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http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/99147完整後設資料紀錄
| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 王家琪 | zh_TW |
| dc.contributor.advisor | Chia-Chi Wang | en |
| dc.contributor.author | 郭瑞芳 | zh_TW |
| dc.contributor.author | Jui-Fang Kuo | en |
| dc.date.accessioned | 2025-08-21T16:34:29Z | - |
| dc.date.available | 2025-08-22 | - |
| dc.date.copyright | 2025-08-21 | - |
| dc.date.issued | 2025 | - |
| dc.date.submitted | 2025-08-01 | - |
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/99147 | - |
| dc.description.abstract | 芬普尼是一種苯基吡唑類殺蟲劑，廣泛應用於農業、家庭害蟲防治與獸醫治療領域， 傳統上被認為對脊椎動物毒性較低。然而，越來越多研究指出，芬普尼暴露可能對肝臟、生 殖系統與神經系統造成預期之外的不良影響。儘管如此，其對免疫功能，特別是 T 淋巴細 胞反應的影響仍未被充分探討。本研究使用體內與體外兩種模型，系統性評估芬普尼對成熟 與發育中 T 淋巴細胞的免疫毒性。結果顯示，在免疫卵白蛋白小鼠中口服投予芬普尼後， 對卵白蛋白的抗原特異性免疫反應顯著增強，包括促進脾臟細胞代謝活性上升、增加細胞激 素 IL-2、IL-4 與 IFN-γ 分泌量，以及同時增加抗原專一性 OVA-IgG 1 與 OVA-IgG 2a 血清抗體 濃度。基因表現的分析顯示，GABA 調控相關的基因受到影響，其中 Gad67 的基因表現下 降，以及 GABA 受體次單元（β2 和 δ）的基因表現則上升。這些結果顯示，芬普尼可能 藉由干擾 GABA 路徑基因調控 T 淋巴細胞的免疫抑制作用，從而增強抗原特異性免疫反應 不正常的活化。
由於胸腺細胞的生成與 T 細胞的成熟分化是後天免疫系統發育的重要作用，我們進一 步評估芬普尼對胸腺發育的影響。結果發現，芬普尼會引起胸腺明顯萎縮、雙陽性胸腺細胞 比例與數量下降，T 細胞成熟受到抑制與 IL-7 與其受體表現下降密切相關。IL-7 是胸腺早期 發育中不可或缺的細胞激素，支持雙陰性階段後 T 淋巴細胞的的存活、增殖和分化。研究亦 發現芬普尼抑制 IL-7 軸相關基因和蛋白（包括 FOXN1、LYL1、SCF 和 c-KIT）的表現，進 一步破壞了細胞增生所需的胸腺微環境。除胸腺發育訊號受到抑制外，芬普尼也誘發胸腺細 胞的氧化壓力，包括細胞內活性氧含量上升、粒線體膜電位去極化、脂質過氧化、鈣離子與 穀胱甘肽濃度下降等現象。同時，BCL-2 家族基因表現失衡，抗凋亡基因抑制、促凋亡基因 如 Bim 與 Bnip3 表現異常，顯示芬普尼誘發粒線體凋亡機制，最終導致胸腺細胞死亡。綜合我們的研究結果所示，芬普尼具有兩種機制，其一是干擾 GABA 相關基因包含合成與傳 遞 GABA 的機制失調，進而誘發 Th1/Th2 細胞激素同時過度分泌，造成 T 細胞的過度活化； 另外是抑制 IL-7 訊號及維持胸腺微環境所需之轉錄因子和誘發氧化性傷害以破壞胸腺 T 淋 巴細胞發育，最終造成免疫細胞調控的失調。我們的研究成果突顯出暴露芬普尼對 T 細胞 功能與發育的潛在毒性作用，全面地重新評估芬普尼對於青春期脊椎動物的安全性為重要的 課題。 | zh_TW |
| dc.description.abstract | Fipronil (FPN) is a phenylpyrazole pesticide widely used in agriculture, household pest control, and veterinary medicine. It is traditionally considered to have low toxicity in vertebrates. However, growing evidence suggests that FPN exposure may lead to unexpected adverse effects on the liver, reproductive system, and nervous system. Despite these findings, its influence on immune function, particularly on T cell responses, remains poorly understood. In this study, I systematically investigated the immunotoxic effects of FPN on both mature and developing T cells using in vivo and ex vivo models. Oral administration of FPN in ovalbumin-sensitized mice enhanced antigen-specific immune responses, as indicated by increased splenocyte metabolic activity, elevated production of IL-2, IL-4, and IFN-γ, and higher serum levels of OVA-IgG 1 and OVA-IgG2a . Gene expression analysis revealed that GABAergic signaling was altered, with a significant decrease in Gad67 and an increase in GABA receptor subunits (β2 and δ). These findings suggest that FPN may interfere with the inhibitory role of GABAergic pathways in T cell regulation, thereby enhancing antigen-specific immune activation.
Because T cell lineage commitment and thymopoiesis are fundamental to functional adaptive immunity, I further examined the impact of FPN on thymic development. FPN exposure induced marked thymic atrophy, reduced the proportion of double-positive thymocytes, and impaired T cell maturation. These effects were closely linked to the suppression of IL-7 and IL-7 receptor expression. As a key cytokine in early thymocyte development, IL-7 supports survival, proliferation, and differentiation beyond the double-negative stage. Downregulation of IL-7 axis-related genes and proteins, including FOXN1, LYL1, SCF, and c-KIT, further disrupted the thymic microenvironment required for progenitor cell expansion. In addition to impairing developmental signaling, FPN exposure triggered oxidative stress in thymocytes. Elevated reactive oxygen species, mitochondrial membrane depolarization, lipid peroxidation, calcium depletion, and glutathione reduction were observed. Moreover, an imbalance in BCL-2 family gene expression was detected, with downregulation of anti-apoptotic genes and dysregulation of pro-apoptotic regulators such as Bim and Bnip3. These alterations activated mitochondrial apoptosis and led to thymocyte death. Taken together, our results demonstrate that FPN compromises immune system integrity through a dual mechanism involving enhanced peripheral T cell activity and disrupted thymic development via GABAergic imbalance, IL-7 signaling suppression, transcriptional factors for supporting thymic microenvironment, and oxidative damage. Our findings highlight the potential risk to immune system integrity from contaminant exposure to FPN and the need for a more comprehensive reassessment of the safety of fipronil in pubertal vertebrates. | en |
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| dc.description.tableofcontents | 國立臺灣大學博士學位論文口試委員會審定書 ......................................................... i
聲明 ......................................................................................... ii 致謝 ........................................................................................ iii 中文摘要 ...................................................................................... v Abstract ................................................................................... vii Contents .................................................................................... ix Figures .................................................................................... xii Tables ..................................................................................... xiv List of Abbreviations ....................................................................... xv Chapter 1. Background and literature review .................................................. 1 1.1 Introduction and applications of fipronil .................................................1 1.1.1 Fipronil: chemical properties and broad applications ....................................1 1.1.2 Fipronil metabolism and pharmacokinetics ................................................2 1.1.3 Sustained bioaccumulation of fipronil metabolites under intermittent exposure regimens ..3 1.1.4 Regulatory toxicological endpoints and human risk assessment of fipronil ................5 1.1.5 Veterinary clinical applications of fipronil ............................................7 1.1.6 Global usage and potential exposure pathways of fipronil ................................9 1.2 Toxicological mechanisms of fipronil .....................................................12 1.2.1 Insecticide modes of action: selective antagonism of insect GABA-gated chloride channels 12 1.2.2 Acute toxicity of FPN in mammals .......................................................13 1.2.2 Non-target toxicity of fipronil in vertebrates .........................................15 1.2.3 Fipronil-induced oxidative damage in mammals ...........................................20 1.2.4 N-acetylcysteine (NAC): biochemical properties and rationale for use ...................22 1.3 Immunotoxicity of fipronil and T cell development ........................................24 1.4 The role of GABAergic signaling in immune regulation .....................................26 1.4.1 GABAergic components and their mediated effects in T-cells .............................27 1.5 T cell development and lineage commitment in the thymus...................................31 1.5.1 IL-7 and IL-7R expression in the thymus ................................................32 1.5.2 Downstream signaling pathways of IL-7 and IL-7R interaction ............................32 1.5.3 Functional roles of IL-7 signaling in T cell development ...............................33 1.5.4 Disruption of IL-7 signaling ...........................................................34 1.5.5 Transcription factors regulating T cell lineage commitment .............................35 1.5.6 The regulatory roles of ROS and apoptosis in thymocyte development .....................37 Chapter 2. Rationale ........................................................................ 40 Chapter 3. Materials and Methods ............................................................ 43 3.1 Reagents .................................................................................43 3.2 Experimental animals .....................................................................43 3.3 Protocol of fipronil administration and murine model .....................................43 3.3.1 Ovalbumin (OVA)-specific immune model ..................................................43 3.3.2 Thymus developing murine model .........................................................46 3.4 Measurement of spleen enlargement ........................................................48 3.5 Measurement of thymus enlargement ........................................................48 3.6 Histological Examination .................................................................48 3.7 Immunohistochemical (IHC) Analysis .......................................................48 3.8 Splenocyte and thymocyte isolation and culture ...........................................49 3.9 Flow cytometric analysis for cellularity of splenocytes ..................................49 3.10 Flow cytometric analysis for cellularity of thymocytes ..................................50 3.11 Metabolic activity by MTT assay .........................................................50 3.12 Enzyme-linked immunosorbent assay (ELISA) ...............................................51 3.12.1 Measurement of OVA-specific antibodies ................................................51 3.12.2 Measurement of cytokines ..............................................................52 3.13 RNA isolation and cDNA synthesis ........................................................52 3.14 Quantitative polymerase chain reaction (qPCR) assay .....................................53 3.15 Preparation of thymus protein extracts ..................................................57 3.16 BCA TM protein assay ....................................................................57 3.17 Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) ....................57 3.18 Western blotting ........................................................................58 3.19 In vitro model ..........................................................................59 3.19.1 Assessment of apoptotic/necrotic indicators ...........................................59 3.19.2 Measurement of mitochondrial depolarization ...........................................60 3.19.3 Measurement of intracellular calcium concentration (Ca2+) .............................61 3.19.4 Detection of glutathione (GSH) activity ...............................................61 3.19.5 Quantification of intracellular ROS levels ............................................62 3.19.6 Evaluation of lipid peroxidation (LPO) ................................................63 3.20 Statistical analysis ....................................................................63 3.21 Bioinformatic analysis ..................................................................64 Chapter 4. Experimental Results ............................................................. 65 4.1 Fipronil perturbs antigen-specific immune responses and alters GABAergic gene expression in ovalbumin-immunized BALB/c mice. .......................................................................65 4.1.1 Effects of FPN exposure on body weight, spleen index, and spleen cellularity in vivo ...65 4.1.2 Modulation of antigen-specific antibody production by FPN administration ...............68 4.1.3 FPN enhanced the cell viability and disturbed IL-2, IL-4, and IFN-γ production ex vivo. 70 4.1.4 FPN slightly down-regulated Il-2, Il-4, and Gata3 expression by OVA-stimulated splenocytes 72 4.1.5 FPN altered GABAergic signaling gene expression by primary splenocytes .................74 4.2 Investigating the potential immunotoxicity of FPN disrupting IL-7 signaling in a young mouse model of thymic development. ..........................................................................76 4.2.1 FPN affected body weight, thymus index, and population of thymocytes in vivo. ..........76 4.2.2 FPN leads to a dose-dependent reduction in thymocyte numbers in mice. ..................80 4.2.3 Effects of the cortex, medulla ratio, and thymus atrophy ...............................80 4.2.4 Impact of FPN exposure on IL-7 protein expression ......................................84 4.2.5 FPN significantly decreases mRNA expression of transcription factors of T-cell lineage and IL-7 signaling in the thymus. .....................................................................86 4.2.6 Reduction of T-Cell lineage transcription factors and IL-7 signaling-associated proteins in the thymus by FPN ................................................................................88 4.2.7 FPN significantly decreased mRNA expression of Il7r, Scf, Gabpα, Lyl1, and Sox13 in ConA- stimulated thymocytes. .......................................................................91 4.2.8 Differential effects of FPN on the production of IL-2, IL-4, and IFN-γ ex vivo. ........93 4.3 The potential mechanism of FPN-induced thymic immunotoxicity through reactive oxygen species-driven mitochondrial apoptosis. .....................................................................96 4.3.1 FPN significantly attenuated the mRNA expression of key Bcl-2 family members in vivo. ..96 4.3.2 FPN significantly attenuated Bcl-2 family mRNA expression in ConA-stimulated thymocytes ex vivo. ..............................................................................................99 4.3.3 Acute in vitro exposure to FPN significantly attenuated anti-apoptotic mRNA expression in primary thymocytes. .................................................................................101 4.3.4 Cytotoxic and immunosuppressive effects of FPN on primary thymocytes ..................103 4.3.5 Effects of FPN treatment on apoptosis in the primary thymocytes in vitro. .............105 4.3.7 Fipronil induces depletion of intracellular calcium in primary thymocytes. ............109 4.3.8 Fipronil reduces intracellular glutathione levels in primary thymocytes. ..............111 4.3.9 Fipronil induces intracellular reactive oxygen species accumulation in primary thymocytes. 113 4.3.10 Fipronil exposure elevates lipid peroxidation in primary thymocytes. .................115 4.4 Bioinformatic analysis of the gene-network and inferring diseases by FPN-altered genes ..117 Chapter 5. Discussion ...................................................................... 128 5.1 Off-target toxicity of FPN ..............................................................128 5.2 Fipronil induced both Th1 and Th2 responses by dysregulation of GABAergic signaling .....129 5.2.1 Immunostimulatory effects of FPN on adaptive immune responses and the complexities of Th1/Th2 balance......................................................................................129 5.2.2 The pivotal role of GABAergic signaling in immune regulation ..........................130 5.2.3 FPN's potential influence on GABA synthesis and transport pathways ....................130 5.2.4 Impact of FPN on GABA A receptor expression and potential compensatory mechanisms .....131 5.3 Impact of FPN on thymic development and its influence on IL-7 signaling and critical transcription factors .....................................................................................134 5.3.1 FPN-induced thymic atrophy and developmental blocks ...................................134 5.3.2 Dysregulation of IL-7 signaling .......................................................136 5.3.3 Alteration of transcription factors associated with thymus development by FPN .........137 5.3.4 FPN alters cytokine secretion in thymocytes ...........................................138 5.3.5 Potential involvement of glucocorticoid pathways in FPN-induced thymic atrophy ........138 5.4 Oxidative stress as a central mechanism in FPN-induced immunotoxicity and apoptosis .....140 5.4.1 Apoptotic dysregulation in the thymus .................................................140 5.4.2 Mitochondrial dysfunction and oxidative stress ........................................142 5.4.3 Antioxidant intervention with N-acetylcysteine ........................................143 5.5 Potential off-target toxicities and disease risks associated with FPN-induced gene dysregulation ............................................................................................ 145 Chapter 6. Summary and Conclusion .......................................................... 147 Chapter 7. Future perspectives ............................................................. 150 Reference .................................................................................. 153 Appendix ................................................................................... 173 | - |
| dc.language.iso | en | - |
| dc.subject | 介白素-7 | zh_TW |
| dc.subject | 細胞凋亡 | zh_TW |
| dc.subject | Bcl-2 家族 | zh_TW |
| dc.subject | 氧化壓力 | zh_TW |
| dc.subject | 粒線體膜電位 | zh_TW |
| dc.subject | 穀胱甘肽 | zh_TW |
| dc.subject | 芬普尼 | zh_TW |
| dc.subject | 脂質過氧化 | zh_TW |
| dc.subject | 胸腺萎縮 | zh_TW |
| dc.subject | 胸腺細胞發育 | zh_TW |
| dc.subject | GABAergic 基因 | zh_TW |
| dc.subject | 抗原特異性免疫反應 | zh_TW |
| dc.subject | 免疫毒性 | zh_TW |
| dc.subject | glutathione | en |
| dc.subject | fipronil | en |
| dc.subject | immunotoxicity | en |
| dc.subject | antigen-specific immune responses | en |
| dc.subject | GABAergic signaling | en |
| dc.subject | thymocyte development | en |
| dc.subject | thymus atrophy | en |
| dc.subject | interleukin-7 | en |
| dc.subject | apoptosis | en |
| dc.subject | Bcl-2 family | en |
| dc.subject | oxidative stress | en |
| dc.subject | mitochondrial membrane potential | en |
| dc.subject | lipid peroxidation | en |
| dc.title | 芬普尼透過誘導粒線體凋亡、介白素-7 基因調控的失調及干擾 GABA 基因介導之免疫調節作用以擾亂免疫功能的恆定 | zh_TW |
| dc.title | Fipronil Disrupts Immune Homeostasis Through Mitochondrial Apoptosis, Dysregulated IL-7 Signaling, and GABAergic Signaling Alterations | en |
| dc.type | Thesis | - |
| dc.date.schoolyear | 113-2 | - |
| dc.description.degree | 博士 | - |
| dc.contributor.oralexamcommittee | 詹東榮;張芳嘉;梁有志;張猷忠;林英琦;曾湘文 | zh_TW |
| dc.contributor.oralexamcommittee | Tong-Rong Jan;Fang-Chia Chang;Yu-Chih Liang;Yu-Chung Chang;Ying-Chi Lin;Hsiang-Wen Tseng | en |
| dc.subject.keyword | 芬普尼,免疫毒性,抗原特異性免疫反應,GABAergic 基因,胸腺細胞發育,胸腺萎縮,介白素-7,細胞凋亡,Bcl-2 家族,氧化壓力,粒線體膜電位,穀胱甘肽,脂質過氧化, | zh_TW |
| dc.subject.keyword | fipronil,immunotoxicity,antigen-specific immune responses,GABAergic signaling,thymocyte development,thymus atrophy,interleukin-7,apoptosis,Bcl-2 family,oxidative stress,mitochondrial membrane potential,glutathione,lipid peroxidation, | en |
| dc.relation.page | 226 | - |
| dc.identifier.doi | 10.6342/NTU202501708 | - |
| dc.rights.note | 同意授權(全球公開) | - |
| dc.date.accepted | 2025-08-05 | - |
| dc.contributor.author-college | 生物資源暨農學院 | - |
| dc.contributor.author-dept | 獸醫學系 | - |
| dc.date.embargo-lift | 2025-08-22 | - |
| 顯示於系所單位： | 獸醫學系 | |
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