Reproductive Science Group, School of Environmental & Life Sciences, University of Newcastle, Callaghan, NSW 2308, Australia.
Toxicol Appl Pharmacol. 2013 Sep 1;271(2):156-67. doi: 10.1016/j.taap.2013.05.009. Epub 2013 May 18.
Cigarette smoke is a reproductive hazard associated with pre-mature reproductive senescence and reduced clinical pregnancy rates in female smokers. Despite an increased awareness of the adverse effects of cigarette smoke exposure on systemic health, many women remain unaware of the adverse effects of cigarette smoke on female fertility. This issue is compounded by our limited understanding of the molecular mechanisms behind cigarette smoke induced infertility. In this study we used a direct nasal exposure mouse model of cigarette smoke-induced chronic obstructive pulmonary disease to characterise mechanisms of cigarette-smoke induced ovotoxicity. Cigarette smoke exposure caused increased levels of primordial follicle depletion, antral follicle oocyte apoptosis and oxidative stress in exposed ovaries, resulting in fewer follicles available for ovulation. Evidence of oxidative stress also persisted in ovulated oocytes which escaped destruction, with increased levels of mitochondrial ROS and lipid peroxidation resulting in reduced fertilisation potential. Microarray analysis of ovarian tissue correlated these insults with a complex mechanism of ovotoxicity involving genes associated with detoxification, inflammation, follicular activation, immune cell mediated apoptosis and membrane organisation. In particular, the phase I detoxifying enzyme cyp2e1 was found to be significantly up-regulated in developing oocytes; an enzyme known to cause molecular bioactivation resulting in oxidative stress. Our results provide a preliminary model of cigarette smoke induced sub-fertility through cyp2e1 bioactivation and oxidative stress, resulting in developing follicle depletion and oocyte dysfunction.
香烟烟雾是一种生殖危害因素，与女性吸烟者的生殖衰老提前和临床妊娠率降低有关。尽管人们越来越意识到香烟烟雾暴露对全身健康的不良影响，但许多女性仍然不知道香烟烟雾对女性生育能力的不良影响。这个问题因我们对香烟烟雾引起不孕的分子机制的有限了解而更加复杂。在这项研究中，我们使用了一种直接鼻腔暴露于香烟烟雾的慢性阻塞性肺疾病小鼠模型，以描述香烟烟雾引起的卵毒性的机制。香烟烟雾暴露导致暴露的卵巢中原始卵泡耗竭、腔前卵泡卵母细胞凋亡和氧化应激增加，导致排卵的卵泡减少。逃避破坏的已排卵卵母细胞中也存在氧化应激的证据，线粒体 ROS 和脂质过氧化增加导致受精能力降低。卵巢组织的微阵列分析将这些损伤与一种涉及与解毒、炎症、卵泡激活、免疫细胞介导的凋亡和膜组织相关的基因的复杂卵毒性机制相关联。特别是，发现一期解毒酶 CYP2E1 在发育中的卵母细胞中显著上调；这种酶已知会导致分子生物活化，从而导致氧化应激。我们的结果提供了一个通过 CYP2E1 生物活化和氧化应激导致卵泡发育耗竭和卵母细胞功能障碍的香烟烟雾引起的低生育力的初步模型。
