Departamento de Toxicología, Centro de Investigación y de Estudios Avanzados del IPN, Ciudad de México, México.
Departamento de Investigación Básica, Instituto Nacional de Cancerología, Ciudad de México, México.
Part Fibre Toxicol. 2019 Jan 28;16(1):7. doi: 10.1186/s12989-019-0289-1.
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/p female mice were exposed to collected UFP (400 μg/kg accumulated dose) by intratracheal instillation and compared to control (nonexposed) and sterile HO (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 (ATR) and angiotensin I-converting enzyme (ACE) in fetuses and lungs of PND 50 male offspring were also assessed.
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 ATR and ACE, which resulted in increased blood pressure in the PND 50 male offspring.
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.
颗粒物（PM）暴露与不良的宫内环境有关，可促进成年人心血管疾病（CVD）风险。超细颗粒（UFP）（粒径小、表面积/质量比大）在全身分布，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）相关元素启动子区域的甲基化改变可能与 UFP 暴露相关的高血压编程有关。我们研究了宫内 UFP 暴露是否通过炎症和氧化应激、羟类固醇 11β型 2（HSD11B2）和 RAS 相关元素的编程改变来促进胎盘应激，从而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 并进行理化特性分析。通过气管内滴注将收集到的 UFP（400μg/kg 累积剂量）暴露于怀孕的 C57BL/6J p/p 雌性小鼠，并与对照组（未暴露）和无菌 HO（载体）暴露的小鼠进行比较。通过测量子宫、胎盘和胎儿的重量、母鼠血清和胎儿皮质醇、胎盘 HSD11B2 DNA 甲基化和蛋白水平来评估胚胎吸收和胎盘应激。测量胎盘和胎儿中多环芳烃（PAH）生物转化（CYP1A1 和 NQO1（NAD（P）H 脱氢酶（醌）1））酶、炎症和氧化应激。在雄性后代出生后第 50 天测量血压。还评估了 PND 50 雄性后代胎儿和肺部中（RAS）相关元素、血管紧张素 II 受体 1（ATR）和血管紧张素 I 转化酶（ACE）的甲基化和蛋白表达。
宫内 UFP 暴露会导致胎盘应激，表现为胚胎吸收率增加、子宫、胎盘和胎儿重量减少、HSD11B2 过度甲基化和蛋白下调。宫内 UFP 暴露会增加 PAH 生物转化酶、宫内氧化损伤和炎症，并刺激 ATR 和 ACE 的编程和激活，导致 PND 50 雄性后代血压升高。
宫内 UFP 暴露通过炎症和氧化应激促进胎盘应激，并编程 RAS 相关元素，导致后代血压改变。胎儿发育期间暴露于 UFP 可能会影响成年人心血管疾病的易感性。
