Impact of cadmium exposure during pregnancy on hepatic glucocorticoid receptor methylation and expression in rat fetus.
Impact of cadmium exposure during pregnancy on hepatic glucocorticoid receptor methylation and expression in rat fetus.
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DOI：
10.1371/journal.pone.0044139
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Ronco AM
中科院分区：
文献类型：
--
作者：
Castillo P;Ibáñez F;Guajardo A;Llanos MN;Ronco AM
由于母亲营养不良或接触环境化学物质而导致的不利胎儿环境会改变糖皮质激素（GC）代谢，增加成年后代谢紊乱的风险。在这项研究中，我们研究了母亲在怀孕期间接触镉（Cd，50 ppm）对胎儿肝糖皮质激素受体启动子（GR）甲基化的影响及其与 DNA 甲基转移酶（DNMT1a 和 3a）表达的相关性。我们还研究了肝脏磷酸烯醇丙酮酸羧激酶（PEPCK）和酰基辅酶A氧化酶（AOX）的表达，这两种酶分别参与碳水化合物和脂质的代谢。通过焦磷酸测序分析了大鼠GR基因外显子110（GR110）在核苷酸-2536至-2361处的甲基化。定量实时 PCR 用于通过蛋白质印迹分析评估肝脏 GR、PEPCK 和 AOX mRNA 及其蛋白质水平。在 GR 外显子 110 的所有 CpG 位点上均以性别依赖性方式注意到各组间的差异甲基化。在雄性中，CpG 比对照组甲基化程度更高（185±21%，p<0.001），但只有 CpG 位点 1、6、7 和 9 显示出显着不同的甲基化程度。此外，还发现 GR（mRNA 和蛋白质）表达较低。相反，在女性中，CpG 的甲基化程度低于对照组（62±11%，p<0.05）并且过度表达，影响了 PEPCK 和 AOX 的表达，而在男性中则没有变化。 GR 甲基化谱与 DNMT3a 表达相关，这可以解释 Cd 处理诱导的 GR110 启动子的表观遗传性别依赖性变化。总之，怀孕期间接触镉会影响胎儿肝脏 DNMT3a，导致 GR110 甲基化和表达发生性别依赖性变化。尽管这些影响似乎与低出生体重和身高没有直接关系，但它们可能对长期健康产生相关影响。
Adverse fetal environment due to maternal undernutrition or exposure to environmental chemicals alters glucocorticoid (GC) metabolism increasing the risk of metabolic disorders in adulthood. In this study, we investigated the effects of maternal exposure to cadmium (Cd, 50 ppm) during pregnancy in the methylation of fetal hepatic glucocorticoid receptor promoter (GR) and the correlation with its expression and that of the DNA methyltransferases (DNMT1a and 3a). We also studied the expression of liver phosphoenolpyruvate carboxykinase (PEPCK) and acyl-CoA oxidase (AOX), two enzymes involved in the metabolism of carbohydrates and lipids respectively. The methylation of the rat GR gene exon 110 (GR110) in nucleotides -2536 to -2361 was analyzed by pyrosequencing. Quantitative real time PCR was used to assess hepatic GR, PEPCK and AOX mRNA, and their protein levels using Western blotting analysis. Differential methylation was noted across groups at all CpG sites in the GR exon 110 in a sex-dependent manner. In males, CpG were more methylated than the controls (185±21%, p<0.001) but only CpG sites 1,6,7 and 9 showed a significantly different extent of methylation. In addition, a lower expression of GR (mRNA and protein) was found. On the contrary, in females, CpG were less methylated than the controls (62±11%, p<0.05) and overexpressed, affecting PEPCK and AOX expression, which did not change in males. The GR methylation profile correlates with DNMT3a expression which may explain epigenetic sex-dependent changes on GR110 promoter induced by Cd treatment. In conclusion, Cd exposure during pregnancy affects fetal liver DNMT3a resulting in sex-dependent changes in methylation and expression of GR110. Although these effects do not seem to be directly involved in the low birth weight and height, they may have relevant implications for long-term health.
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影响因子：
3.6
作者：
Baccarelli A;Bollati V
通讯作者：
Bollati V
影响因子：
3.8
作者：
Doi, Takashi;Puri, Prem;Thompson, Jennifer
通讯作者：
Thompson, Jennifer
影响因子：
8.3
作者：
Berglund, Marika;Lindberg, Anna-Lena;Vahter, Marie
通讯作者：
Vahter, Marie
宫内生长限制后，新生儿的胞嘧啶甲基化失调。
影响因子：
3.7
作者：
Einstein F;Thompson RF;Bhagat TD;Fazzari MJ;Verma A;Barzilai N;Greally JM
通讯作者：
Greally JM
DOI：
10.1152/ajpregu.00122.2010
发表时间：
2010-07-01
影响因子：
2.8
作者：
Baserga, Mariana;Kaur, Rajwinderjit;Lane, Robert H.
通讯作者：
Lane, Robert H.