Sadeghi Niloofar, Boissonneault Guylain, Tavalaee Marziyeh, Nasr-Esfahani Mohammad Hossein
Department of Biochemistry and Functional Genomics, Université de Sherbrooke, Sherbrooke, QC, Canada.
Department of Animal Biotechnology, Reproductive Biomedicine Research Center, Royan Institute for Biotechnology, ACECR, Isfahan, Iran.
Syst Biol Reprod Med. 2023 Feb;69(1):20-31. doi: 10.1080/19396368.2022.2119181. Epub 2022 Oct 10.
Despite the long-standing notion of "oxidative stress," as the main mediator of many diseases including male infertility induced by increased reactive oxygen species (ROS), recent evidence suggests that ROS levels are also increased by "reductive stress," due to over-accumulation of reductants. Damaging mechanisms, like guanidine oxidation followed by DNA fragmentation, could be observed following reductive stress. Excessive accumulation of the reductants may arise from excess dietary supplementation over driving the one-carbon cycle and transsulfuration pathway, overproduction of NADPH through the pentose phosphate pathway (PPP), elevated levels of GSH leading to impaired mitochondrial oxidation, or as a result NADH accumulation. In addition, lower availability of oxidized reductants like NAD, oxidized glutathione (GSSG), and oxidized thioredoxins (Trx-S2) induce electron leakage leading to the formation of hydrogen peroxide (HO). In addition, a lower level of NAD impairs poly (ADP-ribose) polymerase (PARP)-regulated DNA repair essential for proper chromatin integrity of sperm. Because of the limited studies regarding the possible involvement of reductive stress, antioxidant therapy remains a central approach in the treatment of male infertility. This review put forward the concept of reductive stress and highlights the potential role played by reductive vs oxidative stress at pre-and post-testicular levels and considering dietary supplementation.
尽管长期以来一直认为“氧化应激”是包括活性氧（ROS）增加所致男性不育症在内的许多疾病的主要介质，但最近有证据表明，由于还原剂的过度积累，“还原应激”也会导致ROS水平升高。在还原应激后，可以观察到诸如胍氧化后DNA片段化等损伤机制。还原剂的过度积累可能源于过量的膳食补充，从而驱动一碳循环和转硫途径，通过磷酸戊糖途径（PPP）过量产生NADPH，谷胱甘肽水平升高导致线粒体氧化受损，或者是由于NADH积累。此外，像NAD、氧化型谷胱甘肽（GSSG）和氧化型硫氧还蛋白（Trx-S2）等氧化型还原剂的可用性降低会诱导电子泄漏，导致过氧化氢（HO）的形成。此外，较低水平的NAD会损害聚（ADP-核糖）聚合酶（PARP）调节的DNA修复，而这种修复对于精子正常的染色质完整性至关重要。由于关于还原应激可能参与的研究有限，抗氧化治疗仍然是治疗男性不育症的核心方法。本综述提出了还原应激的概念，并强调了还原应激与氧化应激在睾丸前和睾丸后水平以及考虑膳食补充方面所起的潜在作用。
