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研究生:翁紹評
研究生(外文):Shao-Ping Weng
論文名稱:乙二醇甲醚對卵巢功能之影響可能會傳遞至下一代
論文名稱(外文):The Impact of Ethylene Glycol Monomethyl Ether on Ovarian Function May Extend to the Next Generation in Female Mice: A Preliminary Study
指導教授:陳保中陳保中引用關係
口試委員:陳思原楊雅倩郭育良許昺奇
口試日期:2012-05-21
學位類別:博士
校院名稱:國立臺灣大學
系所名稱:職業醫學與工業衛生研究所
學門:醫藥衛生學門
學類:公共衛生學類
論文出版年:2012
畢業學年度:100
語文別:英文
論文頁數:104
中文關鍵詞:環境毒化物生殖細胞生殖毒理乙二醇甲醚細胞凋亡胚胎植入前遺傳診斷男性不孕症
外文關鍵詞:environmental toxicantgerm cellreproductive toxicologyethylene glycol monomethyl etherapoptosispreimplantation genetic diagnosismale infertility
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研究目的: 不孕症在人口中比率約十分之一到七分之一, 人數不少並逐年上升, 加上晚婚者亦越來越多, 使更多婦女加長其暴露在職業環境一些不利因子中的時間, 2005年科學雜誌 (Science) 報導環境毒化物可以干擾生殖細胞的基因調控並可影響之後數代, 重要的是這些毒化物有的是可逆或可預防的。 依目前對這些物質的女性生殖毒理研究較少有從卵、受精模式、基因調控、胚胎發育等結合到妊娠結果及子代的發育等微觀機轉直接並一系列之觀察。因此,本研究依美國National Toxicology Program選擇常用溶劑乙二醇甲醚 (ethylene glycol monomethyl ether; EGME) 為毒性暴露物, 以小鼠體外受精為研究模式, 試圖結合傳統荷爾蒙檢測, 精、卵受精情形及胚胎發育,卵巢及顆粒細胞 (granulosa cells) 受毒化物影響導致細胞凋亡 (apoptosis) 與基因調控因子受干擾情形, 和子代發育及其生育力,希望發展出合適的檢測模式, 以期對預防與不孕症的治療有所幫助。
研究方法: 第一步,導入體外受精技術 (in-vitro fertilization; IVF) ,以檢驗EGME在第零代 (暴露代; F0) 與子代 (第一代; F1) 卵與卵丘複合體 (cumulus-oocyte complex; COC) 所造成毒性。先於第零代母鼠暴露EGME一週,劑量分別為0%, 0.05%, 0.1%, 0.2%,之後予以誘導排卵後取卵,每隻留下10顆COC,其餘去除cumulus cells 只留下卵。這些卵與COC 先經terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) 染色,再以4'',6-diamidino-2-phenylindole (DAPI)染出所有細胞核,以確定細胞核數目。第一代到第六週體重接近25-30 gm之成熟母鼠則只予以誘導排卵後取卵,之後進行相同實驗步驟。最後計算apoptosis 的程度= The number of TUNEL-positive cells/The number of DAPI-positive cells
第二步,因人類基因檢測模組之取得較易,但人類無法進行暴露毒化物,因此使用嚴重型態之男性不孕症患者之精蟲,即副睪(microsurgical epididymal sperm aspiration; MESA) 與睪丸 (testicular sperm extraction; TESE) 直接取精,對照組為自然射精 (EJAC)。這些異常率較高之精子被用來暫代已暴露的配子,我們在執行IVF治療同時使用胚胎植入前遺傳診斷 (preimplantation genetic diagnosis; PGD) 的病人身上觀察其染色體異常率,並可以此當作未來建立檢驗之model. PGD 技術以螢光融合技術(fluorescence in situ hybridization; FISH) 為主。異常染色體分型為: 多套體 (polyploidy),單套體 (haploidy),非整倍體 (aneuploidy) 與複雜型異常 (complex abnormal)。
結果與討論: 第一個實驗,巨觀上,所有第一代母鼠都可以生下小鼠,雖然統計上每一暴露組平均所產下的子代小鼠沒有差異,但隨者劑量增加,變異的情形也加大。卵丘複合體COC 的凋亡率 (apoptosis ratio) 在沒有暴露的子代卻隨著暴露劑量增加而上升。PGD 的觀察研究裡,副睪,睪丸與自然射精所受精之胚胎,染色體異常率並無統計上顯著分別,但其正常率均低於50% (分別為41 ± 31%, 48 ± 38%, and 48 ± 31%, in MESA, TESA, and EJAC) 。 胚胎型態分類包含blastomere number 與分級 (embryo grading),是與染色體型態及正常率成正相關。
結論: 在卵丘細胞所呈現之凋亡率增加的現象應與EGME所造成的生殖毒性有關。而這種生殖毒性似乎會傳遞到下一代,如果可以檢測到第二與第三代(F2, F3),並將觀察後的胚胎植入(embryo transfer) 無暴露之母鼠,便能更確定EGME 的生殖遺傳隔代穿透之特性。PGD 檢驗可以提供更詳細分子層次的檢查,讓我們更清楚異常發於分子層次之位址。合併 IVF 與PGD 之研究系統 (study model),可為生殖毒理帶來更清楚的發生機轉。


Background and objectives: Environmental hazards, such as ethylene glycol monomethyl ether (EGME) and numerous new chemicals cannot be excluded from the impact on the reproductive function. To date, there are guidelines, based on in-vivo animal studies, for reproductive toxicological tests. However, those studies were mostly focused on developmental results such as teratogenicity. Much less molecular information related to fertility had been gained. So far, no sufficient knowledge from in-vitro models can pinpoint the mechanism of hazards on reproduction system. Therefore, within the frame of reproductive toxicology in females, there is an urgent necessity for toxicity-testing systems which are prognostic at the early stage, provide a better approach into the mechanisms leading to reproductive failure, and detect quantitatively and qualitatively the toxic damage to the process of oogenesis. After the animal experiment of reproductive toxicity, we tried to introduce the preimplantation genetic diagnosis (PGD) technology in in-vitro fertilization (IVF) system to clarify the molecular impact of EGME. Thereafter, we established the PGD system by evaluating the patterns of chromosome abnormalities in embryos that derived from intracytoplasmic sperm injection (ICSI) in microsurgical epididymal sperm aspiration (MESA) and testicular sperm extraction (TESE) patients in comparison to embryos derived from naturally ejaculated patients (EJAC). Those sperm from severe male factors may be damaged by some reasons, including environmental hazards, before fertilization. Thus, the main aim of this study is to explore the effects of EGME on reproductive functions by means of in-vitro culture and fertilization systems. Then, PGD was performed in severe male infertility.
Materials and Methods: First, this study assessed the toxicity of EGME on oocytes and cumulus-oocyte-complexes (COCs) by analyzing the number of oocytes in the F0 and F1 generations and evaluating apoptosis in oocytes and COCs after treating the F0 generation with EGME. There was a dose-dependent increase in the apoptosis ratios in the COCs from F1 mice, which were not directly exposed to EGME, with apoptosis ratios of 0.065, 0.102, 0.184, and 0.212 for the 0%, 0.05%, 0.1%, and 0.2% EGME dose groups, respectively. The retrieved COCs and denuded oocytes were prepared for terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining. As a negative control, the cells were labeling solution without the TdT enzyme; as a positive control, the cells were treated with DNase I. Blue fluorescent nuclei were observed in non-apoptotic cells that were only stained with 4'',6-diamidino-2-phenylindole (DAPI). Greenish-blue nuclei were observed in apoptotic cells stained with fluorescein in the TUNEL assay. Second, PGD was performed by fluorescence in situ hybridization (FISH). Chromosome abnormalities were categorized into polyploidy, haploidy, aneuploidy, and complex abnormality, which involved more than two chromosomes. The relationship between the embryo scoring system, combining embryo grading and blastomere numbers, and chromosomal were studied.
Results: All of the mice gave birth. There were no significant differences among these groups; however, the variance in pup number among the mice was much higher in the highest dose (0.2%) group compared to the other groups. The apoptosis ratios in the F1 animals, which were not directly exposed to EGME, were significantly different (p=0.002) among the four groups and showed dose-dependent increases. In the PGD study, there was no difference in the rates of fertilization and pregnancy and the percentages of euploid embryos among the MESA, TESE, and EJAC patient groups. In all three groups, less than half of the embryos that were analyzed by PGD were normal (41 ± 31%, 48 ± 38%, and 48 ± 31%, in MESA, TESA, and EJAC, respectively). Complex chromosomal abnormality was significantly more frequent in the MESA group than in the EJAC group (48.3% versus 26.5%, p<0.001). When both blastomere numbers and grades were considered, the 7–8 A/B subgroup had the highest euploidy rates in the MESA/TESE (58.3%), ICSI/EJAC (61.3%) and IVF/EJAC (59.7%) groups.
Conclusion: The increased apoptosis of cumulus cells may play a role in the toxicity of EGME toward ovarian function. EGME toxicity seems to affect female offspring in future generation(s). This study model for reproductive toxicology appears useful in diagnosing environmental hazards but further studies including embryo transfer should be considered to bring out more solid results. PGD seems applicable to explore the molecular damage of environmental chemicals. However, advanced technology, such as array comparative genomic hybridization, for whole genome survey should be considered instead of FISH.


目 錄
口試委員會審定書 .……………i
誌謝 .……………ii
中文摘要 ……………iii
英文摘要 …………….v
目 錄 ……………viii
圖目錄 ………….…xi
表目錄 ……………xiii

論文內文
Chapter 1 Overview of Reproductive Toxicology of Ethylene Glycol Monomethyl Ether (EGME)
1.1 Introduction ……………1
1.2 Reproductive toxicological studies of EGME ……………2
1.3 Apoptosis in reproductive biology ……………4
1.4 Purposes of this study ……………7
1.5 References ……………8

Chapter 2 The Impact of Ethylene Glycol Monomethyl Ether on Ovarian Function May Extend to the Next generation in Female mice: A Preliminary Study
2.1 Introduction ……………12
2.2 Material and methods ……………14
2.3 Results ……………17
2.4 Discussion ……………19
2.5 References ……………24

Chapter 3 Chromosome abnormalities in embryos derived from microsurgical epididymal sperm aspiration (MESA) and testicular sperm extraction (TESE)
3.1 Introduction ……………32
3.2 Material and methods ……………34
3.3 Results ……………35
3.4 Discussion ……………37
3.5 References ……………40

Chapter 4 The Chromosomal Complement and its Correlation to Embryonic Morphology in In-vitro Fertilization Cycles
4.1. Introduction ……………48
4.2. Material and methods ……………50
4.3. Results ……………54
4.4. Discussion ……………58
4.5. References ……………61

Chapter 5 Future research ……………73

附錄
Appendix 1 ……………75
S.P. Weng, T.C. Wu, S.U. Chen, J. Wu, C.C. Lin, Y.C. Yang, P.C. Chen. The impact of ethylene glycol monomethyl ether on ovarian function may extend to the next generation in female mice: a preliminary study. Reproductive Toxicology. 2010, 29(4)
Appendix 2 ……………82
Accept letter from Taiwanese journal of Obstetrics and Gynecology
Appendix 3 ……………83
S.P. Weng, M.W. Surrey, H.C. Danzer, D.L. Hill, P.C. Chen, T.C.J. Wu. Chromosome abnormalities in embryos derived from microsurgical epididymal sperm aspiration (MESA) and testicular sperm extraction (TESE). Taiwanese Journal of Obstetrics and Gynecology, in press.

圖目錄
Figure 2.1 ……………30
Apoptosis determined by TUNEL staining of COCs and oocytes from the F1 generation groups treated with various doses of EGME. The study included 994 oocytes (448 from the F0 generation and 546 from the F1 generation) and 97 COCs (34 from the F0 generation and 63 from the F1 generation). Optical differential interference contrast images (left panel), DAPI staining for all cell nuclei (blue, middle panel; D), and TUNEL staining for apoptotic nuclei (green, right panel; T) are shown. Apoptosis ratios were determined by dividing the number of TUNEL-positive cells by the number of DAPI-positive cells.
Figure 4.1 ……………68
Demonstration of chromosomal patterns by fluorescence in situ hybridization analysis. A: euploidy, B: haploidy ([13], [18], [21]), C: polyploidy (6[13], 6[18], 6[21]), D: simple aneuploidy (ex. trisomy 21), E: complex abnormality (4[13], 2[18], 4[21], 4[X], 3[Y]). Red: chromosome 13, Blue: chromosome 18, Green: chromosome 21, Purple: chromosome X, Yellow: chromosome Y, “Courtesy and with permission, Santiago Munne”
Figure 4.2 ……………69
The definition of embryo grading. A: A grade “A” (8-cell) embryo with negligible fragmentation, regular blastomeres, homogeneous cytoplasm, and no cytoplasmic defects such as vacuoles. B: A grade “B” (8-cell) embryo with up to 20% cellular fragmentation and blastomeres with mildly unequal sizes. C: A grade “C” (6-cell) embryo with up to 50% fragmentation and a noticeable amount of defects in the blastomere cytoplasm, always with blastomeres of unequal sizes. D: A grade “D” (5-cell) embryo with more than 50% cellular fragmentation and rarely displaying discernible blastomeres.
Figure 4.3 ……………70
The relationship between embryo grading and chromosomal abnormalities. The euploidy rates were not statistically different among the three groups for each embryo grade. There were, however, statistically significant differences in the average euploidy rate between grade A and B embryos (p < 0.001) and between grade B and C/D embryos (p < 0.001). The total embryo numbers in groups A, B, and C/D were 488, 877 and 341, respectively.
Figure 4.4 ……………71
The relationship between blastomere number and chromosomal abnormalities. The euploidy rates were not statistically different among the three groups. The average euploidy rates were significantly different between the ≥9 and the 7–8 group (p =0.001), and between the 7–8 group and the ≤6 group (p < 0.001) as well as between the ≥9 group and the ≤6 group (p < 0.001). The total embryo numbers in the ≥9, 7–8, and ≤6 groups were 298, 863 and 545, respectively.
Figure 4.5 ……………72
The relationship between embryo development (combining embryo grading and blastomere number) and chromosome abnormalities. The highest euploidy rate was observed in the 7–8 A/B subgroup at 60.9%. The total embryo numbers in each group (from left to right) were 263, 800, 83, 333, and 224, respectively.

表目錄
Table 2.1 ……………28
The EGME toxicity experiments: apoptosis ratios of COCs in the F1 generation rise as the EGME doses increases.
Table 3.1 ……………43
The demographic data of the three investigated groups.
Table 3.2 ……………44
Chromosome abnormalities in MESA-, TESE-, and EJAC-derived embryos.
Table 3.3 ……………45
Chromosome abnormalities in MESA-, TESE-, and EJAC-derived embryos using only five probes (chromosomes 13, 18, 21, X, and Y).
Table 3.4 ……………46
The number of abnormal copy in each studied chromosome.
Table 4.1 ……………65
The demographic data of the investigated groups.
Table 4.2 ……………66
Adjusted pregnancy rates by the logistic regression model
Table 4.3 ……………67
Chromosome patterns in MESA/TESE-, and ICSI/EJAC- derived embryos vs. those from IVF/EJAC.


Chapter 1
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Chapter 2
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[16] Corcoran G, Fix L, Jones D, Moslen M, Nicotera P, Oberhammer F, et al. Apoptosis: molecular control point in toxicity. Toxicol Appl Pharmacol 1994;128:169-81.
[17] Billig H, Chun SY, Eisenhauer K, Hsueh AJ. Gonadal cell apoptosis: hormone-regulated cell demise. Hum Reprod Update 1996;2:103-17.
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Chapter 3
1.Palermo, G., et al., Pregnancies after intracytoplasmic injection of single spermatozoon into an oocyte. Lancet, 1992. 340(8810): p. 17-8.
2.Temple-Smith, P., et al., Human pregnancy by in vitro fertilization (IVF) using sperm aspirated from the epididymis. J In Vitro Fert Embryo Transf, 1985. 2(3): p. 119-22.
3.Silber, S., et al., Pregnancy with sperm aspiration from the proximal head of the epididymis: a new treatment for congenital absence of the vas deferens. Fertil Steril, 1988. 50(3): p. 525-8.
4.Silber, S., et al., The use of epididymal and testicular spermatozoa for intracytoplasmic sperm injection: the genetic implications for male infertility. Hum Reprod, 1995. 10(8): p. 2031-43.
5.Silber, S., et al., The effect of female age and ovarian reserve on pregnancy rate in male infertility: treatment of azoospermia with sperm retrieval and intracytoplasmic sperm injection. Hum Reprod, 1997. 12(12): p. 2693-700.
6.Beil, R.E. and C.N. Graves, Nuclear decondensation of mammalian spermatozoa: changes during maturation and in vitro storage. J Exp Zool, 1977. 202(2): p. 235-40.
7.Palermo, G., et al., Fertilization and pregnancy outcome with intracytoplasmic sperm injection for azoospermic men. Hum Reprod, 1999. 14(3): p. 741-8.
8.Moore, H. and M. Akhondi, In vitro maturation of mammalian spermatozoa. Rev Reprod, 1996. 1(1): p. 54-60.
9.Pellestor, F., A. Girardet, and B. Andreo, Effect of long abstinence periods on human sperm quality. Int J Fertil Menopausal Stud, 1994. 39(5): p. 278-82.
10.Steele, E., et al., A comparison of DNA damage in testicular and proximal epididymal spermatozoa in obstructive azoospermia. Mol Hum Reprod, 1999. 5(9): p. 831-5.
11.Dozortsev, D., et al., Embryos generated using testicular spermatozoa have higher developmental potential than those obtained using epididymal spermatozoa in men with obstructive azoospermia. Fertil Steril, 2006. 86(3): p. 606-11.
12.Silber, S., et al., Chromosomal abnormalities in embryos derived from testicular sperm extraction. Fertil Steril, 2003. 79(1): p. 30-8.
13.Bonduelle, M., et al., Seven years of intracytoplasmic sperm injection and follow-up of 1987 subsequent children. Hum Reprod, 1999. 14(Suppl 1): p. 243-64.
14.Aboulghar, H., et al., A prospective controlled study of karyotyping for 430 consecutive babies conceived through intracytoplasmic sperm injection. Fertil Steril, 2001. 76(2): p. 249-53.
15.Ludwig, M., et al., Is intracytoplasmic sperm injection itself an indication to perform preimplantation genetic diagnosis (PGD)? About PGD, invasive prenatal diagnosis and genetic sonography. Fetal Diagn Ther, 2001. 16(2): p. 68-82.
16.Huang, W., et al., Germ-cell nondisjunction in testes biopsies of men with idiopathic infertility. Am J Hum Genet, 1999. 64(6): p. 1638-45.
17.Gianaroli, L., et al., Frequency of aneuploidy in sperm from patients with extremely severe male factor infertility. Hum Reprod, 2005. 20(8): p. 2140-52. Epub 2005 Apr 21.
18.Pang, M., et al., The high incidence of meiotic errors increases with decreased sperm count in severe male factor infertilities. Hum Reprod, 2005. 20(6): p. 1688-94. Epub 2005 Feb 25.
19.Saowaros, W. and S. Panyim, The formation of disulfide bonds in human protamines during sperm maturation. Experientia, 1979. 35(2): p. 191-2.
20.Munne, S., et al., Embryo morphology, developmental rates, and maternal age are correlated with chromosome abnormalities. Fertil Steril, 1995. 64(2): p. 382-91.
21.Marquez, C., et al., Chromosome abnormalities in 1255 cleavage-stage human embryos. Reprod Biomed Online, 2000. 1(1): p. 17-26.
22.Chang, L.J., et al., An update of preimplantation genetic diagnosis in gene diseases, chromosomal translocation, and aneuploidy screening. Clin Exp Reprod Med, 2011. 38(3): p. 126-34.
23.Chen, Y.L., et al., Successful application of the strategy of blastocyst biopsy, vitrification, whole genome amplification, and thawed embryo transfer for preimplantation genetic diagnosis of neurofibromatosis type 1. Taiwan J Obstet Gynecol, 2011. 50(1): p. 74-8.
Chapter 4
1. Scott L (2004) The Biological Basis of Oocyte and Embryo competence: Morphodynamic Criteria for Embryo Selection in In-Vitro Fertilization. In: Van BlerKom J, Gregory L, editors. Essential IVF: Basic Research and Clinical Applications. 1 ed. Norwell: Kluwer Academic Publishers. pp. 333-376.
2. Lundin K, Bergh C, Hardarson T (2001) Early embryo cleavage is a strong indicator of embryo quality in human IVF. Hum Reprod 16: 2652-2657.
3. Munne S, Cohen J (1998) Chromosome abnormalities in human embryos. Hum Reprod Update 4: 842-855.
4. Magli M, Gianaroli L, Ferraretti A (2001) Chromosomal abnormalities in embryos. Mol Cell Endocrinol 183: S29-34.
5. Balakier H, Bouman D, Sojecki A, Librach C, Squire J (2002) Morphological and cytogenetic analysis of human giant oocytes and giant embryos. Hum Reprod 17: 2394-2401.
6. Rosenbusch B, Schneider M, Glaser B, Brucker C (2002) Cytogenetic analysis of giant oocytes and zygotes to assess their relevance for the development of digynic triploidy. Hum Reprod 17: 2388-2393.
7. Magli MC, Gianaroli L, Ferraretti AP, Lappi M, Ruberti A, et al. (2007) Embryo morphology and development are dependent on the chromosomal complement. Fertil Steril 87: 534-541.
8. Moore HD, Akhondi MA (1996) In vitro maturation of mammalian spermatozoa. Rev Reprod 1: 54-60.
9. Eaton JL, Hacker MR, Barrett CB, Thornton KL, Penzias AS (2010) Influence of patient age on the association between euploidy and day-3 embryo morphology. Fertil Steril 94: 365-367.
10. Pellestor F, Girardet A, Andreo B (1994) Effect of long abstinence periods on human sperm quality. Int J Fertil Menopausal Stud 39: 278-282.
11. Donoso P, Platteau P, Papanikolaou EG, Staessen C, Van Steirteghem A, et al. (2006) Does PGD for aneuploidy screening change the selection of embryos derived from testicular sperm extraction in obstructive and non-obstructive azoospermic men? Hum Reprod 21: 2390-2395.
12. Beil RE, Graves CN (1977) Nuclear decondensation of mammalian spermatozoa: changes during maturation and in vitro storage. J Exp Zool 202: 235-240.
13. Saowaros W, Panyim S (1979) The formation of disulfide bonds in human protamines during sperm maturation. Experientia 35: 191-192.
14. Genesca A, Caballin MR, Miro R, Benet J, Germa JR, et al. (1992) Repair of human sperm chromosome aberrations in the hamster egg. Hum Genet 89: 181-186.
15. Schatten G (1994) The centrosome and its mode of inheritance: the reduction of the centrosome during gametogenesis and its restoration during fertilization. Dev Biol 165: 299-335.
16. Sathananthan AH, Ratnam SS, Ng SC, Tarin JJ, Gianaroli L, et al. (1996) The sperm centriole: its inheritance, replication and perpetuation in early human embryos. Hum Reprod 11: 345-356.
17. Perrin A, Louanjli N, Ziane Y, Louanjli T, Le Roy C, et al. (2011) Study of aneuploidy and DNA fragmentation in gametes of patients with severe teratozoospermia. Reprod Biomed Online 22: 148-154.
18. Silber S, Escudero T, Lenahan K, Abdelhadi I, Kilani Z, et al. (2003) Chromosomal abnormalities in embryos derived from testicular sperm extraction. Fertil Steril 79: 30-38.
19. Magli MC, Gianaroli L, Ferraretti AP, Gordts S, Fredericks V, et al. (2009) Paternal contribution to aneuploidy in preimplantation embryos. Reprod Biomed Online 18: 536-542.
20. Silber SJ, Nagy Z, Devroey P, Camus M, Van Steirteghem AC (1997) The effect of female age and ovarian reserve on pregnancy rate in male infertility: treatment of azoospermia with sperm retrieval and intracytoplasmic sperm injection. Hum Reprod 12: 2693-2700.
21. Vecchione A, Baldassarre G, Ishii H, Nicoloso MS, Belletti B, et al. (2007) Fez1/Lzts1 absence impairs Cdk1/Cdc25C interaction during mitosis and predisposes mice to cancer development. Cancer Cell 11: 275-289.
22. Gavet O, Pines J (2010) Activation of cyclin B1-Cdk1 synchronizes events in the nucleus and the cytoplasm at mitosis. J Cell Biol 189: 247-259.
23. Jackman M, Lindon C, Nigg EA, Pines J (2003) Active cyclin B1-Cdk1 first appears on centrosomes in prophase. Nat Cell Biol 5: 143-148.
24. Tsichlis P, Hatziapostolou M, PW H (2007) Timing is everything: regulation of Cdk1 and aneuploidy. Dev Cell 12: 477-479.



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