In utero exposure to ultrafine particles promotes placental stress-induced programming of renin-angiotensin system-related elements in the offspring results in altered blood pressure in adult mice
In utero exposure to ultrafine particles promotes placental stress-induced programming of renin-angiotensin system-related elements in the offspring results in altered blood pressure in adult mice
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DOI：
10.1186/s12989-019-0289-1
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发表时间：
2019-01-28
影响因子：
10
通讯作者：
De Vizcaya-Ruiz, Andrea
中科院分区：
文献类型：
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作者：
Morales-Rubio, Russell A.;Alvarado-Cruz, Isabel;De Vizcaya-Ruiz, Andrea
背景：暴露于颗粒物（PM）与不良的宫内环境有关，可增加成人心血管疾病（CVD）的风险。超细颗粒（UFP）（体积小，表面积/质量比大）全身分布，可引起炎症和氧化应激，并与血管内皮功能障碍和动脉血管收缩有关，增加高血压风险。胎盘应激和肾素-血管紧张素系统（RAS）相关元件启动子区域甲基化的改变可能与UFP暴露相关的高血压编程有关。我们研究了子宫内UFP暴露是否通过炎症和氧化应激促进胎盘应激，改变羟基类固醇脱氢酶11b- 2 （HSD11B2）和ras相关元件的编程，并导致成年后代血压改变。使用气溶胶浓缩器从环境空气中收集UFP，并对其进行了物理化学表征。将妊娠C57BL/6J p(un)/p（un）雌性小鼠经气管内滴注收集的UFP （400 μ g/kg累积剂量），并与对照组（未暴露）和无菌H2O（对照）暴露小鼠进行比较。通过测量子宫、胎盘和胎儿体重、血清和胎儿皮质醇、胎盘HSD11B2 DNA甲基化和蛋白水平来评估胚胎重吸收和胎盘应激。测定胎盘和胎儿多环芳烃（PAH）生物转化酶(CYP1A1和NQO1 （NAD(P)H脱氢酶（醌）1)）、炎症和氧化应激水平。测定雄性子代产后血压（PND） 50。并对PND 50雄性子代胎儿和肺中（RAS）相关元件、血管紧张素II受体1型（AT(1)R）和血管紧张素i转换酶（ACE）的甲基化和蛋白表达进行了评估。结果：子宫内UFP暴露诱导胎盘应激，表现为胚胎重吸收增加，子宫、胎盘和胎儿体重减少，HSD11B2高甲基化和蛋白下调。子宫内UFP暴露诱导pah生物转化酶增加，宫内氧化损伤和炎症，并刺激AT(1)R和ACE的编程和激活，导致PND 50雄性后代血压升高。结论：子宫内UFP暴露通过炎症和氧化应激促进胎盘应激，并计划ras相关因素，导致后代血压改变。胎儿发育期间暴露于UFP可能影响成年后对心血管疾病的易感性。
Background: Exposure to particulate matter (PM) is associated with an adverse intrauterine environment, which can promote adult cardiovascular disease (CVD) risk. Ultrafine particles (UFP) (small size and large surface area/mass ratio) are systemically distributed, induce inflammation and oxidative stress, and have been associated with vascular endothelial dysfunction and arterial vasoconstriction, increasing hypertension risk. Placental stress and alterations in methylation of promoter regions of renin-angiotensin system (RAS)-related elements could be involved in UFP exposure-related programming of hypertension. We investigated whether in utero UFP exposure promotes placental stress by inflammation and oxidative stress, alterations in hydroxysteroid dehydrogenase 11b-type 2 (HSD11B2) and programming of RAS-related elements, and result in altered blood pressure in adult offspring. UFP were collected from ambient air using an aerosol concentrator and physicochemically characterized. Pregnant C57BL/6J p(un)/p(un) female mice were exposed to collected UFP (400 mu g/kg accumulated dose) by intratracheal instillation and compared to control (nonexposed) and sterile H2O (vehicle) exposed mice. Embryo reabsorption and placental stress by measurement of the uterus, placental and fetal weights, dam serum and fetal cortisol, placental HSD11B2 DNA methylation and protein levels, were evaluated. Polycyclic aromatic hydrocarbon (PAH) biotransformation (CYP1A1 and NQO1 (NAD(P)H dehydrogenase (quinone) 1)) enzymes, inflammation and oxidative stress in placentas and fetuses were measured. Postnatal day (PND) 50 in male offspring blood pressure was measured. Methylation and protein expression of (RAS)-related elements, angiotensin II receptor type 1 (AT(1)R) and angiotensin I-converting enzyme (ACE) in fetuses and lungs of PND 50 male offspring were also assessed.Results: In utero UFP exposure induced placental stress as indicated by an increase in embryo reabsorption, decreases in the uterus, placental, and fetal weights, and HSD11B2 hypermethylation and protein downregulation. In utero UFP exposure induced increases in the PAH-biotransforming enzymes, intrauterine oxidative damage and inflammation and stimulated programming and activation of AT(1)R and ACE, which resulted in increased blood pressure in the PND 50 male offspring.Conclusions: In utero UFP exposure promotes placental stress through inflammation and oxidative stress, and programs RAS-related elements that result in altered blood pressure in the offspring. Exposure to UFP during fetal development could influence susceptibility to CVD in adulthood.