PFOS的肝脏和心脏发育毒性研究
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摘要
PFOS即全氟辛烷磺酸,是一种全球性的持续性有机污染物,可以通过食物链富集,诱导多种毒性效应；且PFOS可以通过胎盘屏障,对子代的生存、生长发育影响很大,所以对它的研究越来越多；近年来研究的热点是它的肝毒性(肝肿大,肝细胞腺癌)和发育毒性(死亡率升高,生长发育迟缓),因为PFOS的这两种毒性效应比较显著。但是,由于机体是由一个复杂调控网络构成,所以此两种毒性的机制尚不清楚,不同的研究报道的结果也不尽相同,如PPARa是否在肝毒性进展中的具有重要性,或肺不张是否在出生后迅速死亡效应中的关键因素。
而近年来,由于表观遗传学的发展,研究发现许多疾病特别是肝损伤或肝癌均与表观遗传改变相关,而发育毒性也与线粒体尤为相关。本论文以表观遗传毒性和线粒体损伤毒性为研究途径,分别从肝脏细胞表观遗传效应中的DNA总甲基化和特异基因甲基化水平改变与否的角度出发,研究PFOS肝毒性机制是否与其相关；另外,从心脏线粒体损伤及相关核酸、蛋白分子水平研究角度出发,对PFOS的心脏发育毒性的可能机制进行探讨。
第一部分、胚胎期PFOS暴露对大鼠出生后断乳期肝脏DNA总甲基化水平的影响
目的：研究对大鼠出生前暴露于PFOS与其出生后生长发育状况和肝脏可能发生的DNA的甲基化修饰程度的改变之间的关系。方法：用阴道冲洗涂片法检测受孕情况；在雌性SD大鼠受孕后的2-21天,对其进行不同剂量PFOS(对照,0.1 mg/kg/d,0.6mg/kg/d,2.0 mg/kg/d)灌胃染毒；记录母鼠孕期生长速度和子鼠出生后的生存率和生长速度。子鼠出生后21天,即生长至断乳期,收集血清和肝脏器官样本。用HE染色观测肝脏细胞正常与否；用液质联用法(LC/MS)检测血清和肝脏中PFOS含量；用总甲基化检测试剂盒进行DNA总甲基化水平的检测；并用BSP产物纯化结合质粒克隆后测序法检测LINE-1的甲基化状态；以及用AP-PCR方法评估CpG岛的甲基化状态；最后用定量PCR检测DNA甲基转移酶(DNA methyltransferase, DNMT)的表达情况。结果：母鼠孕期生长速度和子鼠出生后的生长速度在高剂量组均显著性减慢(p<0.05)；总甲基化水平在最高剂量组有显著性降低(p<0.05)；测序显示LINE-1的甲基化水平各组间无显著性差异(p>0.05)；AP-PCR方法显示各剂量组的CpG岛甲基化水平均与对照组有显著性差异(p<0.05)；另外,DNMT3a在最高剂量组的表达水平有显著性升高。结论：出生前暴露于PFOS降低大鼠出生后的生存率和减慢其生长发育速度；大鼠出生后21天肝脏总甲基化水平的降低也与出生前PFOS暴露水平相关,CpG岛甲基化水平降低也与出生前PFOS暴露水平相关。
第二部分、胚胎期PFOS暴露引起出生后大鼠肝组织中个体基因甲基化状态改变的研究
目的：PFOS能够引起一系列肝脏毒性和发育毒性,但目前机制尚不明确。本研究试图论证DNA甲基化水平是否与PFOS诱导的肝毒性早期过程相关；尤其是是否能发现相关的DNA甲基化方面的生物标志物,用于早期毒性的判断。方法：在雌性SD大鼠受孕后的2-21天,对其进行不同剂量PFOS(对照,0.1 mg/kg/d,0.6 mg/kg/d, 2.0 mg/kg/d)灌胃染毒；在子鼠出生后21天,即断乳时,收集肝脏组织样本。用HE染色观测肝脏细胞正常与否；用亚硫酸氢钠测序PCR法(Bisulfite sequencing PCR,BSP),即BSP产物纯化结合质粒克隆后测序法检测GSTP(谷胱甘肽S-转移酶pi)、p16等特定的可能为标志性基因启动子区域的甲基化状态；最后用定量PCR检测GSTP等基因的表达情况。结果：虽然显微镜下未见明显的肝组织病理学(肝细胞肿大,空泡化等)改变,但GSTP的甲基化状态在染毒组的断乳期大鼠肝脏中发生了上升(高剂量组中,GSTP的启动子的关键位点+79,81,84的甲基化水平改变高达30%,而对照组无甲基化发生),其CpG岛甲基化状态与出生前PFOS暴露水平呈剂量-反应关系。然而GSTP的表达却与其甲基化水平不一致,后通过检测调控GSTP的通路Keap1-Nrf2/MafK发现,虽然GSTP的转录因子Nrf2/MafK并没有发生量的变化,但是Nrf2的抑制因子Keap1的表达降低了,这可能间接导致了GSTP的表达上调。同时,GSTP的这种表达上调与机体处于氧化应激状态一致。结论：出生前暴露于PFOS使得出生后的大鼠肝脏中GSTP基因启动子关键位点高甲基化,这种指标比普通病理学观察指标更灵敏,且反映了潜在毒性的发展趋势；虽然大鼠机体朝着毒性效应方向发展,但是短期内却是表现的氧化应激,这点正好被GSTP启动子关键位点的高甲基化和GSTP的表达上调分别证实。
第三部分、胚胎期PFOS暴露与出生后断乳期大鼠心脏线粒体内膜结构功能改变的研究
目的：大鼠出生前暴露于PFOS对大鼠出生后的生长发育造成很大影响,达到剂量阈值之后,子鼠的死亡率明显升高,生长发育也相对迟缓。而心脏是生长发育过程中的一个关键器官；线粒体是功能细胞器,在心肌细胞中起着重要作用。本研究试图探讨心肌细胞线粒体微观改变与这种发育毒性之间的相关性。方法：本实验中使用了电镜切片观察线粒体,表达谱芯片筛选线粒体功能相关基因,并用定量PCR和蛋白水平检测进行芯片结果的验证,以及用光学显微镜对传统病理学和分子毒理学方面的可能性改变进行观察。结果：线粒体电镜照片观察到空泡化,内膜溶解等现象；表达谱芯片结果筛选选出了部分与线粒体功能相关的表达上调或下调超过1.5倍的基因,其中包括下调的线粒体内膜构成蛋白,ATP合成酶,ATP消耗酶,和上调的线粒体保护蛋白Ucp系列基因等；通过定量PCR和蛋白水平的验证得到一致结果,且有剂量-效应关系。另外在线粒体损伤的后续效应观察中,虽然心脏切片细胞形态学观察结果无显著差异；但PCNA增殖及TUNEL凋亡染色观察结果在暴露组比对照组间有一定增加。结论：大鼠出生前暴露于PFOS对大鼠出生后心脏线粒体造成损伤,虽然在心脏切片形态学观察无显著性改变,但是线粒体微观观察结果和功能相关基因的分子水平检测发生了显著性改变,与损伤效应一致；且一定程度上表现出了损伤后的增殖及凋亡效应。
Perfluorooctane sulfonate (PFOS), a widespread environmental pollutant, is a breakdown product of related perfluorooctanesulfonamides, which were used in many industrial and commercial applications. Due to the extremely stable and accumulative nature of PFOS, it has been considered as a persistent organic pollutant and has been found in high concentrations in serum and liver in wildlife and humans. Increased incidences of hepatotoxicity and developmental toxicity have been reported to be the main toxicity and hazard profile of PFOS. However, the mechanism underlying hepatic effects and developmental toxicity observed in the PFOS-treated mammalians was not well known. Notably, it is proven that PFOS can cross the placental barrier and cause toxicity in developmental mammalians.
As we known, early life stage exposure to toxicants would increase the risk of adverse effects. In the past decade, increasing evidence has been reported to support the associations between exposures during the intrauterine period and health outcomes later in life. So it is possible to find predictive biomarkers for increased incidence of liver toxicity and cardiac developmental toxicity induced by PFOS.
To test the hypothesis whether prenatal exposure of PFOS to the livers of postnatal rat, may related with the alteration of genomic DNA methylation level and promoter region methylation of individual genes; and to investigate whether prenatal exposure of PFOS to the hearts of postnatal rat, may related with the alteration of cardiac mitochondrial dysfunction and structure damage. Pregnant Sprague-Dawley (SD) rats were exposed to perfluorooctane sulfonate (PFOS) and then livers and hearts of weaned (Postnatal Day 21) offspring rats were investigated through epigenetic effects and mitochondrial injury, respectively.
Part I:Prenatal exposure to PFOS altered DNA methylation levels in postnatal SD rat livers
Objectives:To study whether prenatal exposure of PFOS to the livers of postnatal rat, may related with the alteration of DNA methylation level. Methods:After sperm positive was observed, the pregnant rats gavage exposed to different doses of PFOS (control,0.1 mg/kg/d,0.6 mg/kg/d,2.0 mg/kg/d) during the gestational day 2-21, then the dams was allowed to give birth and the livers of postnatal day 21 were collected, and the global DNA methylation level, the methylation status of LINE-1 and the methylation status of CpG islands were evaluated with the global DNA methylation kit, BSP combined cloned sequencing, and AP-PCR, respectively. Results:The global DNA methylation level at the highest dose group decreased significantly (p<0.05); but there were no significant differences of methylation levels of LINE-1 among the groups (p>0.05); The AP-PCR method showed significant difference of CpG islands methylation in three dosed group compared to the control (p<0.05); in addition, the expression of DNMT3a at the highest dose group was significantly increased (p<0.05). Conclusion:In livers of postnatal rats, the global DNA hypomethylation level and the decrease of CpG islands methylation were related to prenatal exposure to PFOS.
Part II:Prenatal exposure to PFOS altered individual genes methylation levels of livers from postnatal SD rat
Objectives:The adverse environmental exposure in early life may have deleterious effects on animals through epigenetic aspects. The current study examined the possibility of early epigenetic alteration in PFOS-exposed rat liver. Methods:Pregnant Sprague-Dawley (SD) rats were exposed to Perfluorooctane sulfonate (PFOS) at doses of 0.1,0.6 and 2.0 mg/kg/d and 0.05% Tween 80 as control by gavage from gestation days 2 to 21. The dams were allowed to give birth and liver samples from weaned (Postnatal Day 21) offspring rats were analyzed for individual genes such as tumor suppressor gene glutathione S-transferase pi (GSTP) and p16 promoter methylation level, as well as related genes expression level. Results:In PFOS exposed weaned rats, compared to the control, methylation of critical CpG sites (+79,81,84) in GSTP promoter was found up to 30% methylated in the livers of treated rats, while p16 promoter methylation was not affected. In addition, the up-regulated expression of GSTP was observed and this increase was associated with its main pathway of transcription regulation:Keapl-Nrf2/MafK. Conclusion:early induced hypermethylation in critical cytosines within the GSTP gene promoter region may be a significant biomarker of hepatic PFOS burden, though their direct role in PFOS induced-hepatotoxicity, including its potential carcinogenic action, needs further research.
Part III:Prenatal exposure to PFOS injured cardiac mitochondrial inner membrane of postnatal SD rat
Objectives:Xenobiotics exposure in early life may have adverse effects on animals' development through mitochondrial damage or dysfunction. The current study demonstrated the possibility of early cardiac mitochondrial damage in PFOS-exposed rat heart. Methods:Pregnant Sprague-Dawley (SD) rats were exposed to Perfluorooctane sulfonate (PFOS) at doses of 0.1,0.6 and 2.0 mg/kg/d and 0.05% Tween 80 as control by gavage from gestation days 2 to 21. The dams were allowed to give birth and heart tissues from weaned (Postnatal Day 21) offspring rats were analyzed for mitochondrial damage through histology observation, ultramicrostructure by electron microscope, global gene expression profile by microarray, related mRNA and proteins or enzymes expression levels by quantitative PCR and western blot. Results:The mitochondria was damaged at 2.0 mg/kg/d dosage group; there were significant vacuolization and inner membrane injury appeared at the hig dosage group; The global gene expression profile showed significant difference in level of some mRNA expression related with mitochondrial structure and function at 2.0 mg/kg/d dosage group, compared to the control; in addition, the expression of several gene at the highest dose group was indeed significantly increased (p<0.05) through quantitative PCR and western blot analysis. Finally, the changes among groups were almost dose-dependent. Conclusion:In hearts of postnatal rats, the mitochondrial injury level and the status of their function were related to prenatal exposure to PFOS. Thus, early induced changes in cardiac mitochondrial structure and function may be a significant phenomenon in rat development after PFOS exposure, though their direct role in PFOS induced developmental toxicity, including its contribution to development of heart or the whole organism, needs further research.
而近年来,由于表观遗传学的发展,研究发现许多疾病特别是肝损伤或肝癌均与表观遗传改变相关,而发育毒性也与线粒体尤为相关。本论文以表观遗传毒性和线粒体损伤毒性为研究途径,分别从肝脏细胞表观遗传效应中的DNA总甲基化和特异基因甲基化水平改变与否的角度出发,研究PFOS肝毒性机制是否与其相关；另外,从心脏线粒体损伤及相关核酸、蛋白分子水平研究角度出发,对PFOS的心脏发育毒性的可能机制进行探讨。
第一部分、胚胎期PFOS暴露对大鼠出生后断乳期肝脏DNA总甲基化水平的影响
目的：研究对大鼠出生前暴露于PFOS与其出生后生长发育状况和肝脏可能发生的DNA的甲基化修饰程度的改变之间的关系。方法：用阴道冲洗涂片法检测受孕情况；在雌性SD大鼠受孕后的2-21天,对其进行不同剂量PFOS(对照,0.1 mg/kg/d,0.6mg/kg/d,2.0 mg/kg/d)灌胃染毒；记录母鼠孕期生长速度和子鼠出生后的生存率和生长速度。子鼠出生后21天,即生长至断乳期,收集血清和肝脏器官样本。用HE染色观测肝脏细胞正常与否；用液质联用法(LC/MS)检测血清和肝脏中PFOS含量；用总甲基化检测试剂盒进行DNA总甲基化水平的检测；并用BSP产物纯化结合质粒克隆后测序法检测LINE-1的甲基化状态；以及用AP-PCR方法评估CpG岛的甲基化状态；最后用定量PCR检测DNA甲基转移酶(DNA methyltransferase, DNMT)的表达情况。结果：母鼠孕期生长速度和子鼠出生后的生长速度在高剂量组均显著性减慢(p<0.05)；总甲基化水平在最高剂量组有显著性降低(p<0.05)；测序显示LINE-1的甲基化水平各组间无显著性差异(p>0.05)；AP-PCR方法显示各剂量组的CpG岛甲基化水平均与对照组有显著性差异(p<0.05)；另外,DNMT3a在最高剂量组的表达水平有显著性升高。结论：出生前暴露于PFOS降低大鼠出生后的生存率和减慢其生长发育速度；大鼠出生后21天肝脏总甲基化水平的降低也与出生前PFOS暴露水平相关,CpG岛甲基化水平降低也与出生前PFOS暴露水平相关。
第二部分、胚胎期PFOS暴露引起出生后大鼠肝组织中个体基因甲基化状态改变的研究
目的：PFOS能够引起一系列肝脏毒性和发育毒性,但目前机制尚不明确。本研究试图论证DNA甲基化水平是否与PFOS诱导的肝毒性早期过程相关；尤其是是否能发现相关的DNA甲基化方面的生物标志物,用于早期毒性的判断。方法：在雌性SD大鼠受孕后的2-21天,对其进行不同剂量PFOS(对照,0.1 mg/kg/d,0.6 mg/kg/d, 2.0 mg/kg/d)灌胃染毒；在子鼠出生后21天,即断乳时,收集肝脏组织样本。用HE染色观测肝脏细胞正常与否；用亚硫酸氢钠测序PCR法(Bisulfite sequencing PCR,BSP),即BSP产物纯化结合质粒克隆后测序法检测GSTP(谷胱甘肽S-转移酶pi)、p16等特定的可能为标志性基因启动子区域的甲基化状态；最后用定量PCR检测GSTP等基因的表达情况。结果：虽然显微镜下未见明显的肝组织病理学(肝细胞肿大,空泡化等)改变,但GSTP的甲基化状态在染毒组的断乳期大鼠肝脏中发生了上升(高剂量组中,GSTP的启动子的关键位点+79,81,84的甲基化水平改变高达30%,而对照组无甲基化发生),其CpG岛甲基化状态与出生前PFOS暴露水平呈剂量-反应关系。然而GSTP的表达却与其甲基化水平不一致,后通过检测调控GSTP的通路Keap1-Nrf2/MafK发现,虽然GSTP的转录因子Nrf2/MafK并没有发生量的变化,但是Nrf2的抑制因子Keap1的表达降低了,这可能间接导致了GSTP的表达上调。同时,GSTP的这种表达上调与机体处于氧化应激状态一致。结论：出生前暴露于PFOS使得出生后的大鼠肝脏中GSTP基因启动子关键位点高甲基化,这种指标比普通病理学观察指标更灵敏,且反映了潜在毒性的发展趋势；虽然大鼠机体朝着毒性效应方向发展,但是短期内却是表现的氧化应激,这点正好被GSTP启动子关键位点的高甲基化和GSTP的表达上调分别证实。
第三部分、胚胎期PFOS暴露与出生后断乳期大鼠心脏线粒体内膜结构功能改变的研究
目的：大鼠出生前暴露于PFOS对大鼠出生后的生长发育造成很大影响,达到剂量阈值之后,子鼠的死亡率明显升高,生长发育也相对迟缓。而心脏是生长发育过程中的一个关键器官；线粒体是功能细胞器,在心肌细胞中起着重要作用。本研究试图探讨心肌细胞线粒体微观改变与这种发育毒性之间的相关性。方法：本实验中使用了电镜切片观察线粒体,表达谱芯片筛选线粒体功能相关基因,并用定量PCR和蛋白水平检测进行芯片结果的验证,以及用光学显微镜对传统病理学和分子毒理学方面的可能性改变进行观察。结果：线粒体电镜照片观察到空泡化,内膜溶解等现象；表达谱芯片结果筛选选出了部分与线粒体功能相关的表达上调或下调超过1.5倍的基因,其中包括下调的线粒体内膜构成蛋白,ATP合成酶,ATP消耗酶,和上调的线粒体保护蛋白Ucp系列基因等；通过定量PCR和蛋白水平的验证得到一致结果,且有剂量-效应关系。另外在线粒体损伤的后续效应观察中,虽然心脏切片细胞形态学观察结果无显著差异；但PCNA增殖及TUNEL凋亡染色观察结果在暴露组比对照组间有一定增加。结论：大鼠出生前暴露于PFOS对大鼠出生后心脏线粒体造成损伤,虽然在心脏切片形态学观察无显著性改变,但是线粒体微观观察结果和功能相关基因的分子水平检测发生了显著性改变,与损伤效应一致；且一定程度上表现出了损伤后的增殖及凋亡效应。
Perfluorooctane sulfonate (PFOS), a widespread environmental pollutant, is a breakdown product of related perfluorooctanesulfonamides, which were used in many industrial and commercial applications. Due to the extremely stable and accumulative nature of PFOS, it has been considered as a persistent organic pollutant and has been found in high concentrations in serum and liver in wildlife and humans. Increased incidences of hepatotoxicity and developmental toxicity have been reported to be the main toxicity and hazard profile of PFOS. However, the mechanism underlying hepatic effects and developmental toxicity observed in the PFOS-treated mammalians was not well known. Notably, it is proven that PFOS can cross the placental barrier and cause toxicity in developmental mammalians.
As we known, early life stage exposure to toxicants would increase the risk of adverse effects. In the past decade, increasing evidence has been reported to support the associations between exposures during the intrauterine period and health outcomes later in life. So it is possible to find predictive biomarkers for increased incidence of liver toxicity and cardiac developmental toxicity induced by PFOS.
To test the hypothesis whether prenatal exposure of PFOS to the livers of postnatal rat, may related with the alteration of genomic DNA methylation level and promoter region methylation of individual genes; and to investigate whether prenatal exposure of PFOS to the hearts of postnatal rat, may related with the alteration of cardiac mitochondrial dysfunction and structure damage. Pregnant Sprague-Dawley (SD) rats were exposed to perfluorooctane sulfonate (PFOS) and then livers and hearts of weaned (Postnatal Day 21) offspring rats were investigated through epigenetic effects and mitochondrial injury, respectively.
Part I:Prenatal exposure to PFOS altered DNA methylation levels in postnatal SD rat livers
Objectives:To study whether prenatal exposure of PFOS to the livers of postnatal rat, may related with the alteration of DNA methylation level. Methods:After sperm positive was observed, the pregnant rats gavage exposed to different doses of PFOS (control,0.1 mg/kg/d,0.6 mg/kg/d,2.0 mg/kg/d) during the gestational day 2-21, then the dams was allowed to give birth and the livers of postnatal day 21 were collected, and the global DNA methylation level, the methylation status of LINE-1 and the methylation status of CpG islands were evaluated with the global DNA methylation kit, BSP combined cloned sequencing, and AP-PCR, respectively. Results:The global DNA methylation level at the highest dose group decreased significantly (p<0.05); but there were no significant differences of methylation levels of LINE-1 among the groups (p>0.05); The AP-PCR method showed significant difference of CpG islands methylation in three dosed group compared to the control (p<0.05); in addition, the expression of DNMT3a at the highest dose group was significantly increased (p<0.05). Conclusion:In livers of postnatal rats, the global DNA hypomethylation level and the decrease of CpG islands methylation were related to prenatal exposure to PFOS.
Part II:Prenatal exposure to PFOS altered individual genes methylation levels of livers from postnatal SD rat
Objectives:The adverse environmental exposure in early life may have deleterious effects on animals through epigenetic aspects. The current study examined the possibility of early epigenetic alteration in PFOS-exposed rat liver. Methods:Pregnant Sprague-Dawley (SD) rats were exposed to Perfluorooctane sulfonate (PFOS) at doses of 0.1,0.6 and 2.0 mg/kg/d and 0.05% Tween 80 as control by gavage from gestation days 2 to 21. The dams were allowed to give birth and liver samples from weaned (Postnatal Day 21) offspring rats were analyzed for individual genes such as tumor suppressor gene glutathione S-transferase pi (GSTP) and p16 promoter methylation level, as well as related genes expression level. Results:In PFOS exposed weaned rats, compared to the control, methylation of critical CpG sites (+79,81,84) in GSTP promoter was found up to 30% methylated in the livers of treated rats, while p16 promoter methylation was not affected. In addition, the up-regulated expression of GSTP was observed and this increase was associated with its main pathway of transcription regulation:Keapl-Nrf2/MafK. Conclusion:early induced hypermethylation in critical cytosines within the GSTP gene promoter region may be a significant biomarker of hepatic PFOS burden, though their direct role in PFOS induced-hepatotoxicity, including its potential carcinogenic action, needs further research.
Part III:Prenatal exposure to PFOS injured cardiac mitochondrial inner membrane of postnatal SD rat
Objectives:Xenobiotics exposure in early life may have adverse effects on animals' development through mitochondrial damage or dysfunction. The current study demonstrated the possibility of early cardiac mitochondrial damage in PFOS-exposed rat heart. Methods:Pregnant Sprague-Dawley (SD) rats were exposed to Perfluorooctane sulfonate (PFOS) at doses of 0.1,0.6 and 2.0 mg/kg/d and 0.05% Tween 80 as control by gavage from gestation days 2 to 21. The dams were allowed to give birth and heart tissues from weaned (Postnatal Day 21) offspring rats were analyzed for mitochondrial damage through histology observation, ultramicrostructure by electron microscope, global gene expression profile by microarray, related mRNA and proteins or enzymes expression levels by quantitative PCR and western blot. Results:The mitochondria was damaged at 2.0 mg/kg/d dosage group; there were significant vacuolization and inner membrane injury appeared at the hig dosage group; The global gene expression profile showed significant difference in level of some mRNA expression related with mitochondrial structure and function at 2.0 mg/kg/d dosage group, compared to the control; in addition, the expression of several gene at the highest dose group was indeed significantly increased (p<0.05) through quantitative PCR and western blot analysis. Finally, the changes among groups were almost dose-dependent. Conclusion:In hearts of postnatal rats, the mitochondrial injury level and the status of their function were related to prenatal exposure to PFOS. Thus, early induced changes in cardiac mitochondrial structure and function may be a significant phenomenon in rat development after PFOS exposure, though their direct role in PFOS induced developmental toxicity, including its contribution to development of heart or the whole organism, needs further research.
引文
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