六輕石化工業區附近居民多重污染暴露與代謝體關係之暴露體學研究

Exposomic study on the association between multiple pollutants exposure and metabolome in residents living near No. 6 Naphtha Cracking Complex

陳其欣(Chi-Hsin Sally Chen)

指導教授 ： 詹長權

國立臺灣大學/公共衛生學院/職業醫學與工業衛生研究所/博士(2019年)

https://doi.org/10.6342/NTU201901261

摘要

研究背景：暴露體學已成為環境衛生學界的重要方法論，近年來更是發展出 “Public Health Exposome Approach”，探討特定地區的暴露特徵及健康影響。本論文針對台灣最大的石化工業區第六套輕油裂解廠 (簡稱六輕) 附近居民進行暴露體學研究，找出暴露程度、代謝體及早期健康效應生物指標物之間的相關性。
研究方法：本研究依住家與六輕距離、尿中暴露生物指標物濃度 (釩與多環芳香烴暴露生物指標物1－羥基芘) 將 273 位研究對象分為高暴露組 (9－15 歲小孩43 人、> 55 歲老年人 77 人)　與低暴露組 (小孩 75 人、老年人78 人)，分析其 (一) 外在暴露：對六輕主要排放源的距離、住家附近道路面積、住家空氣中釩及多環芳香烴濃度；(二) 內在暴露：尿中石化工業污染暴露生物指標物砷、鎘、鉻、鎳、汞、鉛、釩、錳、銅、鍶、鉈與1－羥基芘濃度；(三) 代謝體：利用二維氣相層析飛行時間質譜儀建立尿液代謝體，以超高壓液相層析－四極柱飛行時間質譜儀分析血液代謝體及血液脂質體；(四) 早期健康效應：尿中氧化壓力指標物與血中醯基肉鹼類濃度。本研究以「中途相遇法」找出潛在可作為連結暴露與早期健康效應的中間生物指標物，並以生物途徑分析找出多重石化工業污染物暴露可能影響的生理途徑。
研究成果：本研究結果顯示在小孩及老年人受試者中，高暴露組比低暴露組居住離六輕主要排放源較近、有較高的住家空氣中釩及多環芳香烴濃度，且高暴露組比低暴露組有較高的尿中暴露生物指標物濃度與氧化壓力生物指標物濃度。尿液代謝體在高低暴露組之間有年齡依賴性的改變可連結多重暴露與氧化壓力，在小孩中是色氨酸代謝等途徑的異常，在老年人中則是甘氨酸、絲氨酸與蘇胺酸代謝等途徑的異常，且在小孩與老年人的尿液代謝體中發現潛在暴露生物指標物癸烷、十二烷、十三烷。小孩的血液代謝體在高低暴露組之間有顯著差異，並找到十個潛在可做為中間生物指標物的代謝物質，連結多重工業致癌物暴露 (國際癌症研究機構定義一級致癌物：砷、鎘、鉻、鎳；二級致癌物：汞、鉛、釩、多環芳香烴) 與早期健康效應氧化壓力增加、血中醯基肉鹼類濃度異常。生物途徑分析結果顯示小孩暴露於多重工業致癌物質可能造成嘌呤代謝途徑異常。小孩的血液脂質體在高低暴露組之間有顯著差異，並發現有 21 個脂質與多重工業污染物暴露相關，包括溶血卵磷脂類、卵磷脂類、神經鞘磷脂類及磷脂酸肌醇類，這四種脂質皆可連結到尿中氧化壓力生物指標物或血中醯基肉鹼類。
結論：Public health exposome approach 可用於探討石化工業影響地區內的易感族群，並釐清多重工業污染暴露如何影響重要生理途徑，導致與慢性和急性疾病相關的早期健康效應。氣相層析方法分析尿液代謝體可用於辨識石化工業附近的易感族群如小孩與老年人，並發現與年齡相關的生理途徑連結多重暴露與氧化壓力。液相層析方法分析血液代謝體可用於尋找多重工業致癌汙染物暴露在小孩與青少年體內影響的生理途徑，並連結癌症相關的早期健康效應。液相層析方法分析血液脂質體可用於辨識多重工業污染暴露在小孩及青少年體內造成與肝功能異常相關的脂質變化。基於本研究的發現，我們建議顯著降低石化工業污染排放量以減少暴露程度、改善代謝異常，並持續追蹤六輕附近居民的健康狀態。本研究也證實，暴露體學可作為公共衛生研究工具，探討工業污染對附近居民既有及潛在的健康效應，未來可作為尋找新的個人化健康效應指標及暴露生物指標物質、建立個人化風險評估指標的參考。

關鍵字

石化工業 ； 暴露體學 ； 代謝體學 ； 脂質體學 ； 重金屬 ； 多環芳香烴

並列摘要

Background: Exposomics is an important methodology in environmental health research. Recently, a branching paradigm, the Public Health Exposome Approach, focuses on the impact of exposures on the overall health of a population within a particular region. This dissertation focuses on the exposomics study of residents living near No. 6 Naphtha Cracking Complex, the largest petrochemical complex in Taiwan, and aim to clarify the association between exposure levels, metabolome, and early health effect biomarkers.
Material and Methods: We classified 273 study subjects as high exposure group (children aged 9-15 N=43; elderly aged > 55 N=77) and low exposure group (children N=75; elderly N=78) by the distance from their homes to the complex, and urinary levels of exposure biomarkers vanadium (V) and polycyclic aromatic hydrocarbon (PAHs) metabolite 1-hydroxypyrene (1-OHP). We analyzed (1) external exposures: distance from their homes to main emission points of the complex, road area surrounding homes, and ambient levels of V and PAHs at homes using previously established models; (2) internal exposures: urinary levels of exposure biomarkers, arsenic (As), cadmium (Cd), chromium (Cr), nickel (Ni), mercury (Hg), lead (Pb), vanadium (V), manganese (Mn), copper (Cu), strontium (Sr), thallium (Tl), and 1-OHP; (3) metabolome: urine metabolomics was analyzed using two dimensional gas chromatography coupled with time-of-flight mass spectrometry (GCxGC-TOFMS), and serum metabolomics and lipidomics were analyzed using ultra-high performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UHPLC-qTOFMS); (4) early health effects: urinary levels of oxidative stress biomarkers, and serum acylcarnitines. We applied “meet-in-the-middle” approach to identify potential intermediate biomarkers connecting exposures with early health effects, and pathway analysis to find biological mechanisms affected by exposure to multiple pollutants.
Results: In both children and elderly subjects, high exposure group lived closer to main emission points of the complex, had elevated ambient levels of V and PAHs at home locations, and increased urinary exposure biomarkers and oxidative stress biomarkers compared to low exposure group. Urine metabolomics identified age-dependent biological pathways that associated multiple pollutants exposure with increased oxidative stress, including tryptophan metabolism in children, and serine, glycine, and threonine metabolism in elderly subjects. In addition, potential exposure biomarkers decane, dodecane, and tridecane were identified in both children and elderly subjects. Serum metabolomics found 10 potential metabolites possibly linking increased exposure to IARC group 1 carcinogens (As, Cd, Cr, Ni) and group 2 carcinogens (V, Hg, PAHs) with elevated oxidative stress and deregulated serum acylcarnitines. Purine metabolism was identified as the possible mechanism affected by children’s exposure to carcinogens. Serum lipidomics results in children also showed significant difference between high and low exposure groups. We found 21 lipids associated with multiple industrial pollutants exposure, including lysophosphatidylcholines, phosphatidylcholines, sphingomyelins, and phosphatidylinositols. All four types of lipids were associated with urinary oxidative stress biomarkers and/or serum acylcarnitines.
Conclusion: Public health exposome approach could be used in a large petrochemical industry influenced region to identify vulnerable populations, and understand how multiple industrial pollutants exposure are affecting critical biological mechanisms, leading to early health effects that may be precursors to chronic and acute diseases. Urine metabolomics analyzed via GC-based method could be used to identify children and elderly as vulnerable populations in regions influenced by a large petrochemical industry, and found age-dependent pathways linking multiple exposures to increased oxidative stress. Serum metabolomics analyzed via LC-based method could be used to find biological pathways affected by multiple industrial carcinogenic pollutants exposure in children and adolescents, that could be linked to cancer-related early health effects. Serum lipidomics analyzed via LC-based method could be used to identify in children and adolescents exposed to multiple industrial pollutants, lipid profile changes that have been implicated in liver dysfunctions. Based on our findings, we suggest significant reduction of petrochemical industrial emissions from the complex to decrease multiple pollutants exposure and metabolic abnormalities, and continued follow up on of residents’ health. This dissertation also attests the application of exposomics as a public health research tool, in the investigation of current and potential health impacts of industrial pollution on nearby residents, providing information for future identification of novel personalized health indicators and exposure biomarkers, and establishment of individual risk index.

並列關鍵字

petrochemical industry ； exposomics ； metabolomics ； lipidomics ； heavy metals ； polycyclic aromatic hydrocarbons

參考文獻

Adler T. 2003. Aging research: The future face of environmental health. Environ Health Perspect 111:A760-765.

Amelio I, Cutruzzola F, Antonov A, Agostini M, Melino G. 2014. Serine and glycine metabolism in cancer. Trends Biochem Sci 39:191-198.

Ayala A, Munoz MF, Arguelles S. 2014. Lipid peroxidation: Production, metabolism, and signaling mechanisms of malondialdehyde and 4-hydroxy-2-nonenal. Oxid Med Cell Longev 2014:360438.

Bartsch H, Nair J. 2005. Accumulation of lipid peroxidation-derived DNA lesions: Potential lead markers for chemoprevention of inflammation-driven malignancies. Mutat Res 591:34-44.

Bester AC, Roniger M, Oren YS, Im MM, Sarni D, Chaoat M, et al. 2011. Nucleotide deficiency promotes genomic instability in early stages of cancer development. Cell 145:435-446.