雙酚A對於DNA甲基化之影響｜國立清華大學博碩士論文庫

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研究生：	黃瑋巧 Huang, Wei Chiao
論文名稱：	雙酚A對於DNA甲基化之影響 Characteristics of bisphenol A affecting DNA methylation
指導教授：	莊淳宇 Chuang, Chun-Yu
口試委員:	莊淳宇張建文林靖愉
學位類別：	碩士 Master
系所名稱：	原子科學院 - 生醫工程與環境科學系 Department of Biomedical Engineering and Environmental Sciences
論文出版年：	2011
畢業學年度：	99
語文別：	英文
論文頁數：	137
中文關鍵詞：	雙酚A 、雌激素受體、脂瘦素、脂聯素、DNA甲基化、基質金屬蛋白酶13 、HOXA10
外文關鍵詞：	BPA, estrogen receptor, leptin, adiponectin, DNA methylation, MM13, HOXA10
相關次數：	點閱：2 下載：0
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雙酚A (bisphenol A; BPA)是一種常見環境荷爾蒙，用做塑膠之塑化劑，具競爭雌激素受體(estrogen receptor; ER)之能力而影響人體內分泌，為內分泌干擾物質(endocrine disruptor)。BPA為脂溶性，有生物累積之特性，會囤積在人體脂肪細胞(adipose cells)中，可能影響脂肪激素(adipokines)分泌和能量代謝之恆定性而造成代謝性疾病。DNA甲基化(DNA methylatiom)為一種不改變基因序列而影響基因調控之方式。有文獻指出，BPA會造成異常基因甲基化，影響染色體的穩定性及基因表現，增加導致乳癌和子宮內膜癌的風險。
本論文研究目的有二，一、探討BPA對人類乳癌MCF-7細胞之存活率和脂肪激素(adipokines)－脂瘦素(leptin)和脂聯素(adiponectin)基因表現量之影響，及造成DNA序列甲基化之評估；二、探討懷孕婦女、子宮內膜增生婦女和不孕症婦女血液中BPA濃度和DNA甲基化之差異。實驗首先以不同濃度BPA (1, 10, 100, 103, 104, 105 nM)處理MCF-7細胞，以MTT assay (3-(4,5-dimethylthiazolyl -2)-2,5-diphenyltetrazolium bromide)檢測細胞存活率，以即時定量聚合連鎖反應(real-time quantitative polymerase reaction)檢測adiponectin及leptin之基因表現量。結果顯示1 nM之BPA會促進細胞之存活率， 104和105 nM之BPA會抑制細胞之存活率。此外，BPA會導致細胞週期S phase時期延長(10和105 nM)或縮短(103 nM)。 BPA (10、104和105 nM)會降低ER□基因表現並誘導ER□的表現。低劑量之BPA (10 nM)增加adiponectin基因表現、降低leptin基因表現；在103 nM BPA處理下，發現adiponectin基因表現上升但leptin之表現並無顯著降低；高劑量BPA (105 nM)增加adiponectin和leptin之基因表現。萃取全基因組DNA (genomic DNA)，利用sodium bisulfite處理後，以甲基化晶片(Illumina Infinium HumanMethylation27 BeadChip)偵測DNA甲基化位點，探究BPA暴露對於基因體甲基化之差異性及分布，以及影響基因之功能性分析，進而篩選受甲基化調控之基因。利用GO term分析甲基化晶片資料具有beta value及M value顯著差異的基因(n=22)，其與代謝、成長以及神經傳遞有關。其中，LIPE (hormone-sensitive lipase)是一參與代謝調控之基因，會受到adiponectin和leptin之影響，在Illumina甲基化測驗中發現BPA (10和105 nM)會導致LIPE去甲基化。基質金屬蛋白酶(matrix metalloproteinase; MMP)為鋅依賴之蛋白水解酵素，參與組織重塑，其啟動子活性受ER調控。本研究發現BPA會使MMP 13基因啟動子去甲基化，伴隨著mRNA表現減少。此外，在婦女樣本中也發現血液中BPA濃度和MMP13表現呈現負相關，可能藉由去甲基化所調控。
利用甲基化特異性PCR (methylation specific PCR; MSP)偵測婦女HOXA10 (homeobox A10)之甲基化程度和HOXA10 mRNA表現量之相關性。HOXA10基因為調控生長發育的重要因子，在子宮內扮演重要角色。懷孕婦女之HOXA10甲基化和mRNA表現呈負相關(r = -0.657)，而子宮內膜增生婦女之HOXA10甲基化和基因表現呈正相關(r = 0.8)。由本研究結果得知，BPA會導致異常之基因表現，其可能藉由甲基化及其他外基因體機制所調控。

Bisphenol A (BPA) is a common environmental estrogen as an endocrine disruptor to mimic endogenous estrogen 17□-estradiol by binding to estrogen receptor. As lipophilicity and bioaccumulation, BPA has the potency to accumulate in adipose tissue and interfere with adipokin secretion and homeostasis of energy metabolism. BPA accumulates in adipose tissue might influence the gene expression of adiponectin and leptin leading to induce metabolic diseases. Due to common use for plastics products, human would expose low doses of BPA in daily life. Otherwise, BPA could cause abnormal DNA methylation affecting the stability of chromosome and gene expression to increase the risk of breast cancer and endometrial cancer. Thus, the purpose of this study was to investigate whether BPA caused cytotoxicity and gene expression in human breast cancer MCF-7 cells, and to explore the difference in DNA methylation and the BPA levels among pregnant women, women with endometrial hyperplasia (EH) and infertile women. The cell proliferation was increased in the 1 nM BPA treatment and attenuated at higher doses of BPA (104 and 105 nM). BPA changed the duration of S phase in cell cycle that prolonged at 10 and 105 nM BPA and shortened at 103 nM BPA. The results of real-time PCR showed that BPA treatment (10, 104 and 105 nM) attenuated the mRNA expression of ER□ and increased the expression of ER□. With the treatment of 103 nM BPA, the gene expression of ER□ was increased as well as ER□. Low-dose of BPA treatment (10 nM) increased the gene expression of adiponectin and decreased the expression of leptin. With the treatment of 105 nM BPA, MCF-7 cells had the increased expression of adiponectin and leptin. This study explored the distribution of DNA methylation and gene ontology to select candidate genes after BPA treatment using Illumina Infinium HumanMethylation27 BeadChip. Twenty-two genes selected from the difference of beta and M value were categorized into metabolic function, development and nervous process in analysis of GO term. LIPE (hormone-sensitive lipase) involved in the metabolic process was hypomethylated after BPA treatment (10 and 105 nM). MMP13 is a matrix metalloproteinase for tissue remodeling and its activity of promoter is regulated by ER. The results of this study showed that MMP13 had the hypomethylation level after BPA treatment in accompany with the low level of MMP13 mRNA expression.
Homeobox A10 (HOXA10) plays an important role in endometrium development. MSP (methyl specific PCR) was used in this study to determine the methylation level of HOXA10. This study found that a negative correlation between the methylation level of HOXA10 and its mRNA expression in pregnant women (r = -0.657), and a positive correlation in EH women (r = 0.8). In conclusion, these results indicated that BPA may influence the gene expression underlying DNA methylation and other epigenetic modulation.

Content
中文摘要 ........................................................................................................................... I
ABSTRACT .................................................................................................................... III
Chapter 1 Introduction ........................................................................................... 1
Chapter 2 Paper review .......................................................................................... 3
2.1 BPA ........................................................................................................................... 3
2.1.1 Biochemical properties of BPA ................................................................... 3
2.1.2 U-shape response of BPA ............................................................................. 5
2.1.3 BPA as an endocrine disruptor ................................................................... 5
2.1.4 Mechanisms of BPA action .......................................................................... 6
2.2 Bisphenol A affects on adipocytes ........................................................................ 13
2.2.1 Adiponectin ................................................................................................. 14
2.2.2 Leptin ........................................................................................................... 14
2.3 Correlation of endometrial diseases between BPA and adipokines .................. 15
2.3.1 Hox genes ..................................................................................................... 16
2.4 Methylation ............................................................................................................ 16
2.4.1 Methylation and BPA ................................................................................. 18
2.4.2 Methylation and Adipocytes ...................................................................... 20
2.4.3 Methylation and endometrial disease ....................................................... 20
2.5 Definition of Beta value and M value .................................................................. 21
Chapter 3 Material and method ........................................................................... 24
3.1 Chemicals ............................................................................................................... 24
3.2 Cell culture ............................................................................................................. 24
3.3 MTT assay .............................................................................................................. 25
3.4 Flow cytometric assay for cell cycle ..................................................................... 25
VI
3.5 Study subjects ......................................................................................................... 26
3.6 Sample preparation of plasma for BPA determination ...................................... 26
3.7 Chromatographic system and conditions ............................................................ 26
3.8 RNA extraction ...................................................................................................... 27
3.9 Reverse transcription polymerase chain reaction (PCR) and quantitative
real-time PCR ........................................................................................................ 28
3.10 Genomic-DNA extracted from MCF-7 cell and Bisulfite conversion ............... 29
3.11 DNA methylation profiling using Infinium human 27K BeadArrays .............. 30
3.12 Methylation Specific PCR ..................................................................................... 31
3.13 Statistical analysis .................................................................................................. 31
3.13.1 SPSS 31
3.13.2 Gene Expression Profile Analysis ................................................................ 32
3.13.3 GO analysis ................................................................................................... 33
Chapter 4 Result ................................................................................................... 34
4.1 Cytotoxicity and effect on gene expression in exposure to BPA ....................... 34
4.1.1 Cytotoxicity of MCF-7 cells in exposure to BPA ......................................... 34
4.1.2 Cell cycle arrest in exposure to BPA ............................................................ 34
4.1.3 Gene expression of estrogen receptors (ER) in exposure to BPA ................ 34
4.1.4 Gene expression of adipokines in exposure to BPA ..................................... 35
4.1.5 ER ratio and adipokine ratio in exposure to BPA ......................................... 35
4.2 Genomic-wide methylation pattern in exposure to BPA .................................... 35
4.2.1 Histograms of beta value and M value ......................................................... 35
4.2.2 Beta value of the Illumina data ..................................................................... 35
4.2.3 TSS and the methylation level ...................................................................... 38
4.2.4 Methylation level and gene expression of MMP13 ...................................... 40
VII
4.2.5 GO terms analysis ......................................................................................... 42
4.3 Correlation between plasma BPA level, gene expression and methylation level
of a specific CpG site in women with endometrial disease ................................ 43
4.3.1 Characteristics of demography among pregnant women, infertile women
and EH women ............................................................................................. 43
4.3.2 BPA level in pregnant women, infertile women and EH women ................. 43
4.3.3 Gene expression between pregnant women and EH women ........................ 43
4.3.4 Correlation between BPA level and gene expression between pregnant
women and EH women ................................................................................. 44
4.3.5 Gene-gene corrletation ................................................................................. 44
4.3.6 Crude and adjusted ORs for pregnant women and EH women .................... 44
4.3.7 Correlation between plasma BPA concentration, gene expression and
methylation level of HOXA10. .................................................................... 45
4.3.8 MMP13 expression and the correlation with BPA in EH women and
pregnant women ........................................................................................... 46
Chapter 5 Discussion ........................................................................................... 47
5.1 BPA exposure mediated cytotoxicity and abnormal gene expression .............. 47
5.2 Genomic-wide methylation pattern in MCF-7 cells exposed to BPA ............... 48
5.2.1 Methylation pattern and its relevant to the distance from TSS in exposure to
BPA 48
5.3 Correlation between plasma BPA level, gene expression and methylation level
in women with endometrial disease ..................................................................... 57
5.4 MMP13 as a marker for EH women .................................................................... 60
5.5 Gene expression of MMP13 and HOXA10 might be mediated by methylation
and other epigenetic modulator ........................................................................... 61
VIII
Chapter 6 Conclusion ........................................................................................... 63
Chapter 7 Future Work ......................................................................................... 65
REFERENCE .................................................................................................................. 68
Figure and Table .............................................................................................................. 83
IX
Index for Figures
Fig. 1 Flow chart of this study ........................................................................................ 2
Fig. 2 BPA structure ........................................................................................................ 4
Fig. 3 In response to high temperature, acidic or basic condition, BPA might
release from polycarbonate due to hydrolysis of the ester bond. .................. 4
Fig. 4 Methylation on cytosine ................................................................................... 18
Fig. 5 Guideline for selecting the genes that changed the methylation level after
BPA treatment. ................................................................................................ 36
Fig. 6 Transduction pathway regulated by PKA mediated the expression of
adiponectin, leptin and LIPE. PKA downstream signal was involved with
the epigenetic modulators (HDAC and microRNA). .................................... 64
Fig. 7 Illustration of the findings and future work in this study for MCF-7 cells
with BPA treatment. ........................................................................................ 66
Fig. 8 Illustration of the findings and future work in this study for human study
subjects. ............................................................................................................ 67
Fig. 9 Cytotoxicity of BPA treatments in MCF-7 cells. (A) standard curve of
MMT assay, (B) cell viability in different doses of BPA.. ............................. 83
Fig. 10 Cell cycle of MCF-7 cells treated with different doses of BPA. (A) control,
(B) 105 nM BPA, and (C) the percentage of G1,G2 and S phase in each
BPA treatment group ....................................................................................... 84
Fig. 11 BPA exposure influenced the gene expression in MCF-7 cells. The gene
expression of (A) ERα, (B) ERβ, (C) adiponectin and (D) leptin ................ 86
Fig. 12 Ratios of ER and adipokines changed after BPA treatment in MCF-7 cells.
(A) ERα/ERβ and (B)adiponectin/leptin ....................................................... 87
Fig. 13 Histograms of beta value (left) and M value (right) from 27,577 specific
X
CpG sites (A) DMSO, (B) 10 nM BPA, (C) 103 nM BPA, and (D) 105 nM
BPA. .................................................................................................................. 89
Fig. 14 Different ΔBeta among the BPA treatment groups and the control group. (A)
the intersection of ΔBeta > 0.08 among 10, 103 and 105 nM BPA treatment
groups, (B) the heatmap and clustering analysis of the BPA treatment
groups, and (C) gene list of ΔBeta clustering ................................................ 91
Fig. 15 The filtered genes of different M-value among BPA treatment groups and
the control group. (A) the intersection of Δbeta > 0.08 among 10, 103 and
105 nM BPA treatment groups, (B) the heatmap and clustering analysis of
the BPA treatment groups, and (C) gene list of ΔBeta clustering ................ 93
Fig. 16 (A) Distribution of genes with different methylation level on each
chromosome. (B) methylation level calculated by beta value. (C)
Methylaiton level calculated by M value ....................................................... 96
Fig.17 Distribution of Δbeta value in the 669 specific genes on each chromosome
among treatment groups of BPA. (A) distribution of ΔBeta values located
in the CpG island, (B) distribution of ΔBeta value located in the non-CpG
island, and (C) genes with the significant ΔBeta value on chromosome 20
and 21 ................................................................................................................ 98
Fig. 18 Methylation level of CpG and non-CpG sites in the specific 94 genes on
each chromosome. (A) mean Δbeta value and (B) mean M value of each
chromosome. .................................................................................................... 99
Fig. 19 Significant M-value difference after BPA treatment in 141 specific genes. (A)
CpG site located at the non-CpG island, and (B) CpG site located at the
CpG island ...................................................................................................... 100
Fig. 20 High methylation changes of CpG sites in analysis of Beta value and M
XI
value. (A)the intersection of M value and beta value, (B) the methylation
level of M value in each chromosome, (C) the methyaltion changes after
BPA treatment in each chromosome ............................................................ 102
Fig. 21 Schematic diagram of the specific 22 genes on each chromosome. (A)
number of genes located on each chromosome, and (B) position of each
genes located on the chromosome. ............................................................... 104
Fig. 22 BPA influence the methylation level on chromosome presented more than
one genes. The methylation difference were selected by (A) ΔBeta > 0.08 in
all the BPA treatment groups. (B) The intersection of M-value (141 genes)
and ΔBeta > 0.08 (94 genes). All of the offered methylation CpG sites were
located in the non-CpG island ...................................................................... 106
Fig. 23 Chromosome loci, CpG site, TSS and mRNA expression level of MMP13
gene. (A) Schematic diagram of CpG site and TSS in MMP13. (B)
Correlation between TSS and btea value. (C) Correlation between TSS
and M value (D) Association between mRNA expression and beta value of
MMP13 ........................................................................................................... 109
Fig. 24 Chromosome loci, CpG site, MSP primers, Illumina probe, and mRNA
expression level of HOXA10 gene. (A) Schematic diagram of MSP primers
and Illumina probe of HOXA10 gene. (B) mRNA expresison and Illumina
beta value. (C) MSP data and Illumina data ............................................... 110
Fig. 25 M value (A) and ΔBeta value of chromosome loci, distance form CpG site to
the TSS and the methyaliton level ................................................................ 112
Fig. 26 Distribution of plasma BPA level among pregnant woman, infertile woman
and EH woman. ............................................................................................. 113
Fig. 27 Gene expression of (A) adiponectin, (B) leptin, and (C) HOXA10) in
XII
pregnant women and EH women ................................................................. 114
Fig. 28 Methylation level of HOXA10 and (A) plasma BPA level, (B) HOXA10
mRNA expression, and (C) box plot for pregnant women, EH women
and infertile women ....................................................................................... 116
Fig. 29 The correlation between methylation and BPA concentration in pregnant
woment, EH women and infertility women ................................................. 117
Fig. 30 The correlation between methylation and.mRNA expression of HOXA10
among pregnant women, women with EH and infertility .......................... 118
Fig. 31 The distribution of MMP13 mRNA expression between EH woment and (A)
pregnant woment and (B) pregnant woment with low and high BPA levels.
(C) The correlation between BPA and MMP13 mRNA
expression…………………………………………………………………...120
Index for Tables
Table 1 Physiological effects on MCF-7 cells in exposure to BPA ......................... 12
Table 2 BPA exposure influences the methylation level .......................................... 19
Table 3 List of the function of these microRNAs influenced by BPA exposure .... 62
Table 4 Correlation of CpG distance from TSS and methylation level in
chromosomes .............................................................................................. 107
Table 5 The GO term clustering of the 94 genes selected by beta value .............. 121
Table 6 GO term clustering of the 141 genes selected by M value ....................... 125
Table 7 The function of the 22 genes selected by the combination of M-value and
Beta value analysis ..................................................................................... 128
Table 8 The cluster of the 22 genes GO terms selected by the combination of
M-value and Beta value analysis. ............................................................. 131
Table 9 The location of CpG sites on the CpG island in specific genes ................ 132
Table 10 Characteristics of pregnant women, EH woman and infertility woman
and the correlation coefficient among gene expressions ........................ 133
Table 11 Correlation coefficient among BPA and gene expressions ..................... 134
Table 12 Unadjusted and adjusted odd ratios of plasma BPA concentration and
several genes expression between EH women and pregnant women .... 135
Table 13 The correlation among methylation and gene expression of the HOXA10
and BPA concentration compared between each groups of women ...... 136
Table 14 Primer sequence for real-time PCR ......................................................... 137
Table 15 Primer sequence for MSP ......................................................................... 137

                                

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