臺灣博碩士論文加值系統

全氟烷基化合物（perfluoroalkyl substances, PFASs）為一種新興的人工環境汙染物，對健康具有多種潛在的有害影響，包括代謝疾病及癌症。過去研究證實台灣最大的科學園區將含有全氟辛烷磺酸(perfluorooctanesulfonic acid, PFOS)的廢水排入新竹的客雅溪，並在這條河中的水生生物體內發現高濃度的PFOS。我們的研究共招募了397名55至75歲居住在新竹的個案，分析血清PFASs濃度與代謝症候群及其組成因子之間的相關性。結果發現，血清PFASs與代謝症候群之間並無相關性，但較高的血清PFOS濃度與血清低密度脂蛋白(low-density lipoprotein, LDL)升高達到顯著相關。血清全氟癸酸(perfluorodecanoic acid, PFDA)、全氟十一烷酸(perfluoroundecanoic acid, PFUnDA)和三酸甘油酯（triglyceride, TG）之間則呈現負相關。血清全氟壬酸(perfluorononanoic acid, PFNA)、PFDA、PFUnDA、全氟己烷磺酸(perfluorohexane sulfonic acid, PFHxS)、PFOS濃度與血清C反應蛋白(C-reactive protein, CRP)呈負相關。按性別分類時，男性血清PFNA，PFHxS，PFOS與尿酸濃度呈正相關，而女性血清PFNA，PFDA，PFUnDA，PFHxS和PFOS與CRP濃度呈負相關。排除降膽固醇藥物使用者後，血清PFOS和LDL濃度的正向相關趨勢更為顯著，而且血清PFHxS與LDL濃度也出現正向相關。總結來說，我們的研究發現血清PFASs對不同血脂肪因子有不等之影響，並且可能對老年人，尤其是女性具有抗發炎作用。未來需要以更大的樣本量和縱向研究來驗證可能機轉及這些相關性。

Perfluoroalkyl substances (PFASs) are a class of artificial emerging environmental chemicals which has multiple potentially harmful effects on health, even causing metabolic disease and malignancy. The largest Science Park in Taiwan discharged wastewater containing perfluorooctanesulfonic acid (PFOS) into the Hsinchu’s Keya river, and a high concentration of PFOS have been discovered in this river and its aquatic creatures. We conducted a study recruiting a total of 397 residents living in the Hsinchu with age from 55 to 75 years old and evaluated the association between serum PFASs concentration and metabolic syndrome and its components. Results indicated that no relationship between serum PFASs concentration and metabolic syndrome was found, but higher serum PFOS concentrations were significantly associated with elevated serum LDL level. Inverse correlation between serum perfluorodecanoic acid (PFDA), perfluoroundecanoic acid (PFUnDA) and triglyceride(TG) were noted. Serum perfluorononanoic acid (PFNA), PFDA, PFUnDA, perfluorohexane sulfonic acid (PFHxS) and PFOS concentrations were negatively associated with serum C-reactive protein (CRP) level significantly. When stratified by gender, we found serum PFNA, PFHxS, PFOS concentration were positively correlated with serum uric acid levels among men, while serum PFNA, PFDA, PFUnDA, PFHxS and PFOS concentration were negatively correlated with CRP level only among women. After excluding people taking lipid-lowering drugs, the positive trend of serum PFOS concentration and serum LDL level was more significant, and serum PFHxS concentration also revealed positive trend with serum LDL level. In conclusion, our study suggested that serum PFASs concentration had different impacts on blood lipid profile and may have anti-inflammation effect in the elderly, especially women. Further investigation with a larger sample size and longitudinal follow-up are needed to elucidate these links.

口試委員會審定書 i
中文摘要 ii
英文摘要 iii
表目錄 vii
圖目錄 viii
第一章 前言 1
1.1研究背景 1
1.2研究目的 4
1.3代謝症候群定義 4
第二章 文獻探討 5
2.1 PFASs的藥物代謝動力學 5
2.2 PFASs與相關疾病及致病機轉 6
2.3 新竹地區可能的PFASs暴露途徑 6
2.4 PFASs之於中老年族群 8
第三章 研究方法 8
3.1研究對象及流程 8
3.2研究項目 9
3.3研究工具 10
3.4資料處理 10
第四章 結果 11
4.1血中PFASs濃度 11
4.2研究群體的基本特徵 11
4.3 PFASs濃度與代謝症候群及慢性疾病指標之相關性 11
4.4性別對PFASs濃度與代謝症候群及慢性疾病指標相關性之影響 11
4.5排除使用降膽固醇藥物族群後，PFASs濃度與代謝症候群及慢性疾病指標之相關性 12
第五章 討論 12
5.1新竹中老年居民血中PFASs與其他族群之比較 12
5.2代謝症候群之探討 13
5.3血脂肪之探討 14
5.4 CRP之探討 15
5.5性別差異性之探討 16
5.6排除使用降膽固醇藥物個案後之探討 17
第六章 結論 18
參考文獻 19
表格及圖像 26

1. Trudel, D., et al., Estimating consumer exposure to PFOS and PFOA. Risk Anal, 2008. 28(2): p. 251-69.
2. Ericson, I., et al., Human exposure to perfluorinated chemicals through the diet: intake of perfluorinated compounds in foods from the Catalan (Spain) market. J Agric Food Chem, 2008. 56(5): p. 1787-94.
3. Strynar, M.J. and A.B. Lindstrom, Perfluorinated Compounds in House Dust from Ohio and North Carolina, USA. Environmental Science & Technology, 2008. 42(10): p. 3751-3756.
4. Chen, W.-L., et al., Concentrations of perfluoroalkyl substances in foods and the dietary exposure among Taiwan general population and pregnant women. Journal of Food and Drug Analysis, 2018. 26(3): p. 994-1004.
5. Johnson, J.D., S.J. Gibson, and R.E. Ober, Cholestyramine-enhanced fecal elimination of carbon-14 in rats after administration of ammonium [14C]perfluorooctanoate or potassium [14C]perfluorooctanesulfonate. Fundam Appl Toxicol, 1984. 4(6): p. 972-6.
6. Seacat, A.M., et al., Sub-chronic dietary toxicity of potassium perfluorooctanesulfonate in rats. Toxicology, 2003. 183(1): p. 117-131.
7. Burkemper, J.L., et al., Radiosynthesis and Biological Distribution of 18F-Labeled Perfluorinated Alkyl Substances. Environmental Science & Technology Letters, 2017. 4(6): p. 211-215.
8. Martin, J., et al., Bioaccumulation of perfluoroalkyl substances in marine echinoderms: Results of laboratory-scale experiments with Holothuria tubulosa Gmelin, 1791. Chemosphere, 2019. 215: p. 261-271.
9. Pizzurro, D.M., et al., Interspecies differences in perfluoroalkyl substances (PFAS) toxicokinetics and application to health-based criteria. Regulatory Toxicology and Pharmacology, 2019. 106: p. 239-250.
10. Kim, S.-J., et al., Gender differences in pharmacokinetics and tissue distribution of 3 perfluoroalkyl and polyfluoroalkyl substances in rats. Food and Chemical Toxicology, 2016. 97: p. 243-255.
11. Lau, C., et al., Perfluoroalkyl acids: a review of monitoring and toxicological findings. Toxicol Sci, 2007. 99(2): p. 366-94.
12. Hundley, S.G., A.M. Sarrif, and G.L. Kennedy, Absorption, distribution, and excretion of ammonium perfluorooctanoate (APFO) after oral administration to various species. Drug Chem Toxicol, 2006. 29(2): p. 137-45.
13. Steenland, K., et al., Association of perfluorooctanoic acid and perfluorooctane sulfonate with serum lipids among adults living near a chemical plant. Am J Epidemiol, 2009. 170(10): p. 1268-78.
14. Steenland, K., et al., Association of perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) with uric acid among adults with elevated community exposure to PFOA. Environ Health Perspect, 2010. 118(2): p. 229-33.
15. Knox, S.S., et al., Perfluorocarbon exposure, gender and thyroid function in the C8 Health Project. J Toxicol Sci, 2011. 36(4): p. 403-10.
16. Gallo, V., et al., Serum perfluorooctanoate (PFOA) and perfluorooctane sulfonate (PFOS) concentrations and liver function biomarkers in a population with elevated PFOA exposure. Environ Health Perspect, 2012. 120(5): p. 655-60.
17. Lin, C.Y., et al., Associations between levels of serum perfluorinated chemicals and adiponectin in a young hypertension cohort in Taiwan. Environ Sci Technol, 2011. 45(24): p. 10691-8.
18. Lin, C.Y., et al., The associations between serum perfluorinated chemicals and thyroid function in adolescents and young adults. J Hazard Mater, 2013. 244-245: p. 637-44.
19. Lin, C.Y., et al., Association between levels of serum perfluorooctane sulfate and carotid artery intima-media thickness in adolescents and young adults. Int J Cardiol, 2013. 168(4): p. 3309-16.
20. Fletcher, T., et al., Associations between PFOA, PFOS and changes in the expression of genes involved in cholesterol metabolism in humans. Environment International, 2013. 57-58: p. 2-10.
21. Behr, A.-C., et al., Activation of human nuclear receptors by perfluoroalkylated substances (PFAS). Toxicology in Vitro, 2020. 62: p. 104700.
22. DeWitt, J.C., et al., Immunotoxicity of perfluorooctanoic acid and perfluorooctane sulfonate and the role of peroxisome proliferator-activated receptor alpha. Crit Rev Toxicol, 2009. 39(1): p. 76-94.
23. Lin, A.Y.-C., S.C. Panchangam, and C.-C. Lo, The impact of semiconductor, electronics and optoelectronic industries on downstream perfluorinated chemical contamination in Taiwanese rivers. Environmental Pollution, 2009. 157(4): p. 1365-1372.
24. Lin, A.Y.-C., et al., Occurrence of perfluorinated compounds in the aquatic environment as found in science park effluent, river water, rainwater, sediments, and biotissues. Environmental Monitoring and Assessment, 2014. 186(5): p. 3265-3275.
25. Meng, J., et al., Are perfluoroalkyl substances in water and fish from drinking water source the major pathways towards human health risk? Ecotoxicology and Environmental Safety, 2019. 181: p. 194-201.
26. Vestergren, R., et al., Dietary exposure to perfluoroalkyl acids for the Swedish population in 1999, 2005 and 2010. Environment International, 2012. 49: p. 120-127.
27. Wang, Y., et al., Dietary Exposure of Chinese Adults to Perfluoroalkyl Acids via Animal-Origin Foods: Chinese Total Diet Study (2005-2007 and 2011-2013). J Agric Food Chem, 2019. 67(21): p. 6048-6055.
28. Christensen, K.Y., et al., Fish Consumption, Levels of Nutrients and Contaminants, and Endocrine-Related Health Outcomes Among Older Male Anglers in Wisconsin. J Occup Environ Med, 2016. 58(7): p. 668-75.
29. Kim, H.-Y., et al., The relationships between sixteen perfluorinated compound concentrations in blood serum and food, and other parameters, in the general population of South Korea with proportionate stratified sampling method. Science of The Total Environment, 2014. 470-471: p. 1390-1400.
30. Coakley, J., et al., Polybrominated diphenyl ethers and perfluorinated alkyl substances in blood serum of New Zealand adults, 2011-2013. Chemosphere, 2018. 208: p. 382-389.
31. Li, Y., et al., Half-lives of PFOS, PFHxS and PFOA after end of exposure to contaminated drinking water. Occupational and Environmental Medicine, 2018. 75(1): p. 46-51.
32. Wang, Y., et al., Association between maternal serum perfluoroalkyl substances during pregnancy and maternal and cord thyroid hormones: Taiwan maternal and infant cohort study. Environmental health perspectives, 2014. 122(5): p. 529-534.
33. Su, T.C., et al., Serum perfluorinated chemicals, glucose homeostasis and the risk of diabetes in working-aged Taiwanese adults. Environ Int, 2016. 88: p. 15-22.
34. Yang, Q., et al., Association of serum levels of perfluoroalkyl substances (PFASs) with the metabolic syndrome (MetS) in Chinese male adults: A cross-sectional study. Sci Total Environ, 2018. 621: p. 1542-1549.
35. Chen, A., et al., Association of perfluoroalkyl substances exposure with cardiometabolic traits in an island population of the eastern Adriatic coast of Croatia. Sci Total Environ, 2019. 683: p. 29-36.
36. Christensen, K.Y., M. Raymond, and J. Meiman, Perfluoroalkyl substances and metabolic syndrome. Int J Hyg Environ Health, 2018.
37. Cardenas, A., et al., Associations of Perfluoroalkyl and Polyfluoroalkyl Substances With Incident Diabetes and Microvascular Disease. Diabetes Care, 2019: p. dc182254.
38. Stanifer, J.W., et al., Perfluorinated Chemicals as Emerging Environmental Threats to Kidney Health: A Scoping Review. Clin J Am Soc Nephrol, 2018. 13(10): p. 1479-1492.
39. Guruge, K.S., et al., Gene Expression Profiles in Rat Liver Treated With Perfluorooctanoic Acid (PFOA). Toxicological Sciences, 2005. 89(1): p. 93-107.
40. Loveless, S.E., et al., Comparative responses of rats and mice exposed to linear/branched, linear, or branched ammonium perfluorooctanoate (APFO). Toxicology, 2006. 220(2): p. 203-217.
41. Martin, M.T., et al., Toxicogenomic Study of Triazole Fungicides and Perfluoroalkyl Acids in Rat Livers Predicts Toxicity and Categorizes Chemicals Based on Mechanisms of Toxicity. Toxicological Sciences, 2007. 97(2): p. 595-613.
42. Seacat, A.M., et al., Subchronic toxicity studies on perfluorooctanesulfonate potassium salt in cynomolgus monkeys. Toxicological Sciences, 2002. 68(1): p. 249-264.
43. Lin, C.Y., et al., Association among serum perfluoroalkyl chemicals, glucose homeostasis, and metabolic syndrome in adolescents and adults. Diabetes Care, 2009. 32(4): p. 702-7.
44. Château-Degat, M.-L., et al., Effects of perfluorooctanesulfonate exposure on plasma lipid levels in the Inuit population of Nunavik (Northern Quebec). Environmental Research, 2010. 110(7): p. 710-717.
45. Winquist, A. and K. Steenland, Modeled PFOA Exposure and Coronary Artery Disease, Hypertension, and High Cholesterol in Community and Worker Cohorts. Environmental Health Perspectives, 2014. 122(12): p. 1299-1305.
46. Sunderland, E.M., et al., A review of the pathways of human exposure to poly- and perfluoroalkyl substances (PFASs) and present understanding of health effects. Journal of Exposure Science & Environmental Epidemiology, 2019. 29(2): p. 131-147.
47. Steenland, K., T. Fletcher, and D.A. Savitz, Epidemiologic Evidence on the Health Effects of Perfluorooctanoic Acid (PFOA). Environmental Health Perspectives, 2010. 118(8): p. 1100-1108.
48. Lin, C.Y., et al., The association between total serum isomers of per- and polyfluoroalkyl substances, lipid profiles, and the DNA oxidative/nitrative stress biomarkers in middle-aged Taiwanese adults. Environ Res, 2019. 182: p. 109064.
49. Frisbee, S.J., et al., Perfluorooctanoic acid, perfluorooctanesulfonate, and serum lipids in children and adolescents: Results from the C8 health project. Archives of Pediatrics and Adolescent Medicine, 2010. 164(9): p. 860-869.
50. Liu, G., et al., Associations of Perfluoroalkyl substances with blood lipids and Apolipoproteins in lipoprotein subspecies: the POUNDS-lost study. Environmental Health, 2020. 19(1): p. 5.
51. Kohan, A.B., Apolipoprotein C-III: a potent modulator of hypertriglyceridemia and cardiovascular disease. Current opinion in endocrinology, diabetes, and obesity, 2015. 22(2): p. 119-125.
52. Ballmoos, M.W.v. and B. Haring, Abstract 17987: Association of Cardiovascular Events and Apolipoprotein CIII - A Systematic Review and Meta-Analysis. Circulation, 2011. 124(suppl_21): p. A17987-A17987.
53. Tian, Y.P., et al., Isomers of perfluoroalkyl substances and overweight status among Chinese by sex status: Isomers of C8 Health Project in China. Environ Int, 2019. 124: p. 130-138.
54. Liu, H.S., et al., Association among total serum isomers of perfluorinated chemicals, glucose homeostasis, lipid profiles, serum protein and metabolic syndrome in adults: NHANES, 2013-2014. Environ Pollut, 2018. 232: p. 73-79.
55. Beesoon, S. and J.W. Martin, Isomer-Specific Binding Affinity of Perfluorooctanesulfonate (PFOS) and Perfluorooctanoate (PFOA) to Serum Proteins. Environmental Science & Technology, 2015. 49(9): p. 5722-5731.
56. Gao, Y., et al., Differential Accumulation and Elimination Behavior of Perfluoroalkyl Acid Isomers in Occupational Workers in a Manufactory in China. Environmental Science & Technology, 2015. 49(11): p. 6953-6962.
57. Chain, E.Panel o.C.i.t.F., et al., Risk to human health related to the presence of perfluorooctane sulfonic acid and perfluorooctanoic acid in food. EFSA Journal, 2018. 16(12): p. e05194.
58. Mollenhauer, M.A.M., et al., Effects of perfluorooctane sulfonate (PFOS) exposure on markers of inflammation in female B6C3F1 mice. Journal of Environmental Science and Health, Part A, 2011. 46(2): p. 97-108.
59. Genser, B., et al., Within- and between-group regression for improving the robustness of causal claims in cross-sectional analysis. Environmental Health, 2015. 14(1): p. 60.
60. Matilla-Santander, N., et al., Exposure to Perfluoroalkyl Substances and Metabolic Outcomes in Pregnant Women: Evidence from the Spanish INMA Birth Cohorts. Environ Health Perspect, 2017. 125(11): p. 117004.
61. Montero-Vega, M.T., The inflammatory process underlying atherosclerosis. Critical Reviews in Immunology, 2012. 32(5): p. 373-462.
62. Hutcheson, R., K. Innes, and B. Conway, Perfluoroalkyl substances and likelihood of stroke in persons with and without diabetes. Diabetes and Vascular Disease Research, 2019: p. 1479164119892223.
63. Conway, B., K.E. Innes, and D. Long, Perfluoroalkyl substances and beta cell deficient diabetes. Journal of Diabetes and its Complications, 2016. 30(6): p. 993-998.
64. Conway, B.N., et al., Perfluoroalkyl substances and kidney function in chronic kidney disease, anemia, and diabetes. Diabetes Metab Syndr Obes, 2018. 11: p. 707-716.
65. Grandjean, P., et al., Estimated exposures to perfluorinated compounds in infancy predict attenuated vaccine antibody concentrations at age 5-years. J Immunotoxicol, 2017. 14(1): p. 188-195.
66. Grandjean, P., et al., Serum Vaccine Antibody Concentrations in Adolescents Exposed to Perfluorinated Compounds. Environ Health Perspect, 2017. 125(7): p. 077018.
67. Kielsen, K., et al., Antibody response to booster vaccination with tetanus and diphtheria in adults exposed to perfluorinated alkylates. J Immunotoxicol, 2016. 13(2): p. 270-3.
68. Ingelido, A.M., et al., Biomonitoring of perfluorinated compounds in adults exposed to contaminated drinking water in the Veneto Region, Italy. Environment International, 2018. 110: p. 149-159.
69. Kang, H., et al., Perfluoroalkyl acids in serum of Korean children: Occurrences, related sources, and associated health outcomes. Sci Total Environ, 2018. 645: p. 958-965.
70. Wong, F., et al., Enhanced Elimination of Perfluorooctane Sulfonic Acid by Menstruating Women: Evidence from Population-Based Pharmacokinetic Modeling. Environmental Science & Technology, 2014. 48(15): p. 8807-8814.
71. Mamsen, L.S., et al., Concentration of perfluorinated compounds and cotinine in human foetal organs, placenta, and maternal plasma. Sci Total Environ, 2017. 596-597: p. 97-105.
72. Bartolomé, M., et al., Perfluorinated alkyl substances in Spanish adults: Geographical distribution and determinants of exposure. Science of The Total Environment, 2017. 603-604: p. 352-360.
73. Siebenaler, R., et al., Serum perfluoroalkyl acids (PFAAs) and associations with behavioral attributes. Chemosphere, 2017. 184: p. 687-693.
74. Qin, X.-D., et al., Positive associations of serum perfluoroalkyl substances with uric acid and hyperuricemia in children from Taiwan. Environmental Pollution, 2016. 212: p. 519-524.
75. Kataria, A., et al., Association between perfluoroalkyl acids and kidney function in a cross-sectional study of adolescents. Environmental Health, 2015. 14(1): p. 89.
76. Shankar, A., J. Xiao, and A. Ducatman, Perfluoroalkyl chemicals and elevated serum uric acid in US adults. Clinical epidemiology, 2011. 3: p. 251-258.
77. Nakagawa, H., et al., Roles of Organic Anion Transporters in the Renal Excretion of Perfluorooctanoic Acid. Basic & Clinical Pharmacology & Toxicology, 2008. 103(1): p. 1-8.
78. Emami Riedmaier, A., et al., Organic Anion Transporters and Their Implications in Pharmacotherapy. Pharmacological Reviews, 2012. 64(3): p. 421-449.
79. Sabolić, I., et al., Gender differences in kidney function. Pflügers Archiv - European Journal of Physiology, 2007. 455(3): p. 397.
80. Breljak, D., et al., Sex-dependent expression of Oat3 (Slc22a8) and Oat1 (Slc22a6) proteins in murine kidneys. American Journal of Physiology-Renal Physiology, 2013. 304(8): p. F1114-F1126.
81. Zhao, B., et al., Inhibition of 3β- and 17β-hydroxysteroid dehydrogenase activities in rat Leydig cells by perfluorooctane acid. The Journal of Steroid Biochemistry and Molecular Biology, 2010. 118(1): p. 13-17.
82. Wan, H.T., et al., Testicular Signaling Is the Potential Target of Perfluorooctanesulfonate-Mediated Subfertility in Male Mice1. Biology of Reproduction, 2011. 84(5): p. 1016-1023.
83. Lopez-Espinosa, M.J., et al., Perfluoroalkyl Substances, Sex Hormones, and Insulin-like Growth Factor-1 at 6-9 Years of Age: A Cross-Sectional Analysis within the C8 Health Project. Environ Health Perspect, 2016. 124(8): p. 1269-75.
84. Shi, L., et al., Role of estrogen in hepatocellular carcinoma: is inflammation the key? J Transl Med, 2014. 12: p. 93.
85. Mu, P.W., et al., Oestrogen exerts anti-inflammation via p38 MAPK/NF-kappaB cascade in adipocytes. Obes Res Clin Pract, 2016. 10(6): p. 633-641.
86. Zhang, E., et al., [Estrogen exerts anti-inflammatory effects by inhibiting NF-kappaB pathway through binding with estrogen receptor beta on synovicytes of osteoarthritis]. Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi, 2016. 32(12): p. 1605-1609.
87. Rosenmai, A.K., et al., Fluorinated alkyl substances and technical mixtures used in food paper-packaging exhibit endocrine-related activity in vitro. Andrology, 2016. 4(4): p. 662-672.
88. Kraugerud, M., et al., Perfluorinated compounds differentially affect steroidogenesis and viability in the human adrenocortical carcinoma (H295R) in vitro cell assay. Toxicology Letters, 2011. 205(1): p. 62-68.
89. Feng, Y., et al., Perfluorononanoic acid induces apoptosis involving the Fas death receptor signaling pathway in rat testis. Toxicology Letters, 2009. 190(2): p. 224-230.
90. Xu, X., et al., Anti-inflammatory and immunomodulatory mechanisms of atorvastatin in a murine model of traumatic brain injury. J Neuroinflammation, 2017. 14(1): p. 167.
91. Taqueti, V.R. and P.M. Ridker, Lipid-Lowering and Anti-Inflammatory Benefits of Statin Therapy. Circulation: Cardiovascular Imaging, 2017. 10(7): p. e006676.