PLACENTAL OXIDATIVE DNA DAMAGE MARKERS AND EPIGENETIC AGING OF PLACENTA

胎盘氧化 DNA 损伤标记物与胎盘表观遗传老化

• 批准号: 10200233
• 负责人: MICHAEL TSAI
• 金额: $ 13.88万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10200233
• 关键词: 37 weeks gestation; 8-hydroxy-2' -deoxyguanosine; Acceleration; Age; Aging; Antioxidants; Biological; Biological Aging; Biological Markers; Blood; Blood Circulation; Cell Aging; Chronology; Clinical; Cohort Studies; Contractor; DNA Damage; DNA Methylation; Development; Enrollment; Epigenetic Process; Fetal Growth; Fetal Growth Retardation; First Pregnancy Trimester; Functional disorder; Genetic; Gestational Age; Glucose; Glycosylated hemoglobin A; Government; Heritability; Homeostasis; Inflammation; Insulin; Low Birth Weight Infant; Measures; Methods; Molecular; National Institute of Child Health and Human Development; Oxidative Stress; Pathologic; Pattern; Placenta; Placental Insufficiency; Plasma; Pre-Eclampsia; Pregnancy; Pregnancy Complications; Premature Birth; Premature aging syndrome; Risk; Sampling; Second Pregnancy Trimester; Signal Transduction; Telomerase; Third Pregnancy Trimester; Time; Tissues; Visit; adverse outcome; adverse pregnancy outcome; early onset; free radical oxygen; histopathological examination; male; methylation biomarker; neonate; novel; oxidative DNA damage; premature; stillbirth; therapeutic target

Altered placental aging is increasingly recognized to be a potential mechanism in the pathophysiology of a scope of pregnancy complications related to placental dysfunction. Several studies have found that premature aging of the placenta is associated with preeclampsia, low birth weight, stillbirth, and preterm birth. The field of biological aging has recently been revolutionized by Steve Horvath’s molecular methods that estimate the biological age of a tissue with high accuracy using DNA methylation markers. This “clock” is particularly valuable in studies of placental aging because traditional histopathological examination and telomerase homeostasis markers may not capture subtle aging alterations and premature cellular senescence caused by DNA damage due to oxidative stress. Placenta-specific epigenetic clocks have been developed. The difference between epigenetic age and gestational age of the placenta, namely placental age acceleration (PAA), indicates whether the “biological age” of the placenta is older than its chronological age. Higher PAA has been associated with increased risk for early-onset preeclampsia in an earlier study, and with low birthweight in male neonates in the NICHD Fetal Growth Studies cohort. The clinical utility of the placental epigenetic clock as a novel preventative and therapeutic target in adverse pregnancy outcomes can be facilitated by identifying non-invasive markers of PAA during gestation. PAA has been found to be under substantial genetic control with heritability of 57%. Moreover, the rate of epigenetic aging is developmentally adjusted, suggesting that the epigenetic aging rate is primarily set in early gestation. Cellular oxidative stress within the placenta leads to increased release of several factors into the maternal circulation. Therefore, biomarkers that the placenta excretes into the maternal circulation may give early signals of pathological changes in a prematurely aging placenta. Markers of oxidative DNA damage that are elevated in placentas from advanced gestational ages similarly to maternal blood of pregnancies with adverse outcomes related to placental insufficiency can be primary candidates. Prior studies have demonstrated that at advanced gestational ages, placentas show high levels of the oxidative DNA damage marker 8OHdG (8-hydroxydeoxyguanosine) accompanied by decreased levels of the antioxidant marker TAC (total antioxidant capacity). 8OHdG is a byproduct generated from oxygen free radical-induced DNA damage either spontaneously or induced by other agents. Similar patterns have been found in maternal plasma levels of these biomarkers in pregnancies complicated by preeclampsia, stillbirth, and fetal growth restriction. Collectively, similarities in the patterns of these biomarkers in late/post-term placentas and in pregnancy complications related to placental aging suggests that placental oxidative DNA damage markers may be potential early signals of premature aging of the placenta.

胎盘老化的改变越来越被认为是与胎盘功能障碍相关的一系列妊娠并发症的潜在病理生理学机制。多项研究发现，胎盘过早老化与先兆子痫、低出生体重、死产和早产有关。最近，Steve Horvath的分子方法给生物老化领域带来了革命性的变化，这种方法使用DNA甲基化标记高精度地估计组织的生物年龄。这个“时钟”在胎盘老化的研究中特别有价值，因为传统的组织病理学检查和端粒酶稳态标记物可能无法捕捉到氧化应激造成的DNA损伤引起的细微衰老变化和细胞过早衰老。胎盘特异的表观遗传学时钟已经被开发出来。胎盘的表观遗传年龄和胎龄之间的差异，即胎盘年龄加速(PAA)，表明胎盘的“生物年龄”是否大于其实际年龄。在NICHD胎儿生长研究队列中，较高的PAA水平与早发性先兆子痫的风险增加以及男性新生儿出生体重较低相关。 胎盘表观遗传时钟作为一种新的预防和治疗不良妊娠结局的靶点的临床应用，可以通过在妊娠期间识别PAA的非侵入性标志物来促进。PAA已被发现受到实质上的遗传控制，遗传率为57%。 此外，表观遗传衰老的速度是发育调整的，这表明表观遗传衰老速度主要设定在妊娠早期。胎盘内的细胞氧化应激导致几种因子释放到母体循环中的增加。因此，胎盘排泄到母体循环中的生物标志物可能会给出过早衰老的胎盘病理变化的早期信号。氧化DNA损伤的标记物在胎龄较高的胎盘中升高，类似于与胎盘功能不全相关的不良结局的孕妇的母血，可能是主要候选。先前的研究表明，在妊娠晚期，胎盘显示出高水平的氧化DNA损伤标记物8OHdG(8-羟基脱氧鸟苷)，同时伴随着抗氧化标记物TAC(总抗氧化能力)的降低。8OHdG是氧自由基自发或由其他因素诱导的DNA损伤的副产物。在妊娠合并子痫前期、死产和胎儿生长受限的孕妇中，也发现了这些生物标志物的母体血浆水平类似的模式。总之，这些生物标记物在晚期/足月胎盘以及与胎盘老化相关的妊娠并发症中的模式相似，提示胎盘DNA氧化损伤标记物可能是胎盘过早老化的潜在早期信号。