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Busulfan is a widely used chemotherapeutic drug for chronic myelogenous leukemia and bone marrow transplantation. As a cell cycle nonspecific alkylation agent, busulfan has a severe side effect on germ cells, especially on spermatogonia before meiosis. Studies have revealed that busulfan causes DNA strand crosslinks in spermatogonia and induces apoptosis, and many corresponding strategies have been developed to ameliorate the side effects. However, fertility maintenance after busulfan treatment is still a challenging project in the clinic. Here, we demonstrated that continuous injection of melatonin effectively alleviated germline cytotoxicity both in recipient mice and cultured spermatogonia, and busulfan/melatonin recipient mice produced normal litters. We further revealed that melatonin rescues spermatogonia from apoptosis by neutralizing reactive oxidative species (ROS) induced by busulfan and recovered the phosphorylation of ATM and p53 to normal levels, and as a result apoptosis in spermatogonial progenitor cells was avoided. This study reports that pineal gland hormone melatonin effectively protects spermatogonia from the stress of chemotherapy and oxidation and reveals the underlying molecular mechanisms, which will provide an important hint for fertility protection in clinic.
This article was published in the following journal.
Name: Free radical biology & medicine
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A biogenic amine that is found in animals and plants. In mammals, melatonin is produced by the PINEAL GLAND. Its secretion increases in darkness and decreases during exposure to light. Melatonin is implicated in the regulation of SLEEP, mood, and REPRODUCTION. Melatonin is also an effective antioxidant.
A family of G-protein-coupled receptors that are specific for and mediate the effects of MELATONIN. Activation of melatonin receptors has been associated with decreased intracellular CYCLIC AMP and increased hydrolysis of PHOSPHOINOSITIDES.
A disturbance in the prooxidant-antioxidant balance in favor of the former, leading to potential damage. Indicators of oxidative stress include damaged DNA bases, protein oxidation products, and lipid peroxidation products (Sies, Oxidative Stress, 1991, pxv-xvi).
Drug treatment designed to further diminish the disease toward complete remission following INDUCTION CHEMOTHERAPY. It helps to consolidate the gains during induction chemotherapy and may be followed by MAINTENANCE CHEMOTHERAPY.
A melatonin receptor subtype primarily found expressed in the BRAIN and RETINA.
Stress is caused by your perception of situations around you and then the reaction of your body to them. The automatic stress response to unexpected events is known as 'fight or flight'. Discovered by Walter Cannon in 1932, it is the release of h...
Pharmacy is the science and technique of preparing as well as dispensing drugs and medicines. It is a health profession that links health sciences with chemical sciences and aims to ensure the safe and effective use of pharmaceutical drugs. The scope of...
Leukemia is a type of cancer of the blood or bone marrow characterized by an abnormal increase of immature white blood cells called "blasts". Leukemia is a broad term covering a spectrum of diseases. In turn, it is part of the even broader grou...