鄰苯二甲酸二(2-乙基己基)酯暴露誘發小鼠代謝性功能異常之探討

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姓名	許至緯(Jhih-Wei Hsu) 查詢紙本館藏	畢業系所	生命科學系
論文名稱	鄰苯二甲酸二(2-乙基己基)酯暴露誘發小鼠代謝性功能異常之探討 (Effects of di‑(2‑ethylhexyl) phthalate exposure on metabolic disorders in mice)
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摘要(中)	研究證據顯示，鄰苯二甲酸酯暴露與代謝異常之間存在正相關，顯示鄰苯二甲酸酯可能具內分泌干擾活性，進而導致代謝異常；另一方面，鄰苯二甲酸二(2-乙基己基)酯(DEHP)的主要代謝物單乙基己基酯(MEHP)，已被證實具有過氧化物酶體增殖物活化受體γ促進劑(PPARγ agonist)的活性，PPARγ可有效地誘發白色脂肪細胞褐化(browning)；本研究初步結果顯示，脂肪細胞經MEHP處理後，呈現細胞能量代謝活性增高及脂肪細胞褐化的特徵；由於白色脂肪組織的褐化可增加能量消耗並抑制肥胖形成，通常被認為具有改善代謝異常的作用。考慮到肥胖同時也是導致代謝異常的主要危險因子，本研究旨在探討DEHP暴露誘發代謝異常之與否，是否與個體之肥胖程度有關；正常小鼠(C57BL/6J)和飲食誘發的肥胖小鼠，經由管餵的方式接受DEHP，劑量為0.1和1.0 毫克/公斤體重/天，持續25週。結果顯示，正常小鼠經DEHP處理後，白色脂肪組織內的褐化標記基因 (Adrb1、Adrb3、Pparg、Ppargc1a、Ucp1)表現上升，血液中FGF21濃度升高，棕色脂肪組織重量增加；微陣列分析顯示，DEHP引發之白色脂肪組織轉錄組的變化，與碳水化合物吸收、白色和棕色脂肪組織數量、及脂肪形成有關；其間，上游調控因子Pparg和Nr4a1參與主要的白色脂肪組織轉錄組調控，這些證據支持DEHP處理在正常小鼠能夠誘發白色脂肪組織褐化。另一方面，肥胖小鼠經DEHP處理後，呈現較高的葡萄糖耐受不良(glucose intolerance)及胰島素阻抗(insulin resistance)，伴隨著血液中瘦素(leptin)、低密度脂蛋白(LDL)、丙氨酸轉氨酶(ALT)的顯著增加，同時觀察到白色脂肪組織及肝臟內巨噬細胞浸潤(macrophage infiltration) 的增加，及脂肪肝(hepatic steatosis)、脂肪性肝炎(steatohepatitis)進一步惡化。值得注意的是，這些DEHP對胖鼠造成的代謝異常，並未在正常小鼠被觀察到。以微陣列分析白色脂肪組織和肝臟內轉錄組變化；對於白色脂肪組織，肥胖和DEHP經由上游調控因子(Pparg、Lipe、Cd44、Irs1)，協同調控碳水化合物的攝取、脂解和脂肪組織的異常；對於肝臟組織，肥胖和DEHP則影響參與不同功能轉錄組的變化，肥胖會影響脂質及膽固醇合成、脂質累積、及發炎反應；對於肥胖小鼠，DEHP則會進一步影響參與誘發肝臟損傷、細胞遷移、和肝糖量調控的相關基因表現。這些微陣列分析結果，對於DEHP在肥胖小鼠誘發之代謝異常，提供可能的作用機轉，這些證據顯示DEHP處理對肥胖小鼠具內分泌干擾活性，進而導致早發性代謝異常。
摘要(英)	Accumulating evidence has revealed the positive association between phthalate exposure and metabolic disorders, highlighting the endocrine-disrupting activity of phthalates. However, the major di‑(2‑ethylhexyl) phthalate (DEHP) metabolite MEHP has been identified as a selective PPARγ agonist. PPARγ has been reported as a potent adipocyte browning factor. Our preliminary results also demonstrated that MEHP-treated adipocytes exhibited an increased energy metabolic activity and brown adipocyte-like characteristics in vitro. By decreasing adiposity and increasing energy expenditure, the browning of white adipose tissue (WAT) is generally considered with beneficial effects on improving metabolic disorders. Considering obesity is the major risk factor for metabolic disorders, the present study aimed to investigate whether DEHP exposure caused metabolic disorders in an obesity-dependent manner. Both normal and diet-induced obese C57BL/6J mice were subjected to environmentally relevant levels of DEHP (i.e., 0.1 and 1.0 mg/kg body weight/day) by gavage for 25 weeks. DEHP-treated normal mice exhibited actively expressed browning marker genes (i.e., Pparg, Adrb1, Adrb3, Ppargc1a, and Ucp1) in WAT, increased blood FGF21 levels, and higher amounts of BAT. Meanwhile, transcriptional changes in WAT were associated with carbohydrate uptake, WAT/brown adipose tissue (BAT) quantity, and adipogenesis. Pparg and Nr4a1 were predicted as the top two upstream regulators in orchestrating transcriptional changes in WAT of DEHP-treated normal mice. The results support the browning activity of DEHP in normal mice. On the other hand, DEHP-treated obese mice exhibited higher glucose intolerance and insulin resistance than obese mice; the metabolic disorders were accompanied by increased blood levels of leptin, low-density lipoprotein (LDL), and alanine transaminase (ALT). Meanwhile, DEHP enhanced macrophage infiltration into WAT and hepatic tissue, and promoted hepatic steatosis/steatohepatitis in obese mice. Notably, the DEHP effects in obese mice were not observed in normal mice. Microarray analysis was used to determine transcriptomic changes in WAT and hepatic tissue. Results indicated that obesity and DEHP synergistically regulated carbohydrate uptake, lipolysis, and abnormality of adipose tissue, via the upstream regulators Pparg, Lipe, Cd44, and Irs1. Meanwhile, obesity and DEHP differentially modulated transcriptomic changes in hepatic tissue. Obesity was associated with lipid/cholesterol synthesis, lipid accumulation, and inflammation in hepatic tissue. In obese mice, DEHP exposure caused hepatic injury, cell migration, and changes in glycogen quantity. Microarray analysis suggested the potential mechanism underlying the early onset of metabolic disorders in DEHP-treated obese mice, supporting the endocrine-disrupting activity of DEHP in obese mice.
關鍵字(中)	★ 能量代謝 ★ 肥胖 ★ 胰島素阻抗 ★ 葡萄糖耐受不良 ★ 白色脂肪褐化 ★ 脂肪肝 ★ 脂肪性肝炎 ★ 巨噬細胞浸潤	關鍵字(英)	★ Energy metabolism ★ Obesity ★ Insulin resistance ★ Glucose intolerance ★ White adipose tissue browning ★ Hepatic steatosis ★ Steatohepatitis ★ Macrophage infiltration
論文目次	Table of Contents Chinese Abstract ⅰ English Abstract ⅲ Acknowledgments ⅴ Table of Contents ⅵ List of Figures ⅺ List of Tables xiii Abbreviations xiv CHAPTER Ⅰ. INTRODUCTION 1.1. Metabolic disorders 1 1.1.1. Causes of metabolic disorders 1 1.1.2. Akt in insulin signals 1 1.1.3. Insulin resistance and hyperinsulinemia 1 1.1.4. NAFLD 2 1.2. Phthalates: from the environment to the human body 5 1.2.1. Physico-chemical properties of phthalates and their application 5 1.2.2. Distribution of phthalates in the environment 5 1.2.3. Routes of phthalate exposure 6 1.2.4. Metabolism of phthalates 6 1.2.5. Biomonitoring of phthalate exposures 6 1.3. Phthalate exposure on metabolic disorders 8 1.3.1. Epidemiological studies 8 1.3.2. Animal studies 9 1.3.3. In vitro studies 10 CHAPTER Ⅱ. PRELIMINARY TESTS, HYPOTHESIS, AND SPECIFIC AIMS 2.1. Browning-like effects of MEHP on adipocytes in vitro 12 2.1.1. MEHP-treated adipocytes secrete increased amounts of FGF21 12 2.1.2. Expression of Fgfr family and βKlotho genes in adipocytes 13 2.1.3. FGF21/FGFR plays critical roles in adipocyte glucose uptake 13 2.1.4. MEHP-treated adipocytes exhibit brown adipocyte-like characteristics 14 2.1.5. MEHP-treated adipocytes exhibit an increased energy metabolic activity 15 2.1.6. PDK4 and PEPCK1 in glucose utilization for mitochondrial mitochondrial respiration 16 2.1.7. Increased mitochondrial and peroxisomal biogenesis in MEHP-treated adipocytes 17 2.1.8. Increased fatty acid β-oxidation in MEHP-treated adipocytes 18 2.1.9. MEHP causes browning-like effects on adipocytes 19 2.2. Hypothesis 19 2.3. Objective and approach strategies 20 CHAPTER Ⅲ. MATERIAL AND METHODS 3.1. Chemicals, mice and cells 21 3.2. ELISA kits 22 3.3. Colorimetric assays kits 22 3.4. Induction of adipogenesis and MEHP treatments 22 3.5. Glucose uptake assay 23 3.6. Measurement of energy metabolism activity 23 3.7. Microarray analysis of transcriptional changes in MEHP/RSG-treated adipocytes 24 3.8. Immunoblot analysis 25 3.9. Analysis of size distribution of lipid droplets in adipocytes 25 3.10. NF-κB luciferase reporter assay 26 3.11. Measurement of mitochondrial biogenesis 26 3.12. Measurement of peroxisomal biogenesis 27 3.13. Measurement of fatty acid β-oxidation 27 3.14. Experimental design of animal studies 28 3.15. Methods of metabolic function evaluations in the animal system 29 3.15.1. Evaluation of glucose clearance capacity 29 3.15.2. Evaluation of insulin sensitivity 29 3.16. Quantification of DEHP metabolites in urine 30 3.16.1 Urine samples preparation 30 3.16.2. LC-MS/MS analysis 30 3.17. Measurement of fat volume in mice 31 3.18. Measurement of glucose homeostasis related parameters in circulating levels of mice 31 3.19. Measurement of adipokine profile in circulating levels of mice 31 3.20. Measurement of total cholesterol, HDL, LDL, and triglycerides 32 3.21. Measurement of ALT and AST levels in mouse blood 32 3.22. Histology and staining 32 3.23. Microarray analysis of transcriptional changes in eWAT and hepatic tissue of mice 33 3.24. RNA isolation and qPCR analysis 33 3.25. Statistical analysis 34 CHAPTER Ⅳ. RESULTS 4.1. DEHP causes significant increases in both body weight of obese mice and BAT of normal mice 35 4.2. Effects of DEHP on cell size of adipocytes in mice 36 4.3. DEHP impairs glucose clearance capacity and insulin sensitivity in obese mice 36 4.4. Changes in adipokine levels in mice in response to obese and DEHP 37 4.5. DEHP enhances macrophage infiltration into eWAT in obese mice 38 4.6. DEHP causes significant increases in blood LDL and hepatic cholesterol/triglyceride accumulation in obese mice 39 4.7. DEHP aggravates steatohepatitis in obese mice 39 4.8. MEHP is the major DEHP metabolite in mice urine 40 4.9. Descriptive statistics of microarray data from eWAT and hepatic tissue 41 4.10. IPA analysis of transcriptional changes in eWAT 42 4.11. Synergistic effects of obesity and DEHP on transcriptional changes in eWAT 44 4.12. DEHP causes eWAT browning in normal mice, but not in obese mice 45 4.13. IPA analysis of transcriptional changes in hepatic tissue 45 4.14. DEHP causes metabolic disorders in an obesity dependent manner 47 CHAPTER Ⅴ. DISCUSSION 5.1. Browning effects of MEHP on 3T3-L1 adipocytes in vitro 49 5.2. Browning effects of DEHP on eWAT in normal mice in vivo 50 5.3. Endocrine-disrupting effects of DEHP on obese mice 51 5.4. Leptin resistance in DEHP-treated obese mice 52 5.5. Effects of obesity and DEHP on inflammation in eWAT 52 5.6. Synergistic effects of obesity and DEHP on transcriptional changes in eWAT 53 5.7. NAFLD in DEHP-treated obese mice 54 5.8. Differential roles of obesity and DEHP in promoting hepatic steatosis and steatohepatitis 55 5.8.1. Obesity associated DEGs in hepatic lipid metabolism and inflammation 55 5.8.2. DEHP-induced DEGs in hepatic inflammation 56 CHAPTER Ⅵ. CONCLUSION 58 References 59 Figures and Figure legends 80 Tables 132 Appendix 146 Publications 182
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指導教授	鄒粹軍高永旭(Tsui-Chun Tsou Yung-Hsi Kao)	審核日期	2021-7-30
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博碩士論文 103881001 詳細資訊