臺灣博碩士論文加值系統

多溴聯苯醚(PBDEs)是一種溴化阻燃劑，主要通過混合聚合物產品來降低火災風險，已被廣泛用於許多產品中。少有研究報告指出是否暴露低劑量四溴二苯醚(BDE-47)對生殖功能的超代影響，而BDE-47對生殖的危害也逐漸的被重視。本研究目的為探討母鼠於妊娠期暴露低劑量BDE-47是否在雄性第三子代產生精子功能毒性之超代效應。SD大鼠(F0)於懷孕第1天至20天每日以胃管餵食玉米油及低劑量0.2 mg/kg之BDE-47，由暴露BDE-47與控制組F0母鼠產下的雄性子代(F1)，分別與未暴露BDE-47母鼠交配產下第二子代(F2)；雄性F2大鼠與未暴露BDE-47母鼠交配產下第三子代(F3)，只有F0懷孕母鼠直接暴露BDE-47。雄性大鼠F1、F2與F3量測體重、尿道口至肛門口距離(AGD)、器官組織重量、精子數量、精子活動力、精子反應性氧化物(ROS)含量、精子粒線體膜電位(MMP)功能、精子DNA傷害指標(DFI)、血清睪固酮濃度、睪丸組織病理學、DNA甲基化轉移酶(DNMTs) mRNA表現量等變化，以探討低劑量BDE-47暴露對雄性大鼠子代精子與睪丸功能之超代影響。研究結果發現F1暴露組的體重、AGD、精子數量、活動力顯著下降；異常MMP、ROS與DFI比控制組顯著上升。F2暴露組的體重、AGD、精子活動力顯著下降；ROS與DFI比控制組顯著上升。F3暴露組的體重、AGD、精子數量顯著下降；異常MMP、ROS與DFI比控制組顯著上升。且DNMT1和DNMT3A mRNA表現量皆顯著低於控制組，顯示BDE-47可能透過表觀基因學影響雄性子代生殖功能。總結而言，親代於妊娠期暴露 低劑量之BDE-47可能會對雄性子代大鼠造成超代睪丸與精子毒性。

Tetrabromodiphenyl ether (BDE-47), a congener of polybrominated diphenyl ethers, is a commonly used brominated flame retardant and a known endocrine disrupting chemical. Knowledge about the effects of prenatal BDE-47 exposure on male reproduction and whether transgenerational effects occur in subsequent generations are scant. Therefore, in this study, we tested the hypothesis that prenatal exposure to BDE-47 disrupted sperm and testicular functions in the F1, F2 and F3 generations of male rats. Pregnant Sprague-Dawley rats were treated by gavage from gestation day 0 to birth with BDE-47 0.2 mg/kg/day. F1 BDE-treated males were bred to unexposed females to generate the F2 treated generation and F2 BDE-treated males were bred to unexposed females to generate the F3 treated generation. On postnatal day 84 for all generations, epididymal sperm counts, motility, morphology, reactive oxygen species (ROS) generation, sperm chromatin DNA structure integrity, testicular DNA content in spermatogenesis, and serum testosterone levels were assessed. DNA methyltransferase (DNMTs) mRNA expression was examined to analyze DNA methylation status in the F3 generation. In the F1 generation, prenatal exposure to BDE-47 disrupted body weight, decreased anogenital distance (AGD), sperm count, and motility; and increased abnormal mitochondrial membrane potential (MMP) rates, ROS generation, and DNA fragmentation index (DFI) of sperm. In the F2 generation, exposure to BDE-47 decreased body weight, AGD, sperm motility, and increased ROS generation and DFI of sperm. In the F3 generation, BDE-47 exposure decreased body weight, AGD, sperm count, and increased abnormal MMP, ROS generation, and DFI of sperm. Compared with the control group, the mRNA expression of DNMT1 and DNMT3A were inhibited in the BDE-47 group in the F3 generation might therefore explain the possible mechanism underlying BDE-47-mediated epigenetic transgenerational effects on the male reproductive system.

摘要 .................................................................................................................. III
Abstract ............................................................................................................. V
誌謝 ................................................................................................................ VII
目錄圖目錄 ...................................................................................................... IX
圖目錄 .............................................................................................................. IX
表目錄 ........................................................................................................... XIV
中英文對照 ..................................................................................................... XV
中英文對照 ................................................................................................... XVI
中英文對照 .................................................................................................. XVII
壹、緒論 ............................................................................................................ 1
1.1前言 ...................................................................................................... 1
1.2研究目的 .............................................................................................. 4
貳、文獻回顧 .................................................................................................... 5
2.1環境荷爾蒙 .......................................................................................... 5
2.1.1多溴二苯醚概論 ........................................................................ 7
2.1.2多溴二苯醚暴露途徑 ................................................................ 8
2.1.3多溴二苯醚危害特性 .............................................................. 10
2.1.4四溴二苯醚基本性質 .............................................................. 11
2.2生殖系統介紹 .................................................................................... 18
2.2.1雄性生殖機能 .......................................................................... 18
2.2.2精子的生成及構造 .................................................................. 20
2.2.3精子細胞週期及睪丸 DNA 含量 .......................................... 23
2.2.4 性荷爾蒙與生殖功能 ............................................................. 25
2.3 粒線體功能介紹 ............................................................................... 26
2.4 反應性氧化物 ................................................................................... 28
2.4.1 何謂反應氧化物 ..................................................................... 28
2.4.2 反應性氧化物與精子功能影響 ............................................. 29
2.5細胞甲基化介紹 ................................................................................ 31
2.5.1 表觀遺傳學簡介 ..................................................................... 31
2.5.2 DNA甲基化 ............................................................................ 31
2.5.3 超代效應 ................................................................................. 34
參、 實驗設計與方法 .................................................................................... 40
3.1研究設計 ............................................................................................ 40
3.2 動物來源 ........................................................................................... 44
3.3 流式細胞儀 ....................................................................................... 45
3.3.1 工作原理 ................................................................................. 45
3.3.2 分析原理 ................................................................................. 47
3.4 雄性生殖毒理評估 ........................................................................... 48
3.4.1藥品與試劑 .............................................................................. 48
3.4.2 儀器與設備 ............................................................................. 52
3.4.3 懸浮液配製 ............................................................................. 53
3.4.4 精子數量 ................................................................................. 54
3.4.5 精子活動力 ............................................................................. 54
3.4.6 精子型態評估 ......................................................................... 55
3.4.7 精子粒線體膜電位分析 ......................................................... 56
3.4.8 精子細胞內過氧化氫 (H2O2) ................................................ 57
3.4.9 精子細胞內超氧陰離子 (O2-) ............................................... 58
3.4.10 精子染色質結構完整性分析 ............................................... 59
3.4.11 睪丸細胞 DNA 含量分析 ................................................... 60
3.4.12 睪丸組織病理學 ................................................................... 61
3.4.13 血清睪固酮 ........................................................................... 61
3.4.14 DNA甲基化轉移酶 .............................................................. 61
3.5 統計分析 ........................................................................................... 63
肆、 結果 ........................................................................................................ 64
4.1 母鼠生育影響 ................................................................................... 64
4.1.1妊娠期母鼠體重變化 .............................................................. 66
4.2 子代生長發育影響評估 ................................................................... 67
4.2.1生長發育指標 .......................................................................... 67
4.2.2離乳前體重觀察 ...................................................................... 69
4.2.3離乳後體重觀察 ...................................................................... 73
4.2.4肛門口至尿道口距離(AGD)觀察 ........................................... 77
4.3 雄性子代生殖功能影響評估 ........................................................... 81
4.3.1體重與臟器組織重量分析 ...................................................... 81
4.3.2精子數量及活動力分析 .......................................................... 84
4.3.3精子染色質DNA結構分析 ................................................... 84
4.3.4精子細胞反應性氧化物分析 .................................................. 85
4.3.5精子粒線體功能分析(MMP) .................................................. 85
4.3.6血清中睪固酮 .......................................................................... 85
4.3.7精子型態 .................................................................................. 87
4.3.8睪丸細胞DNA含量分析 ....................................................... 90
4.3.9睪丸組織病理學 ...................................................................... 93
4.4 DNA甲基化轉移酶 ................................................................... 94
4.5 綜合結果 ........................................................................................... 95
伍、 討論 ........................................................................................................ 96
5.1 生長發育功能影響評估 ................................................................... 96
5.1.1 母鼠生育影響 ......................................................................... 96
5.1.2 BDE-47暴露對生長發育指標與大鼠體重之影響 ................ 96
5.1.3尿道口至肛門口距離(AGD) ................................................... 98
5.1.4 雄性子代臟器組織重量 ......................................................... 99
5.2 生殖功能影響評估 ........................................................................ 100
5.2.3雄性子代精子功能之影響評估 ............................................ 100
5.2.4 BDE-47對睪丸DNA含量之影響 ....................................... 102
5.2.5 DNA甲基化轉移酶 .............................................................. 103
陸、 結論 ...................................................................................................... 106
柒、 參考文獻 .............................................................................................. 107

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