammatory of immune response and made mixed TH1/TH2 adjuvant effect in allergic children, implying that the levels of PAEs were related to the level of IL-5 and IFN-γ in serum.

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張立德, 免疫學, 華格納企業有限公司, 台中市, 2007