雙酚混合物對斑馬魚胚胎心跳減緩的影響：鈣離子幫浦與鈣離子通道的參與

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姓名	沙林(Salim Arrokhman) 查詢紙本館藏	畢業系所	生命科學系
論文名稱	雙酚混合物對斑馬魚胚胎心跳減緩的影響：鈣離子幫浦與鈣離子通道的參與 (The Involvement of Calcium Pump and Channel on the Additive Effects of Bisphenols Mixture in the Development of Bradycardia in Zebrafish Embryos)
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摘要(中)	雙酚A(bisphenol A, BPA)及其取代物雙酚F(bisphenol F, BPF)、雙酚AF(bisphenol AF, BPAF)和雙酚B(bisphenol B, BPB)的廣泛使用，導致人類與野生動物暴露於多種雙酚混合物之中。相對於單一雙酚化合物的毒性測試，雙酚混合物的毒性分析顯得更為重要且有意義。在本研究中，我們利用斑馬魚胚胎(zebrafish embryos, ZFEs)評估雙酚混合物的毒性(mixture toxicity)。我們發現，無論是單獨還是混合處理，這些雙酚化合物均會隨濃度增加而降低ZFE的存活率與心跳率(heart rate)。以濃度相加模型(concentration addition model)可預測雙酚混合物對ZFE心跳率與存活率的影響。雙酚化合物曝露引發的心跳減緩(bradycardia)顯示其心臟毒性潛力。因此，我們進一步探討雙酚減緩心跳的機轉。雙酚化合物曝露會造成斑馬魚與雌激素反應相關的cyp19a1b基因之mRNA表現上升，證實了雙酚已知具有的雌激素活性。然而，利用雌激素受體阻斷劑ICI 182780雖然可以成功降低雌激素活性，卻未能減輕雙酚曝露所引發的心跳減緩。另外，雙酚化合物的影響僅限於心肌傳導，而非在於心肌收縮力。此外，雙酚化合物曝露對心肌細胞數量並無影響，僅輕微影響了與心肌細胞發育相關基因的mRNA表現。但是雙酚化合物可能藉由降低L型鈣離子通道(L-type calcium channel LTCC)的成孔次單位(pore-forming subunit, cacna1c)之mRNA表現與肌漿網鈣離子幫浦(sarco/endoplasmic reticulum Ca2+-ATPase, SERCA)的活性，而擾亂鈣離子平衡(calcium homeostasis)。此外，雙酚化合物可藉由抑制SERCA活性，而加劇LTCC阻斷劑引發的心臟毒性。綜上所述，我們的結果顯示雙酚混合物具有相加效應(additive effect)性質，而雙酚混合物與鈣離子通道阻斷劑的作用可能會造成難以預測的毒性效應，還有待未來進一步的研究探討。
摘要(英)	Widespread use of bisphenols such as bisphenol A (BPA) and its substitutes bisphenol F (BPF), bisphenol AF (BPAF), and bisphenol B (BPB) lead to a concurrent exposure of multiple bisphenols in human and wildlife. Therefore, analyzing the toxicity of bisphenols in a mixture, rather than individually, is more appropriate. In the present study, we used zebrafish embryos (ZFEs) to assess bisphenols mixture toxicity. We discovered that bisphenols, either individually or in a mixture, concentration-dependently reduced the survival and heart rate of ZFEs. Moreover, the concentration addition model could be used to predict the effects of the bisphenols mixture on the ZFE′s heart rate and survival. Heart rate reduction (bradycardia) induced by bisphenol exposure indicated their cardiotoxic potency. Hence, we sought to explore the mechanisms behind bradycardia induced by bisphenols exposure. Bisphenols exposure upregulated mRNA expressions of an estrogen-responsive gene in zebrafish cyp19a1b, in concordance with a well-known estrogenic activity of bisphenols. Pharmacological blocking of estrogen receptors with ICI 182780 successfully reduced the estrogenic activity but failed to rescue bradycardia induced by bisphenols exposure. Bisphenols seem to affect only cardiac conductivity since there is no change in cardiac contractility parameters. Furthermore, bisphenols exposure has no effects on cardiomyocyte numbers and mildly affects mRNA levels of genes related to cardiomyocyte development. We found that bisphenols might compromise calcium homeostasis by reducing mRNA levels of the pore-forming subunit of L-type calcium channel (cacna1c/LTCC) and the activity of sarco/endoplasmic reticulum Ca2+-ATPase (SERCA). In addition, bisphenols potentiated LTCC blocker-mediated cardiotoxicity, possibly through the inhibition of SERCA activity. Altogether, our results revealed an additive nature of bisphenols in a mixture and their unpredicted toxicity with a calcium channel blocker that warrants further study.
關鍵字(中)	★ 關鍵詞：雙酚化合物 ★ 混合物毒性 ★ 心動過緩 ★ 加成作用 ★ 增效作用	關鍵字(英)	★ Bisphenols ★ Mixture toxicity ★ Bradycardia ★ Additive ★ Potentiation
論文目次	中文摘要 iv Abstract v Acknowledgment vi Publication arising during PhD candidature vii Abstracts arising from this thesis viii Table of contents ix List of Figures xi List of Tables xii Explanation of Symbols and Abbreviations xiii Chapter I. Introduction 1 1-1 Human and environmental exposure to bisphenols 1 1-2 Cardiotoxicity of bisphenol A and its analogues 4 1-3 Single and mixture toxicity assessment 5 1-4 Zebrafish as an animal model 6 1-5 Research objectives 6 1-6 Hypotheses 7 Chapter II. Methods 9 2-1 Experimental design 9 2-2 Zebrafish husbandry 11 2-3 Chemical preparation 11 2-4 Chemical exposure – mortality assessment 12 2-5 Chemical exposure – heart rate assessment and others 12 2-6 Mixture toxicity assessment 14 2-7 Cardiac phenotypic analysis 18 2-8 Mechanistic studies 19 2-8-1 Bisphenols affect zebrafish heart rate through estrogen receptors 19 2-8-2 Bisphenols affect zebrafish heart rate through oxidative stress 20 2-8-3 Bisphenols affect zebrafish heart rate through impairing cardiomyocyte development 20 2-8-4 Bisphenols affect zebrafish heart rate through impairing calcium homeostasis 21 2-9 Gene expression analysis 22 2-10 Immunohistochemistry 22 2-11 Sarco/endoplasmic reticulum Ca2+ ATPase (SERCA) activity assay 23 2-12 Statistical analysis 24 Chapter III. Results 26 3-1 Bisphenols additively decreased survival of ZFEs 26 3-2 Bisphenols additively induce bradycardia in the ZFEs 27 3-3 Bisphenols induced bradycardia at concentrations below that of the BMDL10 of mortality 29 3-4. Bisphenols did not affect the cardiac contractility of ZFEs 31 3-5. Bisphenols estrogenic activity was not correlated with their cardiotoxicity 33 3-6. Oxidative stress might not be responsible for the bradycardia-inducing effects of bisphenols 34 3-7. Cardiomyocyte development might not be affected by bisphenols at concentrations that induced bradycardia 35 3-8. Bisphenols affect mRNA levels of Ca2+ channels and pump which are responsible for maintaining cardiac action potential in ZFEs 37 3-9. Bisphenol interacts with an LTCC blocker via SERCA activity inhibition 38 Chapter IV. Discussion 42 Chapter V. Conclusion 47 Bibliography 48 Appendix 54
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指導教授	林嬪嬪羅月霞(Pinpin Lin Yueh-Hsia Luo)	審核日期	2023-12-14
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