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Objective <p>Electronic cigarettes (ECs) differ from traditional tobacco smoke but may contribute to cardiopulmonary remodeling. Pulmonary hypertension (PH), characterized by pulmonary artery and right ventricle remodeling, poses a significant risk of mortality in infants, children, and adolescents. However, the impact of maternal EC exposure on PH development in offspring remains unclear. To address this, we established a PH rat model with maternal EC exposure.</p> Methods <p>Maternal EC exposure was initiated on gestation day&#xa0;12 via electronic nicotine delivery systems. Offspring were administered monocrotaline (MCT)&#xa0;at 6&#xa0;weeks of age (6-wo)&#xa0;to induce PH. Mechanistic experiments were conducted at 10-week-old (10-wo).&#xa0;Protein expression of NADPH oxidases, DNA methyltransferases, and autophagy-related markers was analyzed by Western blot. Morphological changes and the severity of PH were evaluated via hematoxylin and eosin (HE) staining and echocardiography, respectively. Furthermore, the involvement of the oxidative stress/DNA methylation/autophagy axis in response to maternal EC exposure was confirmed through a combination of ELISA, Western blot, HE staining, and echocardiography. Additionally, ATG5 mRNA expression was measured by qRT-PCR.</p> Results <p>Compared with control conditions, maternal EC exposure significantly worsened MCT-induced PH in male offspring. This was associated with increased oxidative stress, DNA hypomethylation, and anomalous autophagy in the offspring. In vivo treatment with chloroquine inhibited autophagy and ameliorated PH development in offspring exposed to maternal EC. Furthermore, N-acetylcysteine (NAC), an antioxidant, attenuated maternal EC exposure-induced oxidative stress, DNA hypomethylation, and excessive autophagy, thereby improving PH. DNA hypermethylation also reversed PH development, accompanied by reduced oxidative stress and suppressed autophagy. ATG5, a key regulator of autophagy, was identified as a potential therapeutic target, as its repression mitigated PH in maternal EC-exposed offspring.</p> Conclusion <p>Maternal EC exposure induces oxidative stress and DNA hypomethylation in offspring, leading to anomalous autophagy and exacerbation of PH development. Targeting ATG5-mediated autophagy may represent a novel therapeutic approach for improving PH outcomes in offspring exposed to maternal EC.</p> Graphical Abstract <p>Pregnant rats were exposed to either EC vapor or standard air from gestation day&#xa0;12 until 2&#xa0;days before delivery, with all offspring undergoing PH induction at 6-wo. Offspring exposed to maternal EC presented increased oxidative stress, which in turn affected DNA methylation patterns. The decreased DNA methylation in male offspring led to the activation of autophagy, exacerbating the development of PH. Treatment with ATG5 siRNA inhibited autophagy and alleviated heightened PH in male offspring with maternal EC exposure.</p> <p></p>

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Maternal Electronic Cigarette Exposure Induces Dysregulation of Autophagy via Oxidative Stress/DNA Methylation in Pulmonary Hypertension Offspring

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年6月24日

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  • Ze-wen Chen,
  • Yi-fan Li,
  • Hai-long Qiu,
  • Wen Xie,
  • Tian-yu Chen,
  • Yong Zhang,
  • Ji-mei Chen,
  • Jian Zhuang,
  • Shu-sheng Wen

摘要

Objective

Electronic cigarettes (ECs) differ from traditional tobacco smoke but may contribute to cardiopulmonary remodeling. Pulmonary hypertension (PH), characterized by pulmonary artery and right ventricle remodeling, poses a significant risk of mortality in infants, children, and adolescents. However, the impact of maternal EC exposure on PH development in offspring remains unclear. To address this, we established a PH rat model with maternal EC exposure.

Methods

Maternal EC exposure was initiated on gestation day 12 via electronic nicotine delivery systems. Offspring were administered monocrotaline (MCT) at 6 weeks of age (6-wo) to induce PH. Mechanistic experiments were conducted at 10-week-old (10-wo). Protein expression of NADPH oxidases, DNA methyltransferases, and autophagy-related markers was analyzed by Western blot. Morphological changes and the severity of PH were evaluated via hematoxylin and eosin (HE) staining and echocardiography, respectively. Furthermore, the involvement of the oxidative stress/DNA methylation/autophagy axis in response to maternal EC exposure was confirmed through a combination of ELISA, Western blot, HE staining, and echocardiography. Additionally, ATG5 mRNA expression was measured by qRT-PCR.

Results

Compared with control conditions, maternal EC exposure significantly worsened MCT-induced PH in male offspring. This was associated with increased oxidative stress, DNA hypomethylation, and anomalous autophagy in the offspring. In vivo treatment with chloroquine inhibited autophagy and ameliorated PH development in offspring exposed to maternal EC. Furthermore, N-acetylcysteine (NAC), an antioxidant, attenuated maternal EC exposure-induced oxidative stress, DNA hypomethylation, and excessive autophagy, thereby improving PH. DNA hypermethylation also reversed PH development, accompanied by reduced oxidative stress and suppressed autophagy. ATG5, a key regulator of autophagy, was identified as a potential therapeutic target, as its repression mitigated PH in maternal EC-exposed offspring.

Conclusion

Maternal EC exposure induces oxidative stress and DNA hypomethylation in offspring, leading to anomalous autophagy and exacerbation of PH development. Targeting ATG5-mediated autophagy may represent a novel therapeutic approach for improving PH outcomes in offspring exposed to maternal EC.

Graphical Abstract

Pregnant rats were exposed to either EC vapor or standard air from gestation day 12 until 2 days before delivery, with all offspring undergoing PH induction at 6-wo. Offspring exposed to maternal EC presented increased oxidative stress, which in turn affected DNA methylation patterns. The decreased DNA methylation in male offspring led to the activation of autophagy, exacerbating the development of PH. Treatment with ATG5 siRNA inhibited autophagy and alleviated heightened PH in male offspring with maternal EC exposure.