Mella Maria Teresa, Kohari Katherine, Jones Richard, Peña Juan, Ferrara Lauren, Stone Joanne, Lambertini Luca
Department of Obstetrics, Gynecology and Reproductive Science, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Department of Preventive Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Placenta. 2016 Sep;45:16-23. doi: 10.1016/j.placenta.2016.07.002. Epub 2016 Jul 9.
Intrahepatic cholestasis of pregnancy (ICP) affects 0.2-2% of pregnant women. While the maternal clinical course of ICP is usually benign, the fetal effects can be severe spanning from spontaneous preterm birth to fetal demise to long term effects on the health of the progeny. ICP is characterized by high maternal serum levels of bile acids and placental and hepatic bile acids accumulation. Intrahepatic cholestasis, in the non-pregnant state, has been also linked to alterations of the mitochondrial activity attributed to high oxidative stress rates driven by high intracellular bile acids concentrations. Here we explored the hypothesis that elevated bile acid levels of ICP modify the placental mitochondrial activity.
By using a set of 12 ICP and 12 control placenta samples, we assessed the expression of all 13 mitochondrial-encoded protein-coding genes and the mitochondrial DNA (mtDNA) relative abundance by real-time PCR. We also assessed the oxidative stress status by measuring DNA damage by ELISA.
We determined that: 1) the expression of MT-ND4L (+53% - p < 0.01), MT-ND4 (-19%-0.05 < p ≤ 0.01), MT-ND5 (+40% - p < 0.01), MT-CYTB (+35% - p < 0.01) is associated with ICP; 2) the mtDNA relative abundance is not associated with ICP (0.098 in ICP vs 0.118 in controls - p > 0.05); 3) the oxidative stress status is associated with ICP (4403.9 pM 8-oxo-dG/μg DNA in ICP vs 3809.8 pM 8-oxo-dG/μg DNA in controls - p < 0.01).
This preliminary study suggests that mitochondria in placenta respond to high oxidative stress to modify their gene expression which may play an important role in the pathophysiology of ICP.
妊娠期肝内胆汁淤积症（ICP）影响0.2%-2%的孕妇。虽然ICP的母体临床病程通常是良性的，但对胎儿的影响可能很严重，范围从自发早产到胎儿死亡，再到对后代健康的长期影响。ICP的特征是母体血清胆汁酸水平升高以及胎盘和肝脏胆汁酸蓄积。在非妊娠状态下，肝内胆汁淤积也与线粒体活性改变有关，这归因于细胞内胆汁酸浓度高导致的高氧化应激率。在此，我们探讨了ICP胆汁酸水平升高会改变胎盘线粒体活性这一假说。
通过使用12份ICP胎盘样本和12份对照胎盘样本，我们通过实时PCR评估了所有13个线粒体编码的蛋白质编码基因的表达以及线粒体DNA（mtDNA）的相对丰度。我们还通过ELISA测量DNA损伤来评估氧化应激状态。
我们确定：1）MT-ND4L（+53% - p < 0.01）、MT-ND4（-19% - 0.05 < p ≤ 0.01）、MT-ND5（+40% - p < 0.01）、MT-CYTB（+35% - p < 0.01）的表达与ICP相关；2）mtDNA相对丰度与ICP无关（ICP中为0.098，对照组中为0.118 - p > 0.05）；3）氧化应激状态与ICP相关（ICP中为4403.9 pM 8-氧代-dG/μg DNA，对照组中为3809.8 pM 8-氧代-dG/μg DNA - p < 0.01）。
这项初步研究表明，胎盘中的线粒体对高氧化应激做出反应以改变其基因表达，这可能在ICP的病理生理学中起重要作用。
