進階搜尋


下載電子全文  
系統識別號 U0026-0202201016135600
論文名稱(中文) 鄰苯二甲酸酯暴露程度與Kiss-1、GPR54基因多型性對性早熟女童之影響研究
論文名稱(英文) The association of phthalate exposure and genetic polymorphism of Kiss-1 and GPR54 on precocious puberty girl
校院名稱 成功大學
系所名稱(中) 環境醫學研究所
系所名稱(英) Institute of Environmental and Occupational Health
學年度 98
學期 1
出版年 99
研究生(中文) 吳喻敏
研究生(英文) Yu-Min Wu
學號 s7696402
學位類別 碩士
語文別 中文
論文頁數 215頁
口試委員 指導教授-李俊璋
口試委員-林秀娟
口試委員-孫孝芳
口試委員-許昺奇
中文關鍵字 性早熟  鄰苯二甲酸酯類  Kisspeptin54  Kiss-1  GPR54  基因多型性 
英文關鍵字 Precocious puberty  Phthalates  Kisspeptin54  Kiss-1  GPR54  polymorphism 
學科別分類
中文摘要 近年來研究顯示小兒性早熟(Precocious puberty)的發生率有逐年上升的趨勢,其中又以女童較為顯著。過去流行病學研究發現鄰苯二甲酸酯類(phthalates, PAEs)暴露可能與孩童青春期啟始的時間有關。PAEs廣泛使用在PVC塑膠製品、食物容器、個人衛生及商業產品中,而研究指出多種PAEs具有顯著的雌激素活性,進入體內後可能與雌激素受體α(estrogen receptorα, ERα)結合,產生模擬雌激素之現象。此外,許多研究證實Kisspeptin peptide (Kiss-1基因生成)與GPR54 (G protein couple receptor 54)系統對於內分泌調控與青春期生長發育影響扮演著重要的角色。Kisspeptin/GPR54系統中具有雌激素受體負責接收雌激素的刺激以調控GnRH (Gonadotropin-releasing hormone)的釋放。因此本研究探討鄰苯二甲酸酯類暴露與Kiss-1、GPR54基因、Kisspeptin對小兒性早熟的影響。本研究目的為:1.利用標準化問卷評估性早熟女童與一般女童日常生活中PAEs之外在暴露,藉由分析兩組女童尿液PAEs代謝物濃度以了解女童之內在暴露劑量。2.評估性早熟女童與一般女童間Kisspeptin54 peptide分泌量之差異3. 評估Kisspeptin54 peptide分泌量與性早熟女童性徵發育程度之關係4.評估女童尿液中PAEs代謝物濃度與Kisspeptin54 peptide分泌量之相關性。5.經由基因定序方式,探討性早熟與一般女童Kiss-1, GPR54基因序列變異表現之情形,並利用相關生物資訊資料庫評估變異序列對蛋白質之影響。研究對象係自成大醫院小兒科門診中招募性早熟女童為病例組,再以自願參與的方式招募一般女童為對照組。使用HPLC-MS/MS分析尿液中七種PAEs之代謝物,並利用市售放射線免疫kit分析女童Kisspeptin54。本研究參與之性早熟女童共40位,一般女童共11位。發現攝取較多高脂肪含量肉品、油炸食品、點心飲料以及補品,以及經常外食(飲)與使用PVC保鮮膜之飲食習慣係鄰苯二甲酸酯之重要暴露來源。此外,住戶屋齡越高或清潔頻率較低亦為PAEs暴露之重要因子。本研究性早熟女童尿中七種鄰苯二甲酸酯濃度皆高於一般女童,兩組間分布之趨勢以MMP、MBP、MEHHP、MEOHP與MBzP濃度達統計顯著差異(MMP:8.35 vs. 4.31 µg/L、P=0.013; MBP:115.10 vs. 32.12 µg/L、P=0.0002;MEHHP:64.86 vs. 27.53 µg/L、P=0.003;MEOHP:59.98 vs. 25.73 µg/L、P=0.003;MBzP:11.17 vs. 2.79 µg/L、P=0.0001)。此外,發現依據女童第二性徵發育程度不同分組,其尿液中七種鄰苯二甲酸酯代謝物中以 MMP、MBP、MBzP、MEHHP與MEOHP濃度亦有顯著上升(P<0.05),進一步校正肌肝酸後僅有MBP、MBzP達顯著差異。由於各種PAEs對於雌激素受體的結合效應皆不相同,本研究進一步估算PAEs對雌激素受體影響之總合效應濃度。發現於性早熟女童暴露之PAEs之ERα總合效應之劑量為6.47 (2.70-16.75) μg/kg/day,顯著地高於一般女童為2.99 (1.04- 10.28)μg/kg/day (P=0.0007)。顯示性早熟女童因鄰苯二甲酸酯之暴露量較高,可能導致其干擾ERα結合之效應程度顯著高於一般女童。此外,性早熟女童Kisspeptin54平均濃度為2.15 (1.39-2.86) pmol/L高於一般女童組為1.95 (1.69-2.18) pmol/L(P=0.06)。分組比較後發現Kisspeptin54分泌量會確實隨著青春期發育程度上升而增加。且發現Kisspeptin54分泌量與性腺激素測驗(LHRH test)之LH反應最高值具顯著之相關性(r=0.4、P=0.03),且與PAEs尿中代謝物MMP、MBP與MBzP皆具有顯著之相關性,但經校正肌酐酸後,僅MBP濃度與Kisspeptin54具顯著相關性(r=0.537、P=0.0006)。於Kiss-1與GPR54定序結果發現,本研究女童於Kiss-1、GPR54基因分別有16與14個sequence variants,其中有9與6個為目前已確認之SNP,且兩基因皆有3個sequence variants會造成胺基酸改變。比較本研究性早熟女童與一般女童不同sequence variants之allele與genotype frequency,各變異序列於兩組間皆未達顯著差異。但本研究認為兩基因變異表現之差異仍可能為重要之基因變異指標,待未來增加樣本數以確認該指標於性早熟女童與一般女童族群之差異。
英文摘要 In recent years, studies have shown the incidence of precocious puberty increased year by year, especially for girls. The epidemiological studies found that phthalate esters (PAEs) exposure may be related to the onset of puberty. PAEs were widely used in PVC plastic products, food containers, personal hygiene and commercial products. The significant estrogenic activities of various PAEs have been observed in different studies. While the PAEs entered the body, it acted as an estrogen analog and bound to estrogen receptor α (ERα). In addiction, several evidences have shown that Kisspeptins were the peptide products of the Kiss1 gene, and its receptor GPR54 (G protein coupled receptor) plays a crucial role in governing reproductive endocrine system and the onset of puberty. Moreover, the ERα regulated the release of GnRH (Gonadotropin -releasing hormone) by interacted with estrogen and therefore played an important role in the feedback loop of Kisspeptin/GPR54 system. In this study, we investigate the association among phthalate exposure, kisspeptin 54 peptide level and Kiss-1/GPR54 gene polymorphism on early onset of girl puberty. The objectives were: (1) to evaluate exposure factor of PAEs in daily life by standardized questionnaires and to assess the internal exposure dose by analyzing of PAEs metabolites in urine; (2) to assess the differences of Kisspeptin54 peptide between two groups; (3) to study the relationship of Kisspeptin54 peptide secretion and degree of sex characteristic development; (4) to assess the relationship of PAEs metabolite concentrations and Kisspeptin54 peptide; (5) to explore the Kiss-1, GPR54 gene sequence variation between case and control, and to assess the protein sequence variation using relevant biological information database. We recruited the precocious puberty girls from the National Cheng Kung University Hospital pediatric clinic as case group, and the control group recruited by voluntary participation of healthy girls. The total of 40 precocious puberty girls and 11 normal girls were recruited in this study. Seven urinary metabolites of PAEs were analysed by HPLC-MS/MS, and the commercial radio immunoassay kit was used for Kisspeptin54 analysis. We found that the higher frequencies and quantities of eating greasy meat, fried foods, beverages, snacks and nutriment, off-premises eating and the usage of PVC plastic wrap were the potential causes of higher phthalate exposure. Futhermore, living in the aged building and less house cleaning may also contribute to higher indoor PAEs exposure. The concentration of seven metabolites of PAEs in urine from precocious puberty girls were higher than normal girls, and the MMP, MBP, MBzP, MEHHP and MEOHP showed significant difference between two groups(MMP:8.35 vs. 4.31 µg/L, P=0.013; MBP: 115.10 vs. 32.12 μg/L , P = 0.0002; MEHHP: 64.86 vs. 27.53 μg/L, P = 0.003; MEOHP: 59.98 vs. 25.73 μg/L, P = 0.003; MBzP: 11.17 vs. 2.79 μg/L, P = 0.0001). After divided all subjects into three development category groups, the MMP, MBP, MBzP, MEHHP and MEOHP concentration were also increased significantly. While adjusted with creatinine, only the MBP and MBzP have show the increased trend (P <0.05). We also calculated the aggregated dose to estimate the internal estrogenic activities of PAEs due to the different ERα binding affinities of PAEs. We found that the aggregated dose of precocious puberty girls (6.47 (2.70-16.75) μg/kg/day) was significantly higher than those of normal girls (2.99 (1.04-10.28) μg/kg/day, P=0.0007). It showed that the higher phthalate exposure in precocious puberty girls may cause more internal estrogenic activites than normal girls. The average Kisspeptin54 concentrations were 2.15 (1.39-2.86) and 1.95 (1.69-2.18) pmol/L (P=0.06) for precocious puberty girls and normal girls, respectively. Moreover, the Kisspeptin54 concentrations were also significantly increased with sexual development. We also found that Kisspeptin54 secretion was significantly correlated with the peak lutenising hormone (LH) concentration analyzed by LHRH test (r=0.4, P= 0.03). The significant correlation between Kisspeptin54 secretion and urinary MMP, MBP and MBzP concentrations (uncorrected for creatinine) were also observed, however, only the correlation between Kisspeptin54 and urinary MBP remained significant after creatinine correction (r=0.537, P =0.0006). The results of gene sequencing showed that 16 and 14 sequence variants in Kiss-1 and GPR54 gene, respectively, were identified in this study. Furthermore, 9 of 16 and 6 of 14 sequence variants in Kiss-1 and GPR54 gene, respectively, were confirmed SNP. Three sequence variants among them could lead to amino acid change in both two genes. For allele and genotype frequency of sequence variants comparison, no significant differences were found between case and control groups. In conclusion, the difference of expression of two genes could be the important index of gene variance. Further studies and more samples are needed to clarify the relationship between precocious puberty and the polymorphism of these genes.
論文目次 中文摘要....................................................i
Abstract.................................................iii
致謝.......................................................v
目錄.....................................................vii
表目錄....................................................xi
圖目錄...................................................xiv
第一章 緒論................................................1
1-1 背景.................................................1
1-2 研究目的..............................................4
1-3 研究意義..............................................4
第二章 文獻回顧.............................................5
2-1 小兒性早熟............................................5
2-1-1 青春期性徵發育的過程...............................5
2-1-2 性早熟的定義與分類.................................6
2-1-3 造成性早熟可能的原因...............................7
2-2 鄰苯二甲酸酯類對孩童青春期的影響.........................9
2-2-1 Phthalate的物化特性...............................9
2-2-2 PAEs對於調控內分泌系統之影響........................9
2-2-3 孩童PAEs之暴露途徑...............................12
2-2-4 PAEs流行病學研究.................................14
2-3 Kiss-1/GPR54基因與Kisspeptin對於青春期與性早熟的影響...16
2-3-1 Kiss-1/GPR54 基因...............................16
2-3-2 Kiss-1/GPR54 與Kisspeptin peptide刺激釋性腺激素釋放 ...............................................17
2-3-3 Kisspeptin的表現與青春期的關係....................18
2-3-4 Kiss-1與GPR54基因與性早熟的相關性.................19
第三章 材料與方法...........................................21
3-1 研究架構.............................................21
3-2 研究對象的選取.......................................23
3-3 樣本採集.............................................25
3-3-1 血液樣本採樣方法....................................25
3-3-2 尿液樣本採集.......................................26
3-4 兒童室內環境中Phthalates暴露來源調查評估之標準化問卷.....27
3-5 分析方法.............................................29
3-5-1 尿液中鄰苯二甲酸酯代謝物濃分析.....................29
3-5-2 Kisspeptin54 peptide分析........................31
3-5-3 Kiss-1與GPR54基因變異分析........................34
3-6 資料處理與數據解析....................................39
第四章 結果與討論...........................................41
4-1 女童基本資料與臨床檢查結果.............................41
4-1-1 基本資料.........................................41
4-1-2 孩童用藥情形與醫療史..............................42
4-1-3 女童性徵發育、荷爾蒙與骨齡檢查結果..................43
4-1-4 性早熟女童不同發育程度荷爾蒙與骨齡分析結果...........44
4-2 鄰苯二甲酸酯暴露來源調查評估之標準化問卷結果解析..........46
4-2-1 飲食與外食狀況...................................46
4-2-2 個人衛生用品與奶瓶/嘴使用情形......................48
4-2-3 家戶環境、清潔行為及建材...........................48
4-2-4 玩具使用及接觸地板機會............................50
4-3 女童尿液中鄰苯二甲酸酯代謝物濃度分析結果.................51
4-3-1 女童尿液中鄰苯二甲酸酯代謝物濃度分析結果.............51
4-3-2 不同性早熟女童分組與一般女童尿液中鄰苯二甲酸酯代謝物濃度
之比較..........................................53
4-3-3 女童性徵發育程度與尿液中鄰苯二甲酸酯代謝物濃度之相關性分
析.............................................53
4-3-4 女童之鄰苯二甲酸酯之日暴露劑量推估..................55
4-3-5 女童PAEs暴露量對雌激素受體(Estrogen receptor)結合能力
效應指標........................................56
4-3-6 與其他各國不同族群之比較...........................57
4-4女童Kisspeptin54分析結果..............................58
4-4-1 Kisspeptin54分析結果.............................58
4-4-2 女童性徵發育程度與Kisspeptin54 peptide濃度之相關性分
析.............................................59
4-4-3 Kisspeptin54分泌量與性腺荷爾蒙、骨齡、BMI之相關性...59
4-4-4 與其他相關文獻比較................................60
4-4-5 女童血液Kisspeptin54與尿液中鄰苯二甲酸酯相關性......61
4-5 Kiss-1與GPR54基因定序結果............................63
4-5-1 Kiss-1與GPR54基因定序結果........................63
4-5-2 Kiss-1與GPR54變異序列相關性分析結果................64
4-5-3 連鎖不平衡(Linkage disequilibrium)分析...........67
4-5-4 Kiss-1與GPR54基因上的序列變異點在其生物功能上造成之改變 ...............................................68
第五章 結論與建議...........................................70
5-1 結論................................................70
5-2 建議................................................72
參考文獻...................................................73
附件 一 說帖..............................................194
附件 二 人體試驗同意書(1)..................................198
附件 三 人體試驗同意書(2)..................................199
附件 四 兒童室內環境PAEs暴露來源調查評估問卷及時間活動模式問卷..200
參考文獻 Antoniazzi F, Zamboni G, Bertoldo F, Lauriola S, Tato L. 2004. Bone development during GH and GnRH analog treatment. Eur J Endocrinol 151 Suppl 1: S47-54.
Antoniazzi F, Zamboni G. 2004. Central precocious puberty: current treatment options. Paediatr Drugs 6(4): 211-231.
Api AM. 2001. Toxicological profile of diethyl phthalate: a vehicle for fragrance and cosmetic ingredients. Food Chem Toxicol 39(2): 97-108.
ATSDR. 1995. Toxicological Profile for Diethyl Phthalate. Atlanta,GA:Agency for Toxic Substances and Disease Registry. (Available: http://wwwatsdrcdcgov/toxprofiles/tp73html [accessed 23 May 2003]
Banerjee I, Clayton P. 2007. The genetic basis for the timing of human puberty. J Neuroendocrinol 19(11): 831-838.
Bartel, D. P. (2004). MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116(2): 281-297.
Bauer MJ, Herrmann R, Martin A, Zellmann H. 1998. Chemodynamics, transport behaviour and treatment of phthalic acid esters in municipal landfill leachates. Water Science Technology 38 (2): 185-192.
Bellingham M, Fowler PA, Amezaga MR, Rhind SM, Cotinot C, Mandon-Pepin B, et al., 2009. Exposure to a complex cocktail of environmental endocrine-disrupting compounds disturbs the kisspeptin/GPR54 system in ovine hypothalamus and pituitary gland. Environ Health Perspect 117(10): 1556-1562.
Brock JW, Caudill SP, Silva MJ, Needham LL, Hilborn ED. 2002. Phthalate monoesters levels in the urine of young children. Bull Environ Contam Toxicol 68(3): 309-314.
Casajuana N, Lacorte S. 2004. New methodology for the determination of phthalate esters, bisphenol A, bisphenol A diglycidyl ether, and nonylphenol in commercial whole milk samples. J Agric Food Chem 52(12): 3702-3707.
Cerrato F, Seminara SB. 2007. Human genetics of GPR54. Rev Endocr Metab Disord 8(1): 47-55.
Cesario SK, Hughes LA. 2007. Precocious puberty: a comprehensive review of literature. J Obstet Gynecol Neonatal Nurs 36(3): 263-274.
Chen ML, Chen JS, Tang CL, Mao IF. 2008. The internal exposure of Taiwanese to phthalate - An evidence of intensive use of plastic materials. Environment International 34(1): 79-85.
Chou YY, Huang PC, Lee CC, Wu MH, Lin SJ. 2009. Phthalate exposure in girls during early puberty. J Pediatr Endocrinol Metab 22(1): 69-77.
CMA. 1999. Comments of the Chemical Manufacturers Association phthalate esters panel in response to request for public input on seven phthalate esters. Washington, DC: Chemical Manufacturers Association: FR Doc. 99-9484.
Colaco P. 1997. Precocious puberty. Indian J Pediatr 64(2): 165-175.
Colon I, Caro D, Bourdony CJ, Rosario O. 2000. Identification of phthalate esters in the serum of young Puerto Rican girls with premature breast development. Environ Health Perspect 108(9): 895-900.
David RM. 2000. Exposure to phthalate esters. Environ Health Perspect 108(10): A440.
De Roux N, Genin E, Carel JC, Matsuda F, Chaussain JL, Milgrom E. 2003. Hypogonadotropic hypogonadism due to loss of function of the KiSS1-derived peptide receptor GPR54. Proceedings of the National Academy of Sciences of the United States of America 100(19): 10972-10976.
de Vries L, Shtaif B, Phillip M, Gat-Yablonski G. 2009. Kisspeptin serum levels in girls with central precocious puberty. Clin Endocrinol (Oxf) 71(4): 524-528.
Dhillo WS, Chaudhri OB, Patterson M, Thompson EL, Murphy KG, Badman MK, et al., 2005. Kisspeptin-54 stimulates the hypothalamic-pituitary gonadal axis in human males. J Clin Endocrinol Metab 90(12): 6609-6615.
Dhillo WS, Chaudhri OB, Thompson EL, Murphy KG, Patterson M, Ramachandran R, et al., 2007. Kisspeptin-54 stimulates gonadotropin release most potently during the preovulatory phase of the menstrual cycle in women. J Clin Endocrinol Metab 92(10): 3958-3966.
Diaz A, Laufer MR, Breech LL. 2006. Menstruation in girls and adolescents: using the menstrual cycle as a vital sign. Pediatrics 118(5): 2245-2250.
Dixon IR, Ahmed SF. 2007. Precocious puberty.pdf. PAEDIATRICS AND CHILD HEALTH 17: 9.
Dunger DB, Ahmed ML, Ong KK. 2005. Effects of obesity on growth and puberty. Best Pract Res Clin Endocrinol Metab 19(3): 375-390.
Duty SM, Calafat AM, Silva MJ, Ryan L, Hauser R. 2005. Phthalate exposure and reproductive hormones in adult men. Hum Reprod 20(3): 604-610.
Ellis BJ, Garber J. 2000. Psychosocial antecedents of variation in girls' pubertal timing: maternal depression, stepfather presence, and marital and family stress. Child Dev 71(2): 485-501.
Fromme H, Lahrz T, Piloty M, Gebhart H, Oddoy A, Ruden H. 2004. Occurrence of phthalates and musk fragrances in indoor air and dust from apartments and kindergartens in Berlin (Germany). Indoor Air 14(3): 188-195.
Funes S, Hedrick JA, Vassileva G, Markowitz L, Abbondanzo S, Golovko A, et al., 2003. The KiSS-1 receptor GPR54 is essential for the development of the murine reproductive system. Biochem Biophys Res Commun 312(4): 1357-1363.
Gottsch ML, Cunningham MJ, Smith JT, Popa SM, Acohido BV, Crowley WF, et al., 2004. A role for kisspeptins in the regulation of gonadotropin secretion in the mouse. Endocrinology 145(9): 4073-4077.
Grumbach MM, Styne DM. 1998. Puberty: Ontogeny, neuroendocrinology, physiology and disorders. Williams' Textbook of Endocrinology, ed 9: 1509-1625.
Gunnarsson D, Leffler P, Ekwurtzel E, Martinsson G, Liu K, Selstam G. 2008. Mono-(2-ethylhexyl) phthalate stimulates basal steroidogenesis by a cAMP-independent mechanism in mouse gonadal cells of both sexes. Reproduction 135(5): 693-703.
Gustafsson JA. 1999. Estrogen receptor beta--a new dimension in estrogen mechanism of action. J Endocrinol 163(3): 379-383.
Hao Q, Wang J, Niu J, Zhao P, Cui Y, Sun L, et al., 2009. [Study on phytoestrogenic-like effects of four kinds of Chinese medicine including Radix Rehmanniae Preparata, Radix Paeoniae Alba, Radix Angelicae Sinensis, Rhizoma Chuanxiong]. Zhongguo Zhong Yao Za Zhi 34(5): 620-624.
Herman-Giddens ME, Sandler AD, Friedman NE. 1988. Sexual precocity in girls. An association with sexual abuse? Am J Dis Child 142(4): 431-433.
Horikoshi Y, Matsumoto H, Takatsu Y, Ohtaki T, Kitada C, Usuki S, et al., 2003. Dramatic elevation of plasma metastin concentrations in human pregnancy: metastin as a novel placenta-derived hormone in humans. J Clin Endocrinol Metab 88(2): 914-919.
Houlihan J, Brody C, Schwan B. 2002. Not Too Pretty: Phthalates, Beauty Products and the FDA. Environmental Working Group, Coming Clean, and Health Care Without Harm. . (Available: http://wwwnottooprettyorg/images/NotTooPretty_finalpdf [accessed 3 September 2003]).
Huang PC, Kuo PL, Guo YL, Liao PC, Lee CC. 2007. Associations between urinary phthalate monoesters and thyroid hormones in pregnant women. Human reproduction 22(10): 2715-22.
Huang PC, Kuo PL, Chou YY, Lin SJ, Lee CC. 2009. Association between prenatal exposure to phthalates and the health of newborns. Environment international 35(1):14-20.
Kawamura Y, Tagai C, Maehara T, Yamada T. 1999. Additives in polyvinyl chloride and polyvinylidene chloride products. Journal of the Food Hygienic Society of Japan 40(4): 274-284.
Keen KL, Wegner FH, Bloom SR, Ghatei MA, Terasawa E. 2008. An Increase in Kisspeptin-54 Release Occurs with the Pubertal Increase in LHRH-1 Release in the Stalk-Median Eminence of Female Rhesus Monkeys In Vivo. Endocrinology.
Koch HM, Bolt HM, Preuss R, Angerer J. 2005. New metabolites of di(2-ethylhexyl)phthalate (DEHP) in human urine and serum after single oral doses of deuterium-labelled DEHP. Arch Toxicol 79(7): 367-376.
Koo HJ, Lee BM. 2004. Estimated exposure to phthaiates in cosmetics and risk assessment. J Toxicol Environ Health A 67(23-24): 1901-1914.
Kotani M, Detheux M, Vandenbogaerde A, Communi D, Vanderwinden JM, Le Poul E, et al., 2001. The metastasis suppressor gene KiSS-1 encodes kisspeptins, the natural ligands of the orphan G protein-coupled receptor GPR54. J Biol Chem 276(37): 34631-34636.
Kronenberg HM, Melmed S, Polonsky KS, Larsen PR. 2008. Williams Textbook of ENDOCRINOLOGY.
Kuohung W, Kaiser UB. 2006. GPR54 and KiSS-1: role in the regulation of puberty and reproduction. Rev Endocr Metab Disord 7(4): 257-263.
Lamb I. 1987. Reproductive effects of four phthalic acid esters in the mouse. Toxicol Appl Pharmacol 88: 255–269.
Lazar L, Kauli R, Bruchis C, Nordenberg J, Galatzer A, Pertzelan A. 1995. High prevalence of abnormal adrenal response in girls with central precocious puberty at early pubertal stages. Eur J Endocrinol 133(4): 407-411.
Lee JH, Miele ME, Hicks DJ, Phillips KK, Trent JM, Weissman BE, et al., 1996. KiSS-1, a novel human malignant melanoma metastasis-suppressor gene. J Natl Cancer Inst 88(23): 1731-1737.
Lee JH, Welch DR. 1997. Suppression of metastasis in human breast carcinoma MDA-MB-435 cells after transfection with the metastasis suppressor gene, KiSS-1. Cancer Res 57(12): 2384-2387.
Lee JM, Appugliese D, Kaciroti N, Corwyn RF, Bradley RH, Lumeng JC. 2007. Weight status in young girls and the onset of puberty. Pediatrics 119(3): e624-630.
Lee PA, Houk CP. 2006. Gonadotropin-releasing hormone analog therapy for central precocious puberty and other childhood disorders affecting growth and puberty. Treat Endocrinol 5(5): 287-296.
Loff S, Kabs F, Subotic U, Schaible T, Reinecke F, Langbein M. 2002. Kinetics of diethylhexyl-phthalate extraction From polyvinylchloride-infusion lines. JPEN J Parenter Enteral Nutr 26(5): 305-309.
Lovekamp TN, Davis BJ. 2001. Mono-(2-ethylhexyl) phthalate suppresses aromatase transcript levels and estradiol production in cultured rat granulosa cells. Toxicol Appl Pharmacol 172(3): 217-224.
Lovekamp-Swan T, Davis BJ. 2003. Mechanisms of phthalate ester toxicity in the female reproductive system. Environ Health Perspect 111(2): 139-145.
Luan X, Yu H, Wei X, Zhou Y, Wang W, Li P, et al., 2007a. GPR54 polymorphisms in Chinese girls with central precocious puberty. Neuroendocrinology 86(2): 77-83.
Luan X, Zhou Y, Wang W, Yu H, Li P, Gan X, et al., 2007b. Association study of the polymorphisms in the KISS1 gene with central precocious puberty in Chinese girls. Eur J Endocrinol 157(1): 113-118.
Maesaka H, Tachibana K, Adachi M, Okada YAT, Tanaka T. 1999. Consecutive Urinary Gonadotropin and Ovarian Hormone Excretory Patterns during LH-RH Analog Treatment in Female Patients with Central Precocious Puberty. Clinical Pediatric Endocrinology 8(1): 23-33.
Massart F, Seppia P, Pardi D, Lucchesi S, Meossi C, Gagliardi L, et al., 2005. High incidence of central precocious puberty in a bounded geographic area of northwest Tuscany: an estrogen disrupter epidemic? Gynecol Endocrinol 20(2): 92-98.
Matsui H, Takatsu Y, Kumano S, Matsumoto H, Ohtaki T. 2004. Peripheral administration of metastin induces marked gonadotropin release and ovulation in the rat. Biochem Biophys Res Commun 320(2): 383-388.
Messager S, Chatzidaki EE, Ma D, Hendrick AG, Zahn D, Dixon J, et al., 2005. Kisspeptin directly stimulates gonadotropin-releasing hormone release via G protein-coupled receptor 54. Proc Natl Acad Sci U S A 102(5): 1761-1766.
Mitchell DC, Abdelrahim M, Weng J, Stafford LJ, Safe S, Bar-Eli M, et al., 2006. Regulation of KiSS-1 metastasis suppressor gene expression in breast cancer cells by direct interaction of transcription factors activator protein-2alpha and specificity protein-1. J Biol Chem 281(1): 51-58.
Morgan WD, Williams GT, Morimoto RI, Greene J, Kingston RE, Tjian R. 1987. Two transcriptional activators, CCAAT-box-binding transcription factor and heat shock transcription factor, interact with a human hsp70 gene promoter. Mol Cell Biol 7(3): 1129-1138.
Mylchreest E, Wallace DG, Cattley RC, Foster PM. 2000. Dose-dependent alterations in androgen-regulated male reproductive development in rats exposed to Di(n-butyl) phthalate during late gestation. Toxicol Sci 55(1): 143-151.
Navarro VM, Castellano JM, Fernandez-Fernandez R, Barreiro ML, Roa J, Sanchez-Criado JE, et al., 2004a. Developmental and hormonally regulated messenger ribonucleic acid expression of KiSS-1 and its putative receptor, GPR54, in rat hypothalamus and potent luteinizing hormone-releasing activity of KiSS-1 peptide. Endocrinology 145(10): 4565-4574.
Navarro VM, Fernandez-Fernandez R, Castellano JM, Roa J, Mayen A, Barreiro ML, et al., 2004b. Advanced vaginal opening and precocious activation of the reproductive axis by KiSS-1 peptide, the endogenous ligand of GPR54. J Physiol 561(Pt 2): 379-386.
Navarro VM, Tena-Sempere M. 2008. The KiSS-1/GPR54 system: putative target for endocrine disruption of reproduction at hypothalamic-pituitary unit? Int J Androl 31(2): 224-232.
Nebesio T, Pescovitz O. 2005. Historical perspectives: Endocrine disruptors and the timing of puberty . The Endocrinologist 15: 44 - 48.
Nishihara T, Nishikawa J, Kanayama T, Dakeyama F, Saito K, Imagawa M, et al., 2000. Estrogenic activities of 517 chemicals by yeast two-hybrid assay. Journal of Health Science 46(4): 282-298.
Ogden CL, Carroll MD, Curtin LR, McDowell MA, Tabak CJ, Flegal KM. 2006. Prevalence of overweight and obesity in the United States, 1999-2004. JAMA 295(13): 1549-1555.
Ohtaki T, Shintani Y, Honda S, Matsumoto H, Hori A, Kanehashi K, et al., 2001. Metastasis suppressor gene KiSS-1 encodes peptide ligand of a G-protein-coupled receptor. Nature 411(6837): 613-617.
Palmert MR, Boepple PA. 2001. Variation in the timing of puberty: clinical spectrum and genetic investigation. J Clin Endocrinol Metab 86(6): 2364-2368.
Parent AS, Teilmann G, Juul A, Skakkebaek NE, Toppari J, Bourguignon JP. 2003. The timing of normal puberty and the age limits of sexual precocity: variations around the world, secular trends, and changes after migration. Endocrine reviews 24(5): 668-693.
Parke D. 1984. Development of detoxication mechanisms in the neonate; in Kacew S, Reasor MJ (eds): Toxicology and the newborn.
Partsch CJ, Sippell WG. 2001. Pathogenesis and epidemiology of precocious puberty. Effects of exogenous oestrogens. Hum Reprod Update 7(3): 292-302.
Peakall DB. 1975. Phthalate esters: Occurrence and biological effects. Residue Rev 54: 1-41.
Plant TM, Ramaswamy S, Dipietro MJ. 2006. Repetitive activation of hypothalamic G protein-coupled receptor 54 with intravenous pulses of kisspeptin in the juvenile monkey (Macaca mulatta) elicits a sustained train of gonadotropin-releasing hormone discharges. Endocrinology 147(2): 1007-1013.
Popa SM, Clifton DK, Steiner RA. 2008. The Role of Kisspeptins and GPR54 in the Neuroendocrine Regulation of Reproduction. Annu Rev Physiol 70: 213-238.
Qiao L, Zheng L, Cai D. 2007. [Study on the di-n-butyl phthalate and di-2-ethylhexyl phthalate level of girl serum related with precocious puberty in Shanghai]. Wei Sheng Yan Jiu 36(1): 93-95.
Seminara SB, Dipietro MJ, Ramaswamy S, Crowley WF, Jr., Plant TM. 2006. Continuous human metastin 45-54 infusion desensitizes G protein-coupled receptor 54-induced gonadotropin-releasing hormone release monitored indirectly in the juvenile male Rhesus monkey (Macaca mulatta): a finding with therapeutic implications. Endocrinology 147(5): 2122-2126.
Seminara SB, Messager S, Chatzidaki EE, Thresher RR, Acierno JS, Jr., Shagoury JK, et al., 2003. The GPR54 gene as a regulator of puberty. N Engl J Med 349(17): 1614-1627.
Shahab M, Mastronardi C, Seminara SB, Crowley WF, Ojeda SR, Plant TM. 2005. Increased hypothalamic GPR54 signaling: a potential mechanism for initiation of puberty in primates. Proc Natl Acad Sci U S A 102(6): 2129-2134.
Sharman M, Read WA, Castle L, Gilbert J. 1994. Levels of di-(2-ethylhexyl)phthalate and total phthalate esters in milk, cream, butter and cheese. Food Addit Contam 11(3): 375-385.
Strachan T, Read AP. 2006. 人類分子遺傳學.
Su PH, Wang SL, Lin CY, Chen JY, Changlai CP, Jian SH, et al., 2005. Leptin changes in Taiwanese girls with central precocious puberty before and during the GnRH agonist treatment. Acta Paediatr Taiwan 46(5): 278-283.
Sun Y, Tian Z, Zhao H, Wong ST, Chen B. 2007. Characteristic of hypothalamic kisspeptin expression in the pubertal development of precocious female rats. Neurosci Lett 420(1): 12-17.
Svechnikova I, Svechnikov K, Soder O. 2007. The influence of di-(2-ethylhexyl) phthalate on steroidogenesis by the ovarian granulosa cells of immature female rats. J Endocrinol 194(3): 603-609.
Takeuchi S, Iida M, Kobayashi S, Jin K, Matsuda T, Kojima H. 2005. Differential effects of phthalate esters on transcriptional activities via human estrogen receptors alpha and beta, and androgen receptor. Toxicology 210(2-3): 223-233.
Teilmann G, Pedersen CB, Jensen TK, Skakkebaek NE, Juul A. 2005. Prevalence and incidence of precocious pubertal development in Denmark: an epidemiologic study based on national registries. Pediatrics 116(6): 1323-1328.
Teles MG, Bianco SD, Brito VN, Trarbach EB, Kuohung W, Xu S, et al., 2008. A GPR54-activating mutation in a patient with central precocious puberty. N Engl J Med 358(7): 709-715.
Tenenbaum-Rakover Y, Commenges-Ducos M, Iovane A, Aumas C, Admoni O, de Roux N. 2007. Neuroendocrine phenotype analysis in five patients with isolated hypogonadotropic hypogonadism due to a L102P inactivating mutation of GPR54. J Clin Endocrinol Metab 92(3): 1137-1144.
Thompson EL, Patterson M, Murphy KG, Smith KL, Dhillo WS, Todd JF, et al., 2004. Central and peripheral administration of kisspeptin-10 stimulates the hypothalamic-pituitary-gonadal axis. J Neuroendocrinol 16(10): 850-858.
Tremblay L, Frigon JY. 2005. Precocious puberty in adolescent girls: a biomarker of later psychosocial adjustment problems. Child Psychiatry Hum Dev 36(1): 73-94.
Tsumura Y, Ishimitsu S, Kaihara A, Yoshii K, Nakamura Y, Tonogai Y. 2001. Di(2-ethylhexyl) phthalate contamination of retail packed lunches caused by PVC gloves used in the preparation of foods. Food Addit Contam 18(6): 569-579.
Tyl RW. 1984. Teratological evaluation of diethylhexylphthalate (CAS No. 117-81-7) in CD-1 mice. National Center for Toxicological Research.
Wams TJ. 1987. Diethylhexylphthalate as an environmental contaminant-a review. Science of the Total Environment 66: 1-16.
West A, Vojta PJ, Welch DR, Weissman BE. 1998. Chromosome localization and genomic structure of the KiSS-1 metastasis suppressor gene (KISS1). Genomics 54(1): 145-148.
Wigginton JE, Cutler DJ, Abecasis GR. 2005. A note on exact tests of Hardy-Weinberg equilibrium. Am J Hum Genet 76(5): 887-893.
Wilson NK, Chuang JC, Lyu C. 2001. Levels of persistent organic pollutants in several child day care centers. J Expo Anal Environ Epidemiol 11(6): 449-458.
Wine RN, Li LH, Barnes LH, Gulati DK, Chapin RE. 1997. Reproductive toxicity of di-n-butylphthalate in a continuous breeding protocol in Sprague-Dawley rats. Environ Health Perspect 105(1): 102-107.
Wittassek M, Heger W, Koch HM, Becker K, Angerer J, Kolossa-Gehring M. 2007. Daily intake of di(2-ethylhexyl)phthalate (DEHP) by German children -- A comparison of two estimation models based on urinary DEHP metabolite levels. Int J Hyg Environ Health 210(1): 35-42.
Yaghmaie F, Saeed O, Garan SA, Freitag W, Timiras PS, Sternberg H. 2005. Caloric restriction reduces cell loss and maintains estrogen receptor-alpha immunoreactivity in the pre-optic hypothalamus of female B6D2F1 mice. Neuro Endocrinol Lett 26(3): 197-203.
Zacharewski TR, Meek MD, Clemons JH, Wu ZF, Fielden MR, Matthews JB. 1998. Examination of the in vitro and in vivo estrogenic activities of eight commercial phthalate esters. Toxicol Sci 46(2): 282-293.
行政院環保署,2005,河川及海洋維護改善計畫與斯德哥爾摩公約計畫-毒性化學物質環境流部調查。
林千喬 2009. 性早熟女童尿液中鄰苯二甲酸酯代謝物檢測與家戶灰塵暴露之相關性研究。
彭純芝. 1999. 簡明小兒科學 -青少年醫學. 合計圖書出版社.
金銓. 1995. 實用小兒科學. 藝軒圖書出版社.
陳佳飛, 陳美蓮, 毛義方. 2002. 食品容器及包裝用塑膠材質之塑化劑溶出研究.
論文全文使用權限
  • 同意授權校內瀏覽/列印電子全文服務,於2015-02-04起公開。
  • 同意授權校外瀏覽/列印電子全文服務,於2015-02-04起公開。


  • 如您有疑問,請聯絡圖書館
    聯絡電話:(06)2757575#65773
    聯絡E-mail:etds@email.ncku.edu.tw