Maternal Electronic Cigarette Exposure Induces Inflammation, Oxidative Stress and Alters Mitochondrial Function in Postnatal Brain

S. Archie, A. Sifat, David Mara, Yong Zhang, T. Abbruscato
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Abstract

Purpose: Electronic nicotine delivery systems (ENDS), also commonly known as cigarettes (e-Cig) are often considered as a safer alternative to tobacco smoke and therefore have become extremely popular among all age groups and sex. Around 15% of pregnant women are now using e-Cigs in the US which keeps increasing at an alarming rate. Harmful effects of tobacco smoking during pregnancy are well documented for both pregnant and postnatal health, however a lack of preclinical and clinical studies exist to evaluate the long-term effects of prenatal e-Cig exposure on postnatal health. In our previous study, we have observed disruption of blood-brain barrier integrity and deteriorated motor, learning and memory function in prenatally e-Cig exposed offspring. In this study, we have evaluated the consequences of maternal e-Cig use on postnatal neuro-inflammation, oxidative stress, hypoxia and mitochondrial function at different age including evaluation of both male and female offspring. Method: In our study, pregnant CD1 mice (E5) were exposed to e-Cig vapor (2.4% nicotine) till postnatal day (PD) 7. Body and brain weight were measured at PD7, PD23, PD45 and PD90. Immunobead assay was performed to measure the level of pro-inflammatory cytokines at PD7, PD23, PD45 and PD90. The expression level of oxidative phosphorylation or OXPHOS Complex (I, II, III, IV and V), hypoxia inducible factor (HIF-1 a ), antioxidant glutathione (GSH), mitochondrial protein TOM20, Manganese superoxide dismutase (MnSOD), EGRI and NRF2 were analyzed in offspring brain using western blot at PD7 and PD23. Results: Significantly reduced brain to body weight ratio was observed at PD7 in prenatally e-Cig exposed offspring. Significantly increased expression of OXPHOS complexes and HIF-1 a and reduced expression of MnSOD, GSH and NRF2 were observed in prenatally e-Cig exposed offspring compared to control (P < 0.05). However, no difference was observed in expression level of TOM20 and EGR1. Additionally, prenatally e-Cig exposed offspring had higher level of pro-inflammatory cytokines (IL-6, TNF-a ) at PD7, PD45 and PD90 (P < 0.05). Conclusions: Our findings suggest that prenatal e-Cig exposure induces neuroinflammation and oxidative stress on neonatal brain by increasing cytokines level, oxidative stress and disrupting mitochondrial function which may alter fetal brain immune function and mitochondrial activity that make such offspring more vulnerable to brain insults. Currently, we are evaluating mitochondrial activity in primary neuron from prenatally e-Cig exposed offspring. Support: NIH R01DA049737 and R01DA02912.
母体电子烟暴露诱导炎症、氧化应激和改变产后大脑线粒体功能
目的:电子尼古丁输送系统(ENDS),通常也被称为香烟(e- cigg),通常被认为是烟草烟雾的更安全替代品,因此在所有年龄组和性别中都非常受欢迎。在美国,大约15%的孕妇现在使用电子烟,这一比例还在以惊人的速度增长。怀孕期间吸烟对怀孕和产后健康的有害影响有充分的记录,但缺乏临床前和临床研究来评估产前接触电子烟对产后健康的长期影响。在我们之前的研究中,我们观察到产前接触电子烟的后代血脑屏障完整性被破坏,运动、学习和记忆功能恶化。在这项研究中,我们评估了母亲使用电子烟对不同年龄的产后神经炎症、氧化应激、缺氧和线粒体功能的影响,包括对雄性和雌性后代的评估。方法:在我们的研究中,怀孕的CD1小鼠(E5)暴露于电子烟蒸汽(含2.4%尼古丁)直到出生后(PD) 7。在PD7、PD23、PD45和PD90时测量体、脑重量。采用免疫珠法检测小鼠PD7、PD23、PD45和PD90的促炎细胞因子水平。采用western blot方法分析子代脑组织中氧化磷酸化或氧化磷酸化复合物(I、II、III、IV和V)、缺氧诱导因子(hif - 1a)、抗氧化谷胱甘肽(GSH)、线粒体蛋白TOM20、锰超氧化物歧化酶(MnSOD)、EGRI和NRF2的表达水平。结果:产前电子烟暴露的后代在PD7时脑体重比显著降低。与对照组相比,电子烟暴露子代的OXPHOS复合物和HIF-1 a表达显著升高(P < 0.05), MnSOD、GSH和NRF2表达显著降低(P < 0.05)。而TOM20和EGR1的表达水平无显著差异。此外,电子烟暴露子代在产前PD7、PD45和PD90的促炎因子(IL-6、TNF-a)水平较高(P < 0.05)。结论:我们的研究结果表明,产前电子烟暴露通过增加细胞因子水平、氧化应激和破坏线粒体功能来诱导新生儿大脑的神经炎症和氧化应激,从而改变胎儿的大脑免疫功能和线粒体活性,使其后代更容易受到脑损伤。目前,我们正在评估产前电子烟暴露后代初级神经元的线粒体活性。支持:NIH R01DA049737和R01DA02912。
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