臺灣博碩士論文加值系統

賽滅寧（cypermethrin, CYP）為一種作用於神經系統的合成除蟲菊精類殺蟲劑，廣泛應用在農業及家庭殺蟲劑使用。本研究探討攝食一般飲食或高脂飲食合併暴露低劑量的CYP，對於雄性小鼠體內脂肪生成以及肝臟代謝之影響。雄性C57BL/6J小鼠分別餵食AIN-93M飼料和高脂飼料（脂肪佔總熱量50%），代表一般飲食和高脂飲食。一般飲食除了正常對照（NC）組，另有三組CYP暴露組，分別為CYP低劑量（CL）組、CYP中劑量（CM）組及CYP高劑量（CH）組，餵食添加CYP的AIN-93M飼料（CYP暴露劑量分別為: 1、2.5及5 mg/kg B.W./day）；而高脂飲食除了高脂對照（HF）組外，另有高脂合併CYP暴露（HFC）組，餵食添加CYP的高脂飼料（CYP暴露劑量: 5 mg/kg B.W./day）。實驗進行60天飼料介入後犧牲所有小鼠，收集血液、肝臟、副睪脂肪及盲腸內容物進行分析。實驗結果顯示，與NC組相比，CH組小鼠副睪脂肪重量增加，血漿總膽固醇相關指標上升，血液促發炎單核球減少，副睪脂肪和肝臟中M1巨噬細胞比例的增加；此外，副睪脂肪的diglyceride acyltransferase (DGAT）1、interleukin-18、plasminogen activator inhibitor-I、adiponectin和leptin基因表現量增加，而肝臟中DGAT2、hydroxymethylglutaryl-CoA reductase、chemokine (C-C motif) ligand 2和TNF receptor superfamily member 6（Fas）的基因表現量亦提升；盲腸的SCFA濃度不受影響，厭氧桿菌屬（Anaerobacterium）為優勢菌種。與HF組相比，HFC組小鼠血漿TG與睪固酮含量提升，副睪脂肪的DGAT2和leptin基因表現量增加，肝臟中DGAT2、aldolase C、lipopolysaccharide binding protein和Fas基因表現量上升，盲腸中乙酸減少而丁酸增加，且丁酸生成的菌種為優勢菌種。本研究結果顯示，雄性C57BL/6J小鼠無論給予一般飲食或高脂飲食，合併低劑量CYP暴露對於體重皆無顯著影響，然而卻會提升血脂濃度，並促進副睪脂肪和肝臟組織中脂肪合成相關基因的表現量，可能會增加肥胖和血脂代謝異常相關慢性病之風險。

Cypermethrin (CYP) is a synthetic pyrethroid insecticide that acts on the nervous system and is widely used in agriculture and household insecticides. This study investigates the effects of low-dose CYP exposure from a normal diet or a high-fat diet on lipogenesis and liver metabolism in male mice. Male C57BL/6J mice were fed either AIN-93M diet or a high-fat diet (with fat accounting for 50% of total calories), representing the normal diet and high-fat diet, respectively. In addition to the normal control (NC) group, the normal diet had three CYP exposure groups: CYP low-dose (CL), CYP medium-dose (CM), and CYP high-dose (CH), fed with AIN-93M diet containing CYP (CYP exposure doses: 1, 2.5, and 5 mg/kg B.W./day, respectively). The high-fat diet included a high-fat control (HF) group and a high-fat diet combined with CYP exposure (HFC) group, fed with a high-fat diet containing CYP (CYP exposure dose: 5 mg/kg B.W./day). After 60 days of dietary intervention, all mice were sacrificed, and blood, liver, epididymal fat, and cecal contents were collected for analysis. The results showed that, compared to the NC group, the CH group mice had increased epididymal fat weight, elevated plasma total cholesterol-related indicators, reduced pro-inflammatory monocytes in the blood, and increased M1 macrophage proportions in epididymal fat and liver. Additionally, in the epididymal fat, the gene expressions of diglyceride acyltransferase (DGAT) 1, interleukin-18, plasminogen activator inhibitor-I, adiponectin, and leptin were increased, while in the liver, the gene expressions of DGAT2, hydroxymethylglutaryl-CoA reductase, chemokine (C-C motif) ligand 2, and TNF receptor superfamily member 6 (Fas) were also elevated. The SCFA concentration in the cecum was not affected, and the dominant strain is Anaerobacterium. Compared to the HF group, the HFC group mice had increased plasma TG and testosterone levels, higher gene expressions of DGAT2 and leptin in the epididymal fat, and elevated gene expressions of DGAT2, aldolase C, lipopolysaccharide binding protein, and Fas in the liver. In the cecum, acetate decreased while butyrate increased, with butyrate-producing bacteria becoming dominant. The results of this study indicate that, regardless of a normal diet or high-fat diet, low-dose CYP exposure in male C57BL/6J mice did not significantly affect body weight. However, CYP increased blood lipid levels and promoted the expression of lipogenesis-related genes in the epididymal fat and liver, which may increase the risk of obesity and lipid metabolism-related chronic diseases.

目錄
中文摘要 I
Abstract III
致謝 V
縮寫表 X
表目次 XII
圖目次 XIII
第一章、 緒論 1
第二章、 文獻回顧 2
第一節、 賽滅寧 2
一、使用背景 2
二、物化性質 2
三、毒性作用機制與體內代謝3
四、CYP暴露狀況 7
五、CYP暴露對健康的影響 9
第二節、 肥胖 12
一、肥胖的原因與影響 12
二、肥胖與發炎反應 15
三、肥胖與代謝異常 18
四、肥胖的動物模式 19
第三節、 肥胖與肝臟代謝 21
一、肝臟的代謝功能 21
二、肥胖與肝臟代謝異常 27
第四節、 肥胖與腸道菌相 29
第五節、 高通量次世代定序（next-generation sequencing, NGS）技術 31
第三章、 實驗設計與方法 35
第一節、 實驗設計 35
一、實驗一 35
二、實驗二 36
第二節、 磁振造影 41
第三節、 檢體採集與處理 42
一、血液 42
二、副睪脂肪 42
三、肝臟 43
四、盲腸內容物 44
第四節、 檢體分析 45
一、飼料 45
二、血漿 48
三、血液 48
四、副睪脂肪50
五、肝臟 55
六、盲腸內容物62
第五節、 統計分析 65
第六節、 所使用藥品與儀器 67
一、實驗試藥與試劑 67
二、飼料 68
三、實驗抗體 69
四、分析試劑組 71
五、儀器設備 71
第四章、 結果 73
第一節、 實驗一 73
第二節、 實驗二 82
一、小鼠體重變化與攝食量 82
二、CYP實際暴露量 85
三、脂肪變化量 87
四、血液生化數值與睪固酮濃度 92
五、血液中白血球比率 94
六、血液中淋巴球比率 96
七、副睪脂肪中Mφ比率 98
八、副睪脂肪中TG合成mRNA表現量 100
九、副睪脂肪中發炎相關mRNA表現量 102
十、副睪脂肪中脂肪激素mRNA表現量 104
十一、肝臟病理組織切片判讀 106
十二、肝臟中淋巴球比率 109
十三、肝臟中Mφ比率 111
十四、肝臟中TG代謝相關之mRNA表現量 113
十五、肝臟中CHO合成相關之mRNA表現量 115
十六、肝臟中醣類代謝相關之mRNA表現量 117
十七、肝臟中發炎相關之mRNA表現量 119
十八、盲腸內容物中SCFA含量與腸道菌相組成 121
第五章、 討論 130
第一節、 一般飲食合併CYP暴露對於肥胖相關指標的影響 130
第二節、 一般飲食暴露CYP對於肝臟代謝的影響 135
第三節、 高脂飲食暴露CYP對於肥胖相關指標的影響 137
第四節、 高脂飲食暴露CYP對於肝臟代謝的影響 139
第五節、 飲食暴露CYP對於SCFA和腸道菌相的影響 141
第六節、 實驗一和實驗二肝臟基因表現之差異 143
第六章、 結論 146
第七章、 參考文獻 147
表目次
表一、2017年-2020年成人過重及肥胖盛行率 14
表二、飼料組成 38
表三、飼料濃度換算表 39
表四、脂肪組織即時定量聚合酶連鎖反應之引子序列 54
表五、肝臟組織即時定量聚合酶連鎖反應之引子序列 60
表六、非酒精性脂肪肝評分 61
表七、檢體分析項目與方法 66
表八、CYP組肝臟在GSEA GO資料庫中具有差異的代表路徑與基因 75
表九、HFC組肝臟在GSEA GO資料庫中具有差異的代表路徑與基因 76
表十、CYP組肝臟在GSEA metabolic pathway資料庫中具有差異的代表路徑與基因 77
表十一、HFC組肝臟在GSEA metabolic pathway資料庫中具有差異的代表路徑與基因 78
表十二、平均體重變化、飲食攝取量及攝食效率 83
表十三、飼料中CYP實際濃度及暴露量 86
表十四、實驗結果總整理 144
圖目次
圖一、CYP與其代謝物 6
圖二、肥胖與發炎反應 17
圖三、葡萄糖在肝臟中的代謝路徑 25
圖四、脂質在肝臟中的代謝路徑 26
圖五、RNA seq的流程 34
圖六、實驗流程圖 40
圖七、CYP定性與定量圖譜 47
圖八、SCFA定性與定量圖譜 64
圖九、轉錄組學DEG cluster plot結果圖 79
圖十、比對GO資料庫的GSEA富集圖 80
圖十一、比對metabolic pathway資料庫的GSEA富集圖 81
圖十二、第一週至第九週之體重變化 84
圖十三、第一週至第八週之MRI結果圖 89
圖十四、脂肪變化量 90
圖十五、皮下脂肪及副睪脂肪重量 91
圖十六、血液生化數值 93
圖十七、血液白血球分布 95
圖十八、血液淋巴球比率 97
圖十九、副睪脂肪中Mφ次群 99
圖二十、副睪脂肪TG合成相關mRNA表現量 101
圖二十一、副睪脂肪中發炎相關mRNA表現量 103
圖二十二、副睪脂肪脂肪激素mRNA表現量 105
圖二十三、肝臟組織切片與評分 107
圖二十四、肝臟淋巴球比率 110
圖二十五、肝臟中Mφ次群 112
圖二十六、肝臟TG代謝相關mRNA表現量 114
圖二十七、肝臟中膽固醇合成相關mRNA表現量 116
圖二十八、肝臟醣類代謝相關mRNA表現量 118
圖二十九、肝臟發炎相關mRNA表現量 120
圖三十、盲腸內容物中SCFA的濃度 123
圖三十一、各組腸道菌相α多樣性稀釋曲線 124
圖三十二、腸道菌相α多樣性 125
圖三十三、腸道菌相β多樣性 126
圖三十四、腸道菌相相對豐度 127
圖三十五、腸道菌相菌相組成-LDA分析 129

參考文獻
Abdou, H. M., Hussien, H. M., & Yousef, M. I. (2012). Deleterious effects of cypermethrin on rat liver and kidney: protective role of sesame oil. Journal of Environmental Science Health, Part B, 47(4), 306-314.
Adeghate, E. (2004). An update on the biology and physiology of resistin. Cellular Molecular Life Sciences CMLS, 61, 2485-2496.
Adeva-Andany, M. M., Pérez-Felpete, N., Fernández-Fernández, C., Donapetry-García, C., & Pazos-García, C. (2016). Liver glucose metabolism in humans. Bioscience reports, 36(6), e00416.
Ahmad, R., Thomas, R., Kochumon, S., & Sindhu, S. (2017). Increased adipose tissue expression of IL‐18R and its ligand IL‐18 associates with inflammation and insulin resistance in obesity. Immunity, inflammation disease, 5(3), 318-335.
Al-Hamdani, N. M. H., & Narasinhachary, Y. H. (2011). Endocrine disruptive action of cypermethrin in male mice. Toxicology Environmental Health Sciences, 3, 69-79.
Alicia, H. G., Hakdong Shin, and Mercedes G. López. (2017). Modulation of Gut Microbiota of Overweight Mice by Agavins and Their Association with Body Weight Loss. Nutrients, 9, 821.
Alves-Bezerra, M., & Cohen, D. E. (2017). Triglyceride metabolism in the liver. Comprehensive physiology, 8(1), 1.
Amweg, E. L., Weston, D. P., You, J., & Lydy, M. J. (2006). Pyrethroid insecticides and sediment toxicity in urban creeks from California and Tennessee. Environmental Science & Technology, 40(5), 1700-1706.
Arianna Mayorga-Ramos, C. B.-O., Daniel Simancas-Racines, Linda P. Guamán. (2022). Protective role of butyrate in obesity and diabetes: New insights. Frontiers in Nutrition.
Ariyani, M., Yusiasih, R., Endah, E. S., Koesmawati, T. A., Ridwan, Y. S., Rohman, O., . . . Pitoi, M. M. (2023). Pyrethroid residues in Indonesian river Citarum: A simple analytical method applied for an ecological and human health risk assessment. Chemosphere, 335, 139067.
Bae, S., Ullah, I., Beloor, J., Lim, J., Chung, K., Yi, Y., Lee, S.-K. (2024). Blocking Fas-signaling in adipocytes and hepatocytes prevents obesity-associated inflammation, insulin resistance, and hepatosteatosis. Journal of Industrial Engineering Chemistry
Bargut, T. C. L., Frantz, E. D., Mandarim-de-Lacerda, C. A., & Aguila, M. B. (2014). Effects of a diet rich in n-3 polyunsaturated fatty acids on hepatic lipogenesis and beta-oxidation in mice. Lipids, 49, 431-444.
Begum, G. (2005). Toxicity of cypermethrin on total lipids and free fatty acids in liver, muscle, kidney and ovary of Clarias batrachus (L) and recovery response. Toxicological Environmental Chemistry, 87(2), 253-260.
Bertola, e. a. (2010). Hepatic Expression Patterns of Inflammatory and Immune Response Genes Associated with Obesity and NASH in Morbidly Obese Patients. PLoS One, 5(10).
Bigorgne, A. E., Bouchet–Delbos, L., Naveau, S., Dagher, I., Prévot, S., Durand–Gasselin, I., Perlemuter, G. (2008). Obesity-induced lymphocyte hyperresponsiveness to chemokines: a new mechanism of Fatty liver inflammation in obese mice. Gastroenterology, 134(5), 1459-1469. e1452.
Bradberry, S. M., Cage, S. A., Proudfoot, A. T., & Vale, J. A. (2005). Poisoning due to pyrethroids. Toxicological reviews, 24, 93-106.
Bray, G. A., Frühbeck, G., Ryan, D. H., & Wilding, J. P. (2016). Management of obesity. The Lancet, 387(10031), 1947-1956.
Brehm, A., Pfeiler, G., Pacini, G., Vierhapper, H., & Roden, M. (2004). Relationship between serum lipoprotein ratios and insulin resistance in obesity. Clinical chemistry, 50(12), 2316-2322.
Buettner, R., Schölmerich, J., & Bollheimer, L. C. (2007). High‐fat diets: modeling the metabolic disorders of human obesity in rodents. Obesity, 15(4), 798-808.
Bullen Jr, J. W., Bluher, S., Kelesidis, T., & Mantzoros, C. S. (2007). Regulation of adiponectin and its receptors in response to development of diet-induced obesity in mice. American Journal of Physiology-Endocrinology Metabolism, 292(4), E1079-E1086.
Cani, P. D., Amar, J., Iglesias, M. A., Poggi, M., Knauf, C., Bastelica, D., Chabo, C. (2007). Metabolic endotoxemia initiates obesity and insulin resistance. Diabetes, 56(7), 1761-1772.
Cao, J., Chen, T.-m., Hao, W.-j., Li, J., Liu, L., Zhu, B.-p., & Li, X.-y. (2012). Correlation between sex hormone levels and obesity in the elderly male. The Aging Male, 15(2), 85-89.
Chakraborti, C. K. (2015). New-found link between microbiota and obesity. World journal of gastrointestinal pathophysiology, 6(4), 110.
Chakravorty, S., Helb, D., Burday, M., Connell, N., & Alland, D. (2007). A detailed analysis of 16S ribosomal RNA gene segments for the diagnosis of pathogenic bacteria. Journal of microbiological methods, 69(2), 330-339.
Charlton, M. R. (1996). Protein metabolism and liver disease. Bailliere's clinical endocrinology metabolism, 10(4), 617-635.
Chen, L., Zhang, Q., Yu, C., Wang, F., & Kong, X. (2020). Functional roles of CCL5/RANTES in liver disease. Liver Research, 4(1), 28-34.
Chia-Jung Liao, P.-S. H., Hui-Tzu Chien, Kwang-Huei Lin. (2022). Effects of Thyroid Hormones on Lipid Metabolism Pathologies in Non-Alcoholic Fatty Liver Disease. biomedicines, 10.
Chiarello, M., McCauley, M., Villéger, S., & Jackson, C. R. (2022). Ranking the biases: The choice of OTUs vs. ASVs in 16S rRNA amplicon data analysis has stronger effects on diversity measures than rarefaction and OTU identity threshold. PLoS One, 17(2), e0264443.
Chrustek, A., Hołyńska-Iwan, I., Dziembowska, I., Bogusiewicz, J., Wróblewski, M., Cwynar, A., & Olszewska-Słonina, D. (2018). Current research on the safety of pyrethroids used as insecticides. Medicina, 54(4), 61.
Clarke, S., Walker, C., & McCaffery, A. (1990). A comparison of the in vitro metabolism of cis-cypermethrin in a resistant and susceptible strain of Heliothis virescens. Paper presented at the Proceedings of the Brighton Crop Protection Conference, Pests and Diseases.
Cohen, P. (1999). The hypogonadal–obesity cycle: role of aromatase in modulating the testosterone–estradiol shunt–a major factor in the genesis of morbid obesity. Medical hypotheses, 52(1), 49-51.
Collins, S., Martin, T. L., Surwit, R. S., & Robidoux, J. (2004). Genetic vulnerability to diet-induced obesity in the C57BL/6J mouse: physiological and molecular characteristics. Physiology & behavior, 81(2), 243-248.
Copplestone, J. F. (1988). The development of the WHO Recommended Classification of Pesticides by Hazard. Bulletin of the World Health Organization, 66(5), 545.
Crawford, M. J., Croucher, A., & Hutson, D. H. (1981). Metabolism of cis-and trans-cypermethrin in rats. Balance and tissue retention study. Journal of Agricultural and Food Chemistry, 29(1), 130-135.
De Heredia, F. P., Gómez-Martínez, S., & Marcos, A. (2012). Obesity, inflammation and the immune system. Proceedings of the Nutrition Society, 71(2), 332-338.
De Pergola, G. (2000). The adipose tissue metabolism: role of testosterone and dehydroepiandrosterone. International journal of obesity, 24(2), S59-S63.
Delporte, M.-L., El Mkadem, S. A., Quisquater, M., & Brichard, S. M. (2004). Leptin treatment markedly increased plasma adiponectin but barely decreased plasma resistin of ob/ob mice. American Journal of Physiology-Endocrinology Metabolism, 287(3), E446-E453.
Elisia, I., Lam, V., Cho, B., Hay, M., Li, M. Y., Kapeluto, J., Jia, W. (2020). Exploratory examination of inflammation state, immune response and blood cell composition in a human obese cohort to identify potential markers predicting cancer risk. PLoS One, 15(2), e0228633.
Elmaleh-Sachs, A., Schwartz, J. L., Bramante, C. T., Nicklas, J. M., Gudzune, K. A., & Jay, M. (2023). Obesity management in adults: a review. Jama, 330(20), 2000-2015.
EMEA. (2001). Committee for veterinary medicinal products cypermethrin.
EPA. (2006). Reregistration Eligibility Decision for Cypermethrin.
EPA. (2020). Cypermethrins Proposed Interim Registration Review Decision Case Number 2130.
EQS. (2011). cypermethrin.
Fantuzzi, G. (2005). Adipose tissue, adipokines, and inflammation. Journal of Allergy and Clinical Immunology, 115(5), 911-919.
Faouzi, S., Burckhardt, B. E., Hanson, J. C., Campe, C. B., Schrum, L. W., Rippe, R. A., & Maher, J. J. (2001). Anti-Fas induces hepatic chemokines and promotes inflammation by an NF-κB-independent, caspase-3-dependent pathway. Journal of Biological Chemistry, 276(52), 49077-49082.
Farag, A. T., Goda, N. F., Shaaban, N. A., & Mansee, A. H. (2007). Effects of oral exposure of synthetic pyrethroid, cypermethrin on the behavior of F1-progeny in mice. Reproductive toxicology, 23(4), 560-567.
Fujisaka, S. (2021). The role of adipose tissue M1/M2 macrophages in type 2 diabetes mellitus. Diabetology international, 12, 74-79.
Gallausiaux, M., Camille, Marinelli, L., Blottière, H. M., Larraufie, P., & Lapaque, N. (2021). SCFA: mechanisms and functional importance in the gut. Proceedings of the Nutrition Society, 80(1), 37-49.
Gonzalez-Quintela, A., Alonso, M., Campos, J., Vizcaino, L., Loidi, L., & Gude, F. (2013). Determinants of serum concentrations of lipopolysaccharide-binding protein (LBP) in the adult population: the role of obesity. PLoS One, 8(1), e54600.
Grundy, S. M. (2000). Metabolic complications of obesity. Endocrine, 13, 155-165.
Han, Y., Gao, S., Muegge, K., Zhang, W., & Zhou, B. (2015). Advanced applications of RNA sequencing and challenges. Bioinformatics biology insights 9, BBI. S28991.
Hayek, T., Ito, Y., Azrolan, N., Verdery, R., Aalto-Setälä, K., Walsh, A., & Breslow, J. (1993). Dietary fat increases high density lipoprotein (HDL) levels both by increasing the transport rates and decreasing the fractional catabolic rates of HDL cholesterol ester and apolipoprotein (Apo) AI. Presentation of a new animal model and mechanistic studies in human Apo AI transgenic and control mice. The Journal of clinical investigation, 91(4), 1665-1671.
He, B., Wang, X., Jin, X., Xue, Z., Zhu, J., Wang, C., Fu, Z. (2020). β-Cypermethrin promotes the adipogenesis of 3T3-L1 cells via inducing autophagy and shaping an adipogenesis-friendly microenvironment. Acta biochimica et biophysica Sinica, 52(8), 821-831.
Hu, J. x., Li, Y. f., Li, J., Pan, C., He, Z., Dong, H. y., & Xu, L. c. (2013). Toxic effects of cypermethrin on the male reproductive system: with emphasis on the androgen receptor. Journal of applied toxicology, 33(7), 576-585.
Hu, T., Chitnis, N., Monos, D., & Dinh, A. (2021). Next-generation sequencing technologies: An overview. Human Immunology, 82(11), 801-811.
Huang, K.-P., Ronveaux, C. C., Knotts, T. A., Rutkowsky, J. R., Ramsey, J. J., & Raybould, H. E. (2020). Sex differences in response to short-term high fat diet in mice. Physiology behavior, 221, 112894.
Hutson, D. H., Gaughan, L. C., & Casida, J. E. (1981). Metabolism of the cis‐and trans‐isomers of cypermethrin in mice. Pesticide Science, 12(4), 385-398.
Isidori, A. M., Caprio, M., Strollo, F., Moretti, C., Frajese, G., Isidori, A., & Fabbri, A. (1999). Leptin and androgens in male obesity: evidence for leptin contribution to reduced androgen levels. The Journal of Clinical Endocrinology Metabolism, 84(10), 3673-3680.
Jéquier, E. (2002). Pathways to obesity. International journal of obesity, 26(2), S12-S17.
Jabbar, M. K. (2022). Effect of Toxicity Cypermethrin in Animals: A Review. International Journal of Scientific Trends, 1(2), 1-14.
Jakubzick, C. V., Randolph, G. J., & Henson, P. M. (2017). Monocyte differentiation and antigen-presenting functions. Nature Reviews Immunology, 17(6), 349-362.
James, W. P. T. (2008). WHO recognition of the global obesity epidemic. International journal of obesity, 32(7), S120-S126.
JECFA. (2000). Guidelines for the preparation of toxicological working papers for the Joint FAO/WHO Expert Committee on Food Additives.
JECFA. (2004). Evaluation of certain veterinary drug residues in food. Retrieved from
Ji, C., Yu, C., Yue, S., Zhang, Q., Yan, Y., Fan, J., & Zhao, M. (2019). Enantioselectivity in endocrine disrupting effects of four cypermethrin enantiomers based on in vitro models. Chemosphere, 220, 766-773.
Jin, Y., Lin, X., Miao, W., Wu, T., Shen, H., Chen, S., Fu, Z. (2014). Chronic exposure of mice to environmental endocrine-disrupting chemicals disturbs their energy metabolism. Toxicology letters, 225(3), 392-400.
Jin, Y., Wang, L., Ruan, M., Liu, J., Yang, Y., Zhou, C., Fu, Z. (2011). Cypermethrin exposure during puberty induces oxidative stress and endocrine disruption in male mice. Chemosphere, 84(1), 124-130.
Jung, U. J., & Choi, M.-S. (2014). Obesity and its metabolic complications: the role of adipokines and the relationship between obesity, inflammation, insulin resistance, dyslipidemia and nonalcoholic fatty liver disease. International Journal of Molecular Sciences, 15(4), 6184-6223.
Kadowaki, T., Yamauchi, T., Kubota, N., Hara, K., Ueki, K., & Tobe, K. (2006). Adiponectin and adiponectin receptors in insulin resistance, diabetes, and the metabolic syndrome. The Journal of clinical investigation, 116(7), 1784-1792.
Kamel, M. S., & Reda, L. A. (2020). Toxic Effects of Administration of Cypermethrin, Vitamin E, Zinc and Their Mixtures on the Hormonal Levels of Thyroid, Kidney Functions and some Biochemical Parameters in Male Mice. Journal of Applied Plant Protection, 9(1), 39-49.
Kanbur, M., Liman, B. C., Eraslan, G., & Altinordulu, S. (2008). Effects of cypermethrin, propetamphos, and combination involving cypermethrin and propetamphos on lipid peroxidation in mice. Environmental Toxicology: An International Journal, 23(4), 473-479.
Kanbur, M., Siliğ, Y., Eraslan, G., Karabacak, M., Soyer Sarıca, Z., & Şahin, S. (2016). The toxic effect of cypermethrin, amitraz and combinations of cypermethrin-amitraz in rats. Environmental Science Pollution Research, 23, 5232-5242.
Kelly, D., & Jones, T. (2015). Testosterone and obesity. Obesity Reviews, 16(7), 581-606.
Kelly, D. M., & Jones, T. H. (2013). Testosterone: a metabolic hormone in health and disease. Journal of Endocrinology, 217(3), R25-R45.
Kim, B.-M., Abdelfattah, A. M., Vasan, R., Fuchs, B. C., & Choi, M. Y. (2018). Hepatic stellate cells secrete Ccl5 to induce hepatocyte steatosis. Scientific Reports, 8(1), 7499.
Kim, K.-A., Gu, W., Lee, I.-A., Joh, E.-H., & Kim, D.-H. (2012). High fat diet-induced gut microbiota exacerbates inflammation and obesity in mice via the TLR4 signaling pathway. PLoS One.
Kleiner, D. E., Brunt, E. M., Van Natta, M., Behling, C., Contos, M. J., Cummings, O. W., Unalp‐Arida, A. (2005). Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology, 41(6), 1313-1321.
Krakoff, J., Funahashi, T., Stehouwer, C. D., Schalkwijk, C. G., Tanaka, S., Matsuzawa, Y., Knowler, W. C. (2003). Inflammatory markers, adiponectin, and risk of type 2 diabetes in the Pima Indian. Diabetes care, 26(6), 1745-1751.
Kukurba, K. R., & Montgomery, S. B. (2015). RNA sequencing and analysis. Cold Spring Harbor Protocols, 2015(11), pdb. top084970.
Kumar, P., Manjusha, C., Sahu, I., & Sirisha, D. (2012). Protective effect of leucoverin on Cypermethrin induced toxicity in mice. Bio Innov, 1(2), 33-44.
Kumar Singh, A., Nath Tiwari, M., Prakash, O., & Pratap Singh, M. (2012). A current review of cypermethrin-induced neurotoxicity and nigrostriatal dopaminergic neurodegeneration. Current neuropharmacology, 10(1), 64-71.
López, A., Yusà, V., Villoldo, E., Corpas-Burgos, F., & Coscollà, C. (2021). Indoor air pesticide in dwellings of breastfeeding mothers of the Valencian Region (Spain): Levels, exposure and risk assessment. Atmospheric Environment, 248, 118231.
López-Jaramillo, P., Gómez-Arbeláez, D., López-López, J., López-López, C., Martínez-Ortega, J., Gómez-Rodríguez, A., & Triana-Cubillos, S. (2014). The role of leptin/adiponectin ratio in metabolic syndrome and diabetes. Hormone molecular biology clinical investigation, 18(1), 37-45.
La Cava, A. (2017). Leptin in inflammation and autoimmunity. Cytokine, 98, 51-58.
Laskowski, D. A. (2002). Physieal and Chemical Properties of Pyrethroids. Reviews of Environmental Contamination Toxicology, 49.
Liao, H.-T., Hsieh, C.-J., Chiang, S.-Y., Lin, M.-H., Chen, P.-C., & Wu, K.-Y. (2011). Simultaneous analysis of chlorpyrifos and cypermethrin in cord blood plasma by online solid-phase extraction coupled with liquid chromatography–heated electrospray ionization tandem mass spectrometry. Journal of Chromatography B, 879(21), 1961-1966.
Lin, H. Y., Yu, I. C., Wang, R. S., Chen, Y. T., Liu, N. C., Altuwaijri, S., Sparks, J. D. (2008). Increased hepatic steatosis and insulin resistance in mice lacking hepatic androgen receptor. Hepatology, 47(6), 1924-1935.
Lin, Z., Shi, J.-L., Chen, M., Zheng, Z.-M., Li, M.-Q., & Shao, J. (2023). CCL2: An important cytokine in normal and pathological pregnancies: A review. Frontiers in Immunology, 13, 1053457.
Lindsey, Verhelst, X., Colle, I., Van Vlierberghe, H., & Geerts, A. (2016). The role of macrophages in obesity-driven chronic liver disease. Journal of Leucocyte Biology, 99(5), 693-698.
Liu, Walden, T. B., Cai, D., Ahl, D., Bertilsson, S., Phillipson, M., Holm, L. (2019). Dietary fiber in bilberry ameliorates pre-obesity events in rats by regulating lipid depot, cecal short-chain fatty acid formation and microbiota composition. Nutrients, 11(6), 1350.
Liu, B.-N., Liu, X.-T., Liang, Z.-H., & Wang, J.-H. (2021). Gut microbiota in obesity. World journal of gastroenterology, 27(25), 3837.
Longo, M., Zatterale, F., Naderi, J., Parrillo, L., Formisano, P., Raciti, G. A., Miele, C. (2019). Adipose tissue dysfunction as determinant of obesity-associated metabolic complications. International Journal of Molecular Sciences, 20(9), 2358.
Loskutoff, D. J., & Samad, F. (1998). The adipocyte and hemostatic balance in obesity: studies of PAI-1. Arteriosclerosis, Thrombosis, Vascular Biology, 18(1), 1-6.
Ma, H., Sun, J., Wu, X., Mao, J., & Han, Q. (2024). Percent body fat was negatively correlated with Testosterone levels in male. PLoS One, 19(1), e0294567.
Ma, X., Zhang, W., Song, J., Li, F., & Liu, J. (2022). Lifelong exposure to pyrethroid insecticide cypermethrin at environmentally relevant doses causes primary ovarian insufficiency in female mice. Environmental Pollution, 298, 118839.
Madsen, C. M., Varbo, A., & Nordestgaard, B. G. (2017). Extreme high high-density lipoprotein cholesterol is paradoxically associated with high mortality in men and women: two prospective cohort studies. European heart journal, 38(32), 2478-2486.
Magne, F., Gotteland, M., Gauthier, L., Zazueta, A., Pesoa, S., Navarrete, P., & Balamurugan, R. (2020). The firmicutes/bacteroidetes ratio: a relevant marker of gut dysbiosis in obese patients? Nutrients, 12(5), 1474.
Malarkey, D. E., Johnson, K., Ryan, L., Boorman, G., & Maronpot, R. R. (2005). New insights into functional aspects of liver morphology. Toxicologic pathology, 33(1), 27-34.
Marchesini, G., Moscatiello, S., Di Domizio, S., & Forlani, G. (2008). Obesity-associated liver disease. The Journal of Clinical Endocrinology Metabolism, 93(11_supplement_1), s74-s80.
Morrison, D. J., & Preston, T. (2016). Formation of short chain fatty acids by the gut microbiota and their impact on human metabolism. Gut microbes, 7(3), 189-200.
Otero, M., Lago, R. o., Lago, F., Casanueva, F. F., Dieguez, C., Gómez-Reino, J. J., & Gualillo, O. (2005). Leptin, from fat to inflammation: old questions and new insights. FEBS letters, 579(2), 295-301.
Ozsolak, F., & Milos, P. M. (2011). RNA sequencing: advances, challenges and opportunities. Nature reviews genetics, 12(2), 87-98.
Qin, S., Budd, R., Bondarenko, S., Liu, W., & Gan, J. (2006). Enantioselective degradation and chiral stability of pyrethroids in soil and sediment. Journal of Agricultural Food Chemistry, 54(14), 5040-5045.
Ravula, A. R., & Yenugu, S. (2021). Pyrethroid based pesticides–chemical and biological aspects. Critical Reviews in Toxicology, 51(2), 117-140.
Reeves, P. G., Nielsen, F. H., & Fahey Jr, G. C. (1993). AIN-93 purified diets for laboratory rodents: final report of the American Institute of Nutrition ad hoc writing committee on the reformulation of the AIN-76A rodent diet. The Journal of nutrition, 123(11), 1939-1951.
Rizal, N. S. M., Neoh, H.-m., Ramli, R., Hanafiah, A., Samat, M. N. A., Tan, T. L., . . . Saw, S. H. (2020). Advantages and limitations of 16S rRNA next-generation sequencing for pathogen identification in the diagnostic microbiology laboratory: perspectives from a middle-income country. Diagnostics, 10(10).
Rui, L. (2014). Energy metabolism in the liver. Comprehensive physiology, 4(1), 177.
Sankar, P., Telang, A. G., & Manimaran, A. (2012). Protective effect of curcumin on cypermethrin-induced oxidative stress in Wistar rats. Experimental and Toxicologic Pathology, 64(5), 487-493.
Sanz, Y., Santacruz, A., & Gauffin, P. (2010). Gut microbiota in obesity and metabolic disorders. Proceedings of the Nutrition Society, 69(3), 434-441.
Sharma, P., Firdous, S., & Singh, R. (2014). Neurotoxic effect of cypermethrin and protective role of resveratrol in Wistar rats. International Journal of Nutrition, Pharmacology, Neurological Diseases, 4(2), 104-111.
Sharma, P., Huq, A. U., & Singh, R. (2014). Cypermethrin-induced reproductive toxicity in the rat is prevented by resveratrol. Journal of human reproductive sciences, 7(2), 99-106.
Shoelson, S. E., Herrero, L., & Naaz, A. (2007). Obesity, inflammation, and insulin resistance. Gastroenterology, 132(6), 2169-2180.
Shuklan, P., Raj, A., Chauhan, K., Madan, P., & Rani, S. (2023). Systematic toxicity of cypermethrin and alterations in behavior of albino rats. ACS omega, 8(16), 14766-14773.
Simaremare, S. R. S., Hung, C.-C., Hsieh, C.-J., & Yiin, L.-M. (2020). Relationship between organophosphate and pyrethroid insecticides in blood and their metabolites in urine: a pilot study. International journal of environmental research public health, 17(1), 34.
Singh, D., Bhagat, S., Raijiwala, P., Dighe, V., & Vanage, G. (2017). Perinatal exposure of pregnant rats to cypermethrin delays testicular descent, impairs fertility in F1 male progeny leading to developmental defects in F2 generation. Chemosphere, 185, 376-385.
Speakman, J. R. (2019). Use of high-fat diets to study rodent obesity as a model of human obesity. International journal of obesity, 43(8), 1491-1492.
Stojanov, S., Berlec, A., & Štrukelj, B. (2020). The influence of probiotics on the firmicutes/bacteroidetes ratio in the treatment of obesity and inflammatory bowel disease. Microorganisms, 8(11), 1715.
Surwit, R. S., Kuhn, C. M., Cochrane, C., McCubbin, J. A., & Feinglos, M. N. (1988). Diet-induced type II diabetes in C57BL/6J mice. Diabetes, 37(9), 1163-1167.
Tacke, F., & Zimmermann, H. W. (2014). Macrophage heterogeneity in liver injury and fibrosis. Journal of hepatology, 60(5), 1090-1096.
Takeuchi, T., Kameyama, K., Miyauchi, E., Nakanishi, Y., Kanaya, T., Fujii, T., . . . Negishi, H. (2023). Fatty acid overproduction by gut commensal microbiota exacerbates obesity. Cell metabolism, 35(2), 361-375. e369.
Tan, H.-w., Liu, X., Bi, X.-p., Xing, S.-s., Li, L., Gong, H.-p., Zhang, W. (2010). IL-18 overexpression promotes vascular inflammation and remodeling in a rat model of metabolic syndrome. Atherosclerosis, 208(2), 350-357.
Tantarpale, S. (2011). Cypermethrin impact on total protein in muscle and liver of the freshwater fish Channa striatus. Science Research Reporter, 1.
Teruel, T., Hernandez, R., & Lorenzo, M. (2001). Ceramide mediates insulin resistance by tumor necrosis factor-α in brown adipocytes by maintaining Akt in an inactive dephosphorylated state. Diabetes, 50(11), 2563-2571.
Thomas, F., Hehemann, J.-H., Rebuffet, E., Czjzek, M., & Michel, G. (2011). Environmental and gut bacteroidetes: the food connection. Frontiers in microbiology, 2, 93.
Van Dam, R., & Seidell, J. (2007). Carbohydrate intake and obesity. European journal of clinical nutrition, 61(1), S75-S99.
Votava, J. A., John, S. V., Li, Z., Fan, J., & Parks, B. W. (2020). Hepatic Aldolase C Regulates the Conversion of Carbohydrates Into De Novo Cholesterol Biosynthesis. Arteriosclerosis, Thrombosis, Vascular Biology, 40(Suppl_1), A225-A225.
Walsh, N. O. a. K. (2007). Adiponectin as an anti-inflammatory factor. Clin Chim Acta, 380.
Wang, H., Wang, Q., Zhao, X.-F., Liu, P., Meng, X.-H., Yu, T., Zhang, Y. (2010). Cypermethrin exposure during puberty disrupts testosterone synthesis via downregulating StAR in mouse testes. Archives of toxicology, 84, 53-61.
Wang, J., Tang, H., Zhang, C., Zhao, Y., Derrien, M., Rocher, E., Obin, M. (2015). Modulation of gut microbiota during probiotic-mediated attenuation of metabolic syndrome in high fat diet-fed mice. The ISME journal, 9(1), 1-15.
Wang, L., Chen, L., Liu, Z., Liu, Y., Luo, M., Chen, N., Zhang, L. (2018). PAI-1 exacerbates white adipose tissue dysfunction and metabolic dysregulation in high fat diet-induced obesity. Frontiers in pharmacology, 9, 1087.
Wang, X., & Cairns, M. J. (2014). SeqGSEA: a Bioconductor package for gene set enrichment analysis of RNA-Seq data integrating differential expression and splicing. Bioinformatics, 30(12), 1777-1779.
Wang, Z., Yao, T., & Song, Z. (2010). Involvement and mechanism of DGAT2 upregulation in the pathogenesis of alcoholic fatty liver disease. Journal of lipid research, 51(11), 3158-3165.
Wang, Z. V., & Scherer, P. E. (2016). Adiponectin, the past two decades. Journal of molecular cell biology, 8(2), 93-100.
Wei, Y., Liu, W., & Liu, J. (2023). Environmentally relevant exposure to cypermethrin aggravates diet-induced diabetic symptoms in mice: The interaction between environmental chemicals and diet. Environment international, 178, 108090.
Weisberg, S. P., McCann, D., Desai, M., Rosenbaum, M., Leibel, R. L., & Ferrante, A. W. (2003). Obesity is associated with macrophage accumulation in adipose tissue. The Journal of clinical investigation, 112(12), 1796-1808.
Wensveen, F. M., Valentić, S., Šestan, M., Wensveen, T. T., & Polić, B. (2015). Interactions between adipose tissue and the immune system in health and malnutrition. Paper presented at the Seminars in Immunology.
WHO. (1989). Cypermethrin: World Health Organization.
Woollen, B., Marsh, J., Laird, W., & Lesser, J. (1992). The metabolism of cypermethrin in man: differences in urinary metabolite profiles following oral and dermal administration. Xenobiotica, 22(8), 983-991.
Yang, Y.-Q., & Yiin, L.-M. (2018). Daily intake estimation for young children’s ingestion of residential dust and soils contaminated with chlorpyrifos and cypermethrin in Taiwan. International Journal of Environmental Research and Public Health, 15(7), 1327.
Ye, X., Li, F., Zhang, J., Ma, H., Ji, D., Huang, X., Liu, J. (2017). Pyrethroid insecticide cypermethrin accelerates pubertal onset in male mice via disrupting hypothalamic–pituitary–gonadal axis. Environmental science technology, 51(17), 10212-10221.
Yen, C.-L. E., Stone, S. J., Koliwad, S., Harris, C., & Farese, R. V. (2008). Thematic review series: glycerolipids. DGAT enzymes and triacylglycerol biosynthesis. Journal of lipid research, 49(11), 2283-2301.
Yuwei Yuan, C. C., Chuangmu Zheng, Xiaoli Wang, Guiling Yang, Qiang Wang, Zhiheng Zhang. (2014). Residue of chlorpyrifos and cypermethrin in vegetables and probabilistic exposure assessment for consumers in Zhejiang Province,China. Food Control, 36, 63-68.
Zeyda, M., & Stulnig, T. M. (2007). Adipose tissue macrophages. Immunology letters, 112(2), 61-67.
Zhang, J., Yi, C., Han, J., Ming, T., Zhou, J., Lu, C., Su, X. (2020). Novel high‐docosahexaenoic‐acid tuna oil supplementation modulates gut microbiota and alleviates obesity in high‐fat diet mice. Food Science Nutrition, 8(12), 6513-6527.
Zhang, Q., Gu, S., Wang, Y., Hu, S., Yue, S., & Wang, C. (2023). Stereoselective metabolic disruption of cypermethrin by remolding gut homeostasis in rat. Journal of Environmental Sciences, 126, 761-771.
Zhang, Y., & Scarpace, P. J. (2006). The role of leptin in leptin resistance and obesity. Physiology & behavior, 88(3), 249-256.
Zhao, J., Liu, P., Wu, Y., Guo, P., Liu, L., Ma, N., Zhang, J. (2018). Dietary fiber increases butyrate-producing bacteria and improves the growth performance of weaned piglets. Journal of Agricultural Food Chemistry, 66(30), 7995-8004.
Zhao, S., Zhu, Y., Schultz, R. D., Li, N., He, Z., Zhang, Z., Xiong, W. (2019). Partial leptin reduction as an insulin sensitization and weight loss strategy. Cell metabolism, 30(4), 706-719. e706.
農業部農業藥物試驗所. (2023). 110年度蔬菜農產品農藥殘留監測研究成果報告.
衛生福利部食品藥物管理署. (2024). 113 年 1-2 月份市售不合格農產品之檢出情形及抽樣地點.
衛生福利部國民健康署. (2022a). 國民營養健康狀況變遷調查.
衛生福利部國民健康署. (2022b). 衛生福利部國民健康署委託研究計畫.