ROS promote epigenetic remodeling and cardiac dysfunction in offspring following maternal engineered nanomaterial (ENM) exposure
ROS promote epigenetic remodeling and cardiac dysfunction in offspring following maternal engineered nanomaterial (ENM) exposure
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DOI：
10.1186/s12989-019-0310-8
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发表时间：
2019-06-18
影响因子：
10
通讯作者：
Hollander, John M.
中科院分区：
文献类型：
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作者：
Kunovac, Amina;Hathaway, Quincy A.;Hollander, John M.
纳米二氧化钛（nano-TiO 2）是目前应用最广泛的工程纳米材料之一。然而，很少有人知道的后果，母亲ENM吸入暴露在妊娠期生长的后代。据报道，ENM吸入暴露可降低线粒体生物能量学和心脏功能，但其机制尚不清楚。由于ENM吸入暴露，活性氧（ROS）增加，但尚不清楚它们是否影响胎儿重编程。本研究的目的是确定母体ENM吸入暴露是否会影响子代心脏发育和表观基因组remodel. ResultsPregnancy二氧化钛气雾剂的质量浓度为12.09 ± 0.26mg/m3的FVB母鼠暴露于妊娠第五天（GD 5）开始，在6个非连续的天，6 h。气溶胶粒度分布测量表明，空气动力学计数中值直径（CMD）为156 nm，几何标准偏差（GSD）为1.70。超声心动图成像用于评估母体、胎儿（GD 15）和年轻成年（11周）动物的心脏功能。电子传递链（ETC）复合物的活动，线粒体的大小，复杂性和呼吸进行了评价，沿着与5-甲基胞嘧啶，Dnmt 1蛋白表达，和Hif 1活性。心脏功能分析显示，左心室质量增加43%，心输出量减少25%（胎儿），缩短分数减少18%（年轻成人）。在胎仔中，过氧化氢（H2 O2）水平显著升高（接近10倍），随后抗氧化酶磷脂氢谷胱甘肽过氧化物酶（GPx 4）的表达降低。ETC复合物活性IV下降了68%和46%，分别在胎儿和年轻的成年人心肌线粒体。DNA甲基化显着增加，在胎仔暴露后，沿着增加Hif 1活性和Dnmt 1蛋白表达。线粒体超微结构，包括增加的大小，观察到在胎儿和年轻的成年阶段以下maternal exposure.Conclusions母体吸入暴露于纳米二氧化钛的结果与H2 O2水平增加和胎儿后代的Hif 1/Dnmt 1调节轴失调的心脏功能的不良影响。我们的研究结果表明，ROS和表观遗传重塑之间的独特相互作用，导致持续的心脏收缩功能障碍，在成长和年轻的成年后代母亲ENM吸入暴露。
BackgroundNano-titanium dioxide (nano-TiO2) is amongst the most widely utilized engineered nanomaterials (ENMs). However, little is known regarding the consequences maternal ENM inhalation exposure has on growing progeny during gestation. ENM inhalation exposure has been reported to decrease mitochondrial bioenergetics and cardiac function, though the mechanisms responsible are poorly understood. Reactive oxygen species (ROS) are increased as a result of ENM inhalation exposure, but it is unclear whether they impact fetal reprogramming. The purpose of this study was to determine whether maternal ENM inhalation exposure influences progeny cardiac development and epigenomic remodeling.ResultsPregnant FVB dams were exposed to nano-TiO2 aerosols with a mass concentration of 12.090.26mg/m(3) starting at gestational day five (GD 5), for 6h over 6 non-consecutive days. Aerosol size distribution measurements indicated an aerodynamic count median diameter (CMD) of 156nm with a geometric standard deviation (GSD) of 1.70. Echocardiographic imaging was used to assess cardiac function in maternal, fetal (GD 15), and young adult (11weeks) animals. Electron transport chain (ETC) complex activities, mitochondrial size, complexity, and respiration were evaluated, along with 5-methylcytosine, Dnmt1 protein expression, and Hif1 activity. Cardiac functional analyses revealed a 43% increase in left ventricular mass and 25% decrease in cardiac output (fetal), with an 18% decrease in fractional shortening (young adult). In fetal pups, hydrogen peroxide (H2O2) levels were significantly increased (similar to 10 fold) with a subsequent decrease in expression of the antioxidant enzyme, phospholipid hydroperoxide glutathione peroxidase (GPx4). ETC complex activity IV was decreased by 68 and 46% in fetal and young adult cardiac mitochondria, respectively. DNA methylation was significantly increased in fetal pups following exposure, along with increased Hif1 activity and Dnmt1 protein expression. Mitochondrial ultrastructure, including increased size, was observed at both fetal and young adult stages following maternal exposure.Conclusions Maternal inhalation exposure to nano-TiO2 results in adverse effects on cardiac function that are associated with increased H2O2 levels and dysregulation of the Hif1/Dnmt1 regulatory axis in fetal offspring. Our findings suggest a distinct interplay between ROS and epigenetic remodeling that leads to sustained cardiac contractile dysfunction in growing and young adult offspring following maternal ENM inhalation exposure.