Moazamian Ryan, Polhemus Ashley, Connaughton Haley, Fraser Barbara, Whiting Sara, Gharagozloo Parviz, Aitken Robert John
Priority Research Centre in Reproductive Science, Discipline of Biological Sciences, Faculty of Science and IT, University of Newcastle, University Drive, Callaghan, New South Wales 2308, Australia Hunter Medical Research Institute (HMRI), Newcastle, New South Wales 2310, Australia CellOxess LLC, 15 Roszel Street, Princeton, NJ 08540, USA.
Priority Research Centre in Reproductive Science, Discipline of Biological Sciences, Faculty of Science and IT, University of Newcastle, University Drive, Callaghan, New South Wales 2308, Australia Hunter Medical Research Institute (HMRI), Newcastle, New South Wales 2310, Australia.
Mol Hum Reprod. 2015 Jun;21(6):502-15. doi: 10.1093/molehr/gav014. Epub 2015 Apr 2.
Oxidative stress is known to compromise human sperm function and to activate the intrinsic apoptotic cascade in these cells. One of the key features of oxidatively stressed spermatozoa is the induction of a lipid peroxidation process that results in the formation of aldehydes potentially capable of disrupting sperm function through the formation of adducts with DNA and key proteins. In this study, we have examined the impact of a range of small molecular mass aldehydes generated as a consequence of lipid peroxidation on human sperm function and also compared the two most commonly formed compounds, 4-hydroxynonenal (4HNE) and malondialdehyde (MDA), for their relative ability to reflect a state of oxidative stress in these cells. Dramatic differences in the bioactivity of individual aldehydes were observed, that generally correlated with the second order rate constants describing their interaction with the model nucleophile, glutathione. Our results demonstrate that acrolein and 4HNE were the most reactive lipid aldehydes, inhibiting sperm motility while augmenting reactive oxygen species production, lipid peroxidation, oxidative DNA damage and caspase activation, in a dose-dependent manner (P < 0.001). In contrast, a variety of saturated aldehydes and the well-known marker of oxidative stress, MDA, were without effect on this cell type. While MDA was not cytotoxic per se, its generation did reflect the induction of oxidative stress in vivo and in vitro in a manner that was highly correlated with the bioactive lipid aldehyde, 4HNE. Despite such overall correlations, individual patient samples were observed in which either MDA or 4HNE predominated. Given the relative cytotoxicity of 4HNE, we propose that this aldehyde should be the preferred criterion for diagnosing oxidative stress in the male germ line.
已知氧化应激会损害人类精子功能，并激活这些细胞中的内在凋亡级联反应。氧化应激精子的关键特征之一是诱导脂质过氧化过程，这会导致醛类的形成，这些醛类可能通过与DNA和关键蛋白质形成加合物来破坏精子功能。在本研究中，我们研究了一系列由脂质过氧化产生的小分子质量醛类对人类精子功能的影响，并比较了两种最常见的化合物4-羟基壬烯醛（4HNE）和丙二醛（MDA）反映这些细胞氧化应激状态的相对能力。观察到各个醛类的生物活性存在显著差异，这通常与描述它们与模型亲核试剂谷胱甘肽相互作用的二级速率常数相关。我们的结果表明，丙烯醛和4HNE是反应性最强的脂质醛类，它们以剂量依赖的方式抑制精子活力，同时增加活性氧生成、脂质过氧化、氧化性DNA损伤和半胱天冬酶激活（P < 0.001）。相比之下，多种饱和醛类以及氧化应激的著名标志物MDA对这种细胞类型没有影响。虽然MDA本身没有细胞毒性，但其生成确实反映了体内和体外氧化应激的诱导情况，且与生物活性脂质醛4HNE高度相关。尽管存在这种总体相关性，但观察到个别患者样本中MDA或4HNE占主导地位。鉴于4HNE的相对细胞毒性，我们建议该醛类应作为诊断男性生殖系氧化应激的首选标准。
