宫内多环芳烃暴露对胎儿全基因组基因表达的影响
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摘要
目的：
研究母婴多环芳烃(PAHs)的负荷水平及各种多环芳烃的致癌风险贡献率；研究孕期宫内多环芳烃暴露对胎儿全基因组基因表达的影响；分析宫内PAHs暴露水平与癌症相关基因mRNA表达的关系,并分析各种PAHs对基因表达改变的贡献大小,为探讨PAHs的致癌机制提供参考依据,同时也为探讨孕期健康促进和疾病防治及优先控制环境污染物的筛选提供参考依据。
方法：
1.应用现场流行病学调查方法,对所选待产孕妇进行流行病学调查,并收集孕
妇外周静脉血和新生儿脐带血；
2.采用高效液相色谱-荧光检测法测定孕妇静脉血和新生儿脐带血血清Pyr、BaA、BbF、BkF、BaP、DBahA和BghiP 7种PAHs的浓度,并对各种PAHs的致癌风险的贡献率进行评价；
3.采用Affymetrix和Illumina全基因组基因表达谱芯片检测不同PAHs水平下脐带血全基因组基因表达的改变,并采用Real-time PCR进行验证；
4.采用单因素分析,分析Py、BaA、BbF、BkF、BaP、DBahA和BghiP 7种PAHs及其它可能的影响因素对基因表达改变的影响,采用多元逐步回归分析,筛选影响基因表达改变的主要影响因素；
5采用典型相关分析,分析PAHs和基因表达两组指标间的相互关系及各种PAHs对基因表达影响的贡献大小。
结果：
第一部分母婴多环芳烃体内负荷水平及各种多环芳烃致癌风险贡献率评价
1、母血和脐带血中Pyr的检出率最高,分别为97.62%和96.77%,其余6种PAHs的检出率均在70%以上。脐带血中Pyr、BaA、BaP和DBahA的浓度均高于母血浓度(P<0.05),而BbF的浓度低于母血浓度(P<0.05)；
2、在母血和脐血中,BaP、BbF和DBahA的致癌毒性贡献率较大,分别为36.6%和38.6%、28.0%和19.0%、21.1%和25.9%。
第二部分宫内PAHs暴露引起胎儿全基因组基因表达的改变
1、Illumina芯片得到两组间差异表达的探针共660个,表达上调的差异探针342个,表达下调的差异探针318个；
2、Affymetrix芯片得到5组间的差异表达探针共1847个,表达上调的差异探针998个,表达下调的基因849个；
3、差异表达基因所参与的主要的显著性功能,包括DNA损伤修复、细胞增殖、细胞分化、凋亡调控、信号转导调控、胚胎发育、胎盘发育、神经系统发育、四肢头骨等器官形成、免疫功能及对环状有机物的反应等;
4、差异表达基因所参与的显著性信号转导通路主要包括嗅觉味觉转导通路(Olfactory transduction、Taste transduction)、MAPK信号转导通路(Mitogen-activated protein kinase signaling pathway)、代谢信号转导通路(Metabolic pathways)、黑色素瘤通路(Melanoma)、甲状腺癌通路(Thyroid cancer)、癌症信号通路(Pathways in cancer)、心肌收缩通路(Cardiac muscle contraction)、胰岛素信号通路(Insulin signaling pathway)、神经信号传递通路(Neuroactive ligand-receptor interaction)、细胞黏附分子通路(Cell adhesion molecules (CAMs))、叶酸合成(Folate biosynthesis)、不饱和脂肪酸合成(Biosynthesis of unsaturated fatty acids)等,说明宫内BaP暴露对胎儿的影响可能与肿瘤、糖尿病、心脏病、神经系统疾病及嗅味觉发育等相关;
5、在整个相互作用网络中，pathway in cancer是主要的上游pathway,而MAPK信号通路(MAPK signaling pathway)是主要的最终效应pathway。
第三部分宫内PAHs暴露与核心基因mRNA表达的关系
1、经对性别、母亲年龄、新生儿出生孕周、孕期母亲被动吸烟、常吃煎炸食品、孕期补充叶酸、母亲文化程度对基因表达影响的单因素分析,未发现上述因素对基因表达的影响具有统计学意义；
2、经对血清Pyr、BaA、BbF、BkF、BaP、DBahA、BghiP对基因表达影响的单因素分析,发现SNRPN基因的表达量随着血清Pyr、BaA、BbF、BkF、DBahA和BghiP浓度的增加而增加,表现为表达上调；RPL27A基因的表达量与血清Pyr、BaA、BbF、BkF、BaP和BghiP浓度呈显著正相关,BMP1基因的表达量与血清BbF浓度呈显著正相关,NUDT2基因的表达量与血清BaA、BbF、BaP和DBahA浓度呈显著正相关,RAD54B基因的表达量与血清BaP和BghiP浓度呈显著正相关,即随着血清PAHs水平的增加均表现为表达上调；而E2F1基因与血清BbF、BaP、DBahA和BghiP的浓度呈显著负相关,即随着血清PAHs水平的增加而表现为表达下调。
3、多元逐步回归分析的结果发现,血清BbF是SNRPN mRNA表达的主要影响因素,对SNRPN mRNA的表达具有显著正向影响作用(p=0.033)；血清BkF对RPL27A mRNA表达具有正向影响作用(p=0.001),母亲文化程度对之则呈负向影响作用(p=0.014),血清BkF的标准回归系数b’的绝对值(0.444)大于母亲文化程度(b’=-0.314),表明BkF较之母亲文化程度对RPL27A mRNA表达的影响更大；BMP1 mRNA表达受血清Pyr的正向影响(p=0.043); NUDT2 mRNA表达受血清BaP的正向影响较明显(p=0.035); E2F1 mRNA表达主要受血清BaP的负向影响(p=0.039); RAD54B mRNA表达主要受血清BaP的正向影响(p=0.004)和血清BkF的负向影响(p=0.029),血清BaP的标准回归系数的绝对值(0.428)大于血清BkF(-0.316),表明血清BaP对RAD54B mRNA表达的影响可能略大于BkF。
第四部分各种PAHs对基因mRNA表达影响的作用大小
1、综合代表6个基因表达水平的典型相关变量W1与BbF之间的相关系数最大(05352),其次是BkF(0.4456)和BaP(0.3867),说明BbF与本研究所选6个癌症相关基因的表达关系最密切,对6个基因mRNA表达的影响最大,其次是BkF和BaP；
2、综合代表7种PAHs水平的典型相关变量V1与RPL27A的mRNA表达量之间的相关系数最大(0.4501),其次是SNRPN和NUDT2的表达量,说明受7种PAHs水平影响最大的是RPL27A的表达,其次是SNRPN和NUDT2的表达；
结论：
1、多种致癌性]PAHs可通过胎盘屏障进入胎儿体内,其中BaP、BbF和DBahA的致癌风险贡献最大；
2、宫内PAHs暴露可引起胎儿多种癌症相关基因mRNA表达的改变,可能会增加癌症发生的风险；
3、SNRPN、RPL27A、BMP1、NUDT2和E2F1可作为宫内PAHs暴露健康影响的候选基因；
4、不同PAHs主要影响的基因不尽相同,说明各种PAHs的作用机制可能有所不同；
5、BbF对6个癌症相关基因整体表达水平影响的贡献最大,其次是BkF和BaP；
6、用基因表达的改变来区分各种PAHs致癌毒性的大小和贡献是可行的。
Objective:
To investigate the body burdens of polycyclic aromatic hydrocarbons (PAHs) of pregnant women and fetus and the contribution of each polycyclic aromatic hydrocarbon to the total carcinogenesis of 7 PAHs, to research the genome-wide expression change of fetus caused by PAHs exposure during gestation period, analyze the correlation between PAHs levels and cancer-related gene expression, and evaluate the contribution of each kind of PAHs to gene expression, so that provide evidence for exploring the carcinogenesis mechanism of PAHs and provide reference for selection of environmental priority control pollutants and for maternal gestation healthcare and diseases prevention for the next generation.
Methods:
1. Questionnaire investigation on randomly selected and voluntarily participating pregnant women was conducted by face to face and maternal venous blood and cord blood were collected.
2. Total 7 kinds of PAHs, which were Pyr, BaA, BbF, BkF, BaP, DBahA and BghiP, were detected by high-performance liquid chromatography (HPLC) after maternal blood and cord blood were collected from March to July in 2010. The cord serum PAHs levels were compared with the maternal serum levels and the contribution rate of each PAH to the total carcinogenesis of 7 PAHs in both maternal and cord blood was analyzed.
3. The whole genome mRNA expression of different PAHs exposure groups were tested through both Affymetrix and Illumina genome-wide mRNA expression array and Real-time PCR validation was carried.
4. Simple correlation analysis was used to research the correlation of gene expression with levels of Pyr, BaA, BbF, BkF, BaP, DBahA, BghiP and some other factors such as newborn gender, gestation age, maternal passive smoking, foliate acid supplement, and multivariate linear stepwise regression was also conducted to select the key impact factors of each cancer-related gene expression change.
5. Canonical correlation analysis was used to analyze not only the correlation of two groups of PAHs and six genes as a whole, also the relationship of each PAHs or gene expression with the whole group and the opposite group, so that the contribution of every PAHs to the whole six gene expression was estimated.
Results:
ⅠBody burden of PAHs and carcinogenesis contribution of each PAH of pregnant women and fetus
1. The detection rate of Pyr was the highest which was 97.62% and 96.77% in maternal and cord blood, respectively. The detection rates of the other 6 PAHs were higher than 70% in both maternal and cord serum. The concentrations of Pyr, BaA, BaP and DBahA in cord serum were statistically higher than those in maternal serum (p<0.05), while the concentration of BbF was statistically lower than that in maternal serum (p<0.05).
2. The contribution of BaP, BbF and DBahA were dominant in the total carcinogenesis of 7 PAHs, which were 36.6% and 38.6%,28.0% and 19.0%, 21.1% and 25.9% in maternal and cord serum, respectively.
ⅡThe whole genome mRNA expression change of fetus induced by gestation PAHs exposure
1. According to the results of Illumina array, there're 660 gene probes had different expression between two groups with high and low cord sreum PAHs levels, and 342 probes showed upregulated expression and 318 probes showed downregulated expression.
2. According to the results of Affymetrix array, there're 1847 gene probes had different expression among five groups with different cord sreum PAHs levels, and 998 probes showed upregulated expression and 849 probes showed downregulated expression.
3. The main GOs with statistic significance that different expression genes attend included DNA damage repair, cell proliferation and differentiation, apoptosis regulation, regulation of signaling transduction, embryonic developmental growth, embryonic placenta development, regulation of neurogenesis, eye and embryonic cranial skeleton morphogenesis, regulation of T cell receptor signaling pathway, response to organic cyclic substance, and so on.
4. The main pathways with statistic significance that different expression genes attend included olfactory transduction, taste transduction, MAPK signaling pathway, metabolic pathways, melanoma, thyroid cancer, pathways in cancer, cardiac muscle contraction, Insulin signaling pathway, neuroactive ligand-receptor interaction, cell adhesion molecules (CAMs), folate biosynthesis, biosynthesis of unsaturated fatty acids, and so on. It indicated that the effects of gestation PAHs exposure on fetus may involved in cancer, diabetes, cardiovasculare diseases, neurogenic diseases and development of taste and olfaction, etc.
5. In the whole pathway-net made according to the interaction of pathways noted by the KEGG, the pathway in cancer standed in the main upstream position with 6 downstream pathways, and MAPK signaling pathway were the key final-effects pathway.
ⅢRelationship between gestation PAHs exposure and mRNA expression of key genes
1. According to the results of simple correlation analysis between gene expression and infants gender, maternal passive smoking, fried food taken and foliate acid supplement during pregnant period, maternal education, mother age and gestation age, no significant correlation was found.
2. The simple correlation analysis between six genes expression and cord serum concentrations of Pyr, BaA, BbF, BkF, BaP, DBahA, BghiP showed that the mRNA expression of SNRPN increased with the increasing of cord serum concentrations of Pyr, BaA, BbF, BkF, DBahA and BghiP, that meant it showed upregulated expression with the PAHs exposure increasing; the mRNA expression of RPL27A was positively correlated with the concentrations of Pyr, BaA, BbF, BkF, BaP and BghiP; the mRNA expression of BMP1 was positively correlated with the concentration of BbF; the mRNA expression of NUDT2 was positively correlated with the concentration of BaA, BbF, BaP and DBahA; the mRNA expression of RAD54B was positively correlated with the concentration of BaP and BghiP; while the mRNA expression of E2F1 was positively correlated with the concentration of BbF, BaP, DBahA and BghiP, that was meant it showed down-regulated expression with the increasing of gestation PAHs exposure.
3. The result of multivariate linear stepwise regression showed that cord serum BbF was the key factor that affected the mRNA expression of SNRPN and it significantly positively affected the mRNA expression of SNRPN (p=0.033); the mRNA expression of RPL27A was mainly positively affected by the level of cord serum BkF (p=0.001) and negatively affected by maternal education level (p=0.014), the effect of BkF was stronger than that of maternal education because of the absolute value of standard regression coefficient from BkF (b'=0.444) was bigger than that from maternal education (b'=-0.314); the mRNA expression of BMP1 was mainly positively affected by the level of cord serum Pyr (p=0.043); the mRNA expression of NUDT2 was mainly positively affected by the level of cord serum BaP (p=0.035); the mRNA expression of E2F1 was mainly negtively affected by the level of cord serum BaP (p=0.039); the mRNA expression of RAD54B was mainly positively affected by the level of cord serum BaP (p=0.004) and negtively affected by the level of cord serum BkF (p=0.029), the absolute value of regression coefficient from BaP (0.428) was bigger than that from BkF (-0.316), which meant that the effects of BaP on RAD54B mRNA expression was likely stronger than that of BkF.
IV Comparison of the impacts on mRNA expression of every kinds of PAHs
1 The correlation coefficient of the Canonical correlation variant W1 (which reflected the status of 6 genes expression) with BbF (0.5352) was the biggest one and the second and third was BkF (0.4456) and BaP (0.3867), respectively, which meant that the impact of BbF on the mRNA expression of six cancer-related genes ranked the first, then was that of BkF and BaP.
2 The correlation coefficient of the Canonical correlation variant V1 (which reflected the level of 7 kinds of PAHs) with the mRNA expression of RPL27A was the biggest one, and the second and third was SNRPN and NUDT2, which indicated that the impacts of BbF on the mRNA expression of six cancer-related genes ranked the first, then was that of SNRPN and NUDT2.
Conclusions:
1. Several kinds of carcinogenic PAHs can penetrate the placenta and get into the body of fetus. The contributions to carcinogenesis risk of BaP, BbF and DBahA are bigger than the other kinds of PAHs detected.
2. Gestation PAHs exposure can be involved in the mRNA expression change of many cancer-related genes, and increase the risk of tumor formation.
3. SNRPN, RPL27A, BMP1, NUDT2 and E2F1 can be regarded as the candidate genes of the PAHs'target gene.
4. Different kind of PAHs has effects on mRNA expression of different genes, which means they may have different mechanisms of adverse effects.
5. BbF showed the most contribution on the mRNA expression change of the six cancer-related genes, and then BkF and BaP.
6. It's feasible that discriminating the strengthen and contribution of carcinogenesis of every PAHs by the change of gene expression caused by each kinds of PAHs.
研究母婴多环芳烃(PAHs)的负荷水平及各种多环芳烃的致癌风险贡献率；研究孕期宫内多环芳烃暴露对胎儿全基因组基因表达的影响；分析宫内PAHs暴露水平与癌症相关基因mRNA表达的关系,并分析各种PAHs对基因表达改变的贡献大小,为探讨PAHs的致癌机制提供参考依据,同时也为探讨孕期健康促进和疾病防治及优先控制环境污染物的筛选提供参考依据。
方法：
1.应用现场流行病学调查方法,对所选待产孕妇进行流行病学调查,并收集孕
妇外周静脉血和新生儿脐带血；
2.采用高效液相色谱-荧光检测法测定孕妇静脉血和新生儿脐带血血清Pyr、BaA、BbF、BkF、BaP、DBahA和BghiP 7种PAHs的浓度,并对各种PAHs的致癌风险的贡献率进行评价；
3.采用Affymetrix和Illumina全基因组基因表达谱芯片检测不同PAHs水平下脐带血全基因组基因表达的改变,并采用Real-time PCR进行验证；
4.采用单因素分析,分析Py、BaA、BbF、BkF、BaP、DBahA和BghiP 7种PAHs及其它可能的影响因素对基因表达改变的影响,采用多元逐步回归分析,筛选影响基因表达改变的主要影响因素；
5采用典型相关分析,分析PAHs和基因表达两组指标间的相互关系及各种PAHs对基因表达影响的贡献大小。
结果：
第一部分母婴多环芳烃体内负荷水平及各种多环芳烃致癌风险贡献率评价
1、母血和脐带血中Pyr的检出率最高,分别为97.62%和96.77%,其余6种PAHs的检出率均在70%以上。脐带血中Pyr、BaA、BaP和DBahA的浓度均高于母血浓度(P<0.05),而BbF的浓度低于母血浓度(P<0.05)；
2、在母血和脐血中,BaP、BbF和DBahA的致癌毒性贡献率较大,分别为36.6%和38.6%、28.0%和19.0%、21.1%和25.9%。
第二部分宫内PAHs暴露引起胎儿全基因组基因表达的改变
1、Illumina芯片得到两组间差异表达的探针共660个,表达上调的差异探针342个,表达下调的差异探针318个；
2、Affymetrix芯片得到5组间的差异表达探针共1847个,表达上调的差异探针998个,表达下调的基因849个；
3、差异表达基因所参与的主要的显著性功能,包括DNA损伤修复、细胞增殖、细胞分化、凋亡调控、信号转导调控、胚胎发育、胎盘发育、神经系统发育、四肢头骨等器官形成、免疫功能及对环状有机物的反应等;
4、差异表达基因所参与的显著性信号转导通路主要包括嗅觉味觉转导通路(Olfactory transduction、Taste transduction)、MAPK信号转导通路(Mitogen-activated protein kinase signaling pathway)、代谢信号转导通路(Metabolic pathways)、黑色素瘤通路(Melanoma)、甲状腺癌通路(Thyroid cancer)、癌症信号通路(Pathways in cancer)、心肌收缩通路(Cardiac muscle contraction)、胰岛素信号通路(Insulin signaling pathway)、神经信号传递通路(Neuroactive ligand-receptor interaction)、细胞黏附分子通路(Cell adhesion molecules (CAMs))、叶酸合成(Folate biosynthesis)、不饱和脂肪酸合成(Biosynthesis of unsaturated fatty acids)等,说明宫内BaP暴露对胎儿的影响可能与肿瘤、糖尿病、心脏病、神经系统疾病及嗅味觉发育等相关;
5、在整个相互作用网络中，pathway in cancer是主要的上游pathway,而MAPK信号通路(MAPK signaling pathway)是主要的最终效应pathway。
第三部分宫内PAHs暴露与核心基因mRNA表达的关系
1、经对性别、母亲年龄、新生儿出生孕周、孕期母亲被动吸烟、常吃煎炸食品、孕期补充叶酸、母亲文化程度对基因表达影响的单因素分析,未发现上述因素对基因表达的影响具有统计学意义；
2、经对血清Pyr、BaA、BbF、BkF、BaP、DBahA、BghiP对基因表达影响的单因素分析,发现SNRPN基因的表达量随着血清Pyr、BaA、BbF、BkF、DBahA和BghiP浓度的增加而增加,表现为表达上调；RPL27A基因的表达量与血清Pyr、BaA、BbF、BkF、BaP和BghiP浓度呈显著正相关,BMP1基因的表达量与血清BbF浓度呈显著正相关,NUDT2基因的表达量与血清BaA、BbF、BaP和DBahA浓度呈显著正相关,RAD54B基因的表达量与血清BaP和BghiP浓度呈显著正相关,即随着血清PAHs水平的增加均表现为表达上调；而E2F1基因与血清BbF、BaP、DBahA和BghiP的浓度呈显著负相关,即随着血清PAHs水平的增加而表现为表达下调。
3、多元逐步回归分析的结果发现,血清BbF是SNRPN mRNA表达的主要影响因素,对SNRPN mRNA的表达具有显著正向影响作用(p=0.033)；血清BkF对RPL27A mRNA表达具有正向影响作用(p=0.001),母亲文化程度对之则呈负向影响作用(p=0.014),血清BkF的标准回归系数b’的绝对值(0.444)大于母亲文化程度(b’=-0.314),表明BkF较之母亲文化程度对RPL27A mRNA表达的影响更大；BMP1 mRNA表达受血清Pyr的正向影响(p=0.043); NUDT2 mRNA表达受血清BaP的正向影响较明显(p=0.035); E2F1 mRNA表达主要受血清BaP的负向影响(p=0.039); RAD54B mRNA表达主要受血清BaP的正向影响(p=0.004)和血清BkF的负向影响(p=0.029),血清BaP的标准回归系数的绝对值(0.428)大于血清BkF(-0.316),表明血清BaP对RAD54B mRNA表达的影响可能略大于BkF。
第四部分各种PAHs对基因mRNA表达影响的作用大小
1、综合代表6个基因表达水平的典型相关变量W1与BbF之间的相关系数最大(05352),其次是BkF(0.4456)和BaP(0.3867),说明BbF与本研究所选6个癌症相关基因的表达关系最密切,对6个基因mRNA表达的影响最大,其次是BkF和BaP；
2、综合代表7种PAHs水平的典型相关变量V1与RPL27A的mRNA表达量之间的相关系数最大(0.4501),其次是SNRPN和NUDT2的表达量,说明受7种PAHs水平影响最大的是RPL27A的表达,其次是SNRPN和NUDT2的表达；
结论：
1、多种致癌性]PAHs可通过胎盘屏障进入胎儿体内,其中BaP、BbF和DBahA的致癌风险贡献最大；
2、宫内PAHs暴露可引起胎儿多种癌症相关基因mRNA表达的改变,可能会增加癌症发生的风险；
3、SNRPN、RPL27A、BMP1、NUDT2和E2F1可作为宫内PAHs暴露健康影响的候选基因；
4、不同PAHs主要影响的基因不尽相同,说明各种PAHs的作用机制可能有所不同；
5、BbF对6个癌症相关基因整体表达水平影响的贡献最大,其次是BkF和BaP；
6、用基因表达的改变来区分各种PAHs致癌毒性的大小和贡献是可行的。
Objective:
To investigate the body burdens of polycyclic aromatic hydrocarbons (PAHs) of pregnant women and fetus and the contribution of each polycyclic aromatic hydrocarbon to the total carcinogenesis of 7 PAHs, to research the genome-wide expression change of fetus caused by PAHs exposure during gestation period, analyze the correlation between PAHs levels and cancer-related gene expression, and evaluate the contribution of each kind of PAHs to gene expression, so that provide evidence for exploring the carcinogenesis mechanism of PAHs and provide reference for selection of environmental priority control pollutants and for maternal gestation healthcare and diseases prevention for the next generation.
Methods:
1. Questionnaire investigation on randomly selected and voluntarily participating pregnant women was conducted by face to face and maternal venous blood and cord blood were collected.
2. Total 7 kinds of PAHs, which were Pyr, BaA, BbF, BkF, BaP, DBahA and BghiP, were detected by high-performance liquid chromatography (HPLC) after maternal blood and cord blood were collected from March to July in 2010. The cord serum PAHs levels were compared with the maternal serum levels and the contribution rate of each PAH to the total carcinogenesis of 7 PAHs in both maternal and cord blood was analyzed.
3. The whole genome mRNA expression of different PAHs exposure groups were tested through both Affymetrix and Illumina genome-wide mRNA expression array and Real-time PCR validation was carried.
4. Simple correlation analysis was used to research the correlation of gene expression with levels of Pyr, BaA, BbF, BkF, BaP, DBahA, BghiP and some other factors such as newborn gender, gestation age, maternal passive smoking, foliate acid supplement, and multivariate linear stepwise regression was also conducted to select the key impact factors of each cancer-related gene expression change.
5. Canonical correlation analysis was used to analyze not only the correlation of two groups of PAHs and six genes as a whole, also the relationship of each PAHs or gene expression with the whole group and the opposite group, so that the contribution of every PAHs to the whole six gene expression was estimated.
Results:
ⅠBody burden of PAHs and carcinogenesis contribution of each PAH of pregnant women and fetus
1. The detection rate of Pyr was the highest which was 97.62% and 96.77% in maternal and cord blood, respectively. The detection rates of the other 6 PAHs were higher than 70% in both maternal and cord serum. The concentrations of Pyr, BaA, BaP and DBahA in cord serum were statistically higher than those in maternal serum (p<0.05), while the concentration of BbF was statistically lower than that in maternal serum (p<0.05).
2. The contribution of BaP, BbF and DBahA were dominant in the total carcinogenesis of 7 PAHs, which were 36.6% and 38.6%,28.0% and 19.0%, 21.1% and 25.9% in maternal and cord serum, respectively.
ⅡThe whole genome mRNA expression change of fetus induced by gestation PAHs exposure
1. According to the results of Illumina array, there're 660 gene probes had different expression between two groups with high and low cord sreum PAHs levels, and 342 probes showed upregulated expression and 318 probes showed downregulated expression.
2. According to the results of Affymetrix array, there're 1847 gene probes had different expression among five groups with different cord sreum PAHs levels, and 998 probes showed upregulated expression and 849 probes showed downregulated expression.
3. The main GOs with statistic significance that different expression genes attend included DNA damage repair, cell proliferation and differentiation, apoptosis regulation, regulation of signaling transduction, embryonic developmental growth, embryonic placenta development, regulation of neurogenesis, eye and embryonic cranial skeleton morphogenesis, regulation of T cell receptor signaling pathway, response to organic cyclic substance, and so on.
4. The main pathways with statistic significance that different expression genes attend included olfactory transduction, taste transduction, MAPK signaling pathway, metabolic pathways, melanoma, thyroid cancer, pathways in cancer, cardiac muscle contraction, Insulin signaling pathway, neuroactive ligand-receptor interaction, cell adhesion molecules (CAMs), folate biosynthesis, biosynthesis of unsaturated fatty acids, and so on. It indicated that the effects of gestation PAHs exposure on fetus may involved in cancer, diabetes, cardiovasculare diseases, neurogenic diseases and development of taste and olfaction, etc.
5. In the whole pathway-net made according to the interaction of pathways noted by the KEGG, the pathway in cancer standed in the main upstream position with 6 downstream pathways, and MAPK signaling pathway were the key final-effects pathway.
ⅢRelationship between gestation PAHs exposure and mRNA expression of key genes
1. According to the results of simple correlation analysis between gene expression and infants gender, maternal passive smoking, fried food taken and foliate acid supplement during pregnant period, maternal education, mother age and gestation age, no significant correlation was found.
2. The simple correlation analysis between six genes expression and cord serum concentrations of Pyr, BaA, BbF, BkF, BaP, DBahA, BghiP showed that the mRNA expression of SNRPN increased with the increasing of cord serum concentrations of Pyr, BaA, BbF, BkF, DBahA and BghiP, that meant it showed upregulated expression with the PAHs exposure increasing; the mRNA expression of RPL27A was positively correlated with the concentrations of Pyr, BaA, BbF, BkF, BaP and BghiP; the mRNA expression of BMP1 was positively correlated with the concentration of BbF; the mRNA expression of NUDT2 was positively correlated with the concentration of BaA, BbF, BaP and DBahA; the mRNA expression of RAD54B was positively correlated with the concentration of BaP and BghiP; while the mRNA expression of E2F1 was positively correlated with the concentration of BbF, BaP, DBahA and BghiP, that was meant it showed down-regulated expression with the increasing of gestation PAHs exposure.
3. The result of multivariate linear stepwise regression showed that cord serum BbF was the key factor that affected the mRNA expression of SNRPN and it significantly positively affected the mRNA expression of SNRPN (p=0.033); the mRNA expression of RPL27A was mainly positively affected by the level of cord serum BkF (p=0.001) and negatively affected by maternal education level (p=0.014), the effect of BkF was stronger than that of maternal education because of the absolute value of standard regression coefficient from BkF (b'=0.444) was bigger than that from maternal education (b'=-0.314); the mRNA expression of BMP1 was mainly positively affected by the level of cord serum Pyr (p=0.043); the mRNA expression of NUDT2 was mainly positively affected by the level of cord serum BaP (p=0.035); the mRNA expression of E2F1 was mainly negtively affected by the level of cord serum BaP (p=0.039); the mRNA expression of RAD54B was mainly positively affected by the level of cord serum BaP (p=0.004) and negtively affected by the level of cord serum BkF (p=0.029), the absolute value of regression coefficient from BaP (0.428) was bigger than that from BkF (-0.316), which meant that the effects of BaP on RAD54B mRNA expression was likely stronger than that of BkF.
IV Comparison of the impacts on mRNA expression of every kinds of PAHs
1 The correlation coefficient of the Canonical correlation variant W1 (which reflected the status of 6 genes expression) with BbF (0.5352) was the biggest one and the second and third was BkF (0.4456) and BaP (0.3867), respectively, which meant that the impact of BbF on the mRNA expression of six cancer-related genes ranked the first, then was that of BkF and BaP.
2 The correlation coefficient of the Canonical correlation variant V1 (which reflected the level of 7 kinds of PAHs) with the mRNA expression of RPL27A was the biggest one, and the second and third was SNRPN and NUDT2, which indicated that the impacts of BbF on the mRNA expression of six cancer-related genes ranked the first, then was that of SNRPN and NUDT2.
Conclusions:
1. Several kinds of carcinogenic PAHs can penetrate the placenta and get into the body of fetus. The contributions to carcinogenesis risk of BaP, BbF and DBahA are bigger than the other kinds of PAHs detected.
2. Gestation PAHs exposure can be involved in the mRNA expression change of many cancer-related genes, and increase the risk of tumor formation.
3. SNRPN, RPL27A, BMP1, NUDT2 and E2F1 can be regarded as the candidate genes of the PAHs'target gene.
4. Different kind of PAHs has effects on mRNA expression of different genes, which means they may have different mechanisms of adverse effects.
5. BbF showed the most contribution on the mRNA expression change of the six cancer-related genes, and then BkF and BaP.
6. It's feasible that discriminating the strengthen and contribution of carcinogenesis of every PAHs by the change of gene expression caused by each kinds of PAHs.
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1. Bostrom C E, Gerdep, Hanberg A, et al. Cancer risk assessment, indicators and guidelines for polycyclic aromatic hydrocarbons in the ambient air [J]. Environ Health Perspect,2002,110:451-488.
2. Menzie C A, Potocki B B, Santodonato J. Exposure to carcinogenic PAHs in the environment [J]. Environ Sci Technol,1992,7:1278-1284.
3.李新荣,赵同科,于艳新,等.北京地区人群对多环芳烃的暴露及健康风险评价[J].农业环境科学学报,2009,28(8)：1758-1765.
4. Perera F P, Rauh V, Tsai W Y, et al. Effects of transplacental exposure to environmental pollutants on birth outcomes in a multiethnic pollution [J]. Environ Health Perspect,2003,111:201-205.
5. Choi H, Rauh V, Garfinkel R, et al. Prenatal exposure to airborne polycyclic aromatic hydrocarbons and risk of intrauterine growth restriction [J]. Environ Health Perspect,2008,116:658-665.
6. Dejmek J, Solansky I, Benes I, et al. The impact of polycyclic aromatic hydrocarbons and fine particles on pregnancy outcome [J]. Environ Health Perspect,2000,108:1159-1164.
7. Hin L. Tsang, Shenchun Wu, Clement K.M. Leung, et al. Body burden of POPs of Hong Kong residents, based on human milk, maternal and cord serum [J]. Environ Int.2010, doi:10.1016/j.envint,2010.08.010.
8. Shuang Wang, Stephen Chanock, Deliang Tang, et al. Assessment of interactions between PAH exposure and genetic polymorphisms on PAH-DNA adducts in African American, Dominican and Caucasian mothers and newborns [J]. Cancer Epidemiol Biomarkers Prev,2008,17:405-413.
9.董少霞,丁昌明,张美云,等.胎儿宫内多环芳烃暴露水平及其母婴暴露关系研究过[J].卫生研究,2009,38(3)：339-342.
10.董少霞,刘娅,程义斌,等.太原市大气多环芳烃水平及孕妇体内多环芳烃负荷关系研究[J].环境与健康杂志,2009,26(5)：380-382.
11.董少霞,刘娅,程义斌,等.太原市新生儿多环芳烃暴露水平及其与代谢酶基因多态性的关系[J].环境与健康杂志,2008,25(6)：475-479.
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