Abstract
Busulfan is an anti-cancer chemotherapeutic drug and is often used as conditioning regimens prior to bone marrow transplant for treatment of chronic myelogenous leukemia. Male infertility, including spermatogenesis disturbance, is known to be one of the side effects of anticancer drugs. While hormone preparations and vitamin preparations are used for spermatogenesis disturbance, their therapeutic effects are low. Some traditional herbal medicines have been administered to improve spermatogenesis. In the present study, we administered Gosha-jinki-gan (TJ107; Tsumura Co., Ltd., Tokyo, Japan) to mice suffering from severe aspermatogenesis after busulfan treatment to determine whether TJ107 can recover spermatogenesis. Male 4-week-old C57BL/6J mice were administered a single intraperitoneal injection of busulfan, and they were then fed a normal diet for 60 days and then a TJ107 diet or TJ107-free normal diet for another 60 days. After busulfan treatment, the weight of the testes and the epididymal sperm count progressively decreased in the normal diet group. On the other hand, in the TJ107 group, these variables dramatically recovered at 120 days. These results suggest that busulfan-induced aspermatogenesis is irreversible if appropriate treatment is not administered. Supplementation of TJ107 can completely recover the injured seminiferous epithelium via normalization of the macrophage migration and reduction of the expressions of Tool-like receptor (TLR) 2 and TLR4, suggesting that TJ107 has a therapeutic effect on busulfan-induced aspermatogenesis.
Highlights
Busulfan (BSF; Myleran, 1,4-butanediol dimethanesulfonate) is an alkylating agent that primarily affects hematopoietic stem cells and results in bone marrow ablation. It is employed as an anti-cancer chemotherapeutic drug in childhood and adult chronic myelogenous leukemia before bone marrow transplantation
VInIEWmice, it has been demonstrated that a single dose of BSF d2 oefs1t2royed differentiating spermatogonia and possibly stem cells—with the exception of a small subpopulation of cells attacHhoewd etvoetrh, celibnaicsaalltrmeaetmmbenrtawneithofBtShFehsaesmbeiennifsehroowuns teopciathueseliguomna[d7a–l1d1y]s.fAundcdtiiotnio-anmalelnyo, rwrheefaound previadoneudsstlrayozytoehodastpdeairftfme6ri0aenditnaiaythsiunagmftasenprseBr[mS4F–a6tto]r.geIoanntmimaeiacnnet,d(i4tp0ohmsassigbb/leykegnst)e,dmmemocosetlnlssg—terarwmteidtchethltlhasetwaexescrieenpgdtlieeosndtrooosfyeeaodfs,mBanaSlFdl that not osnulbyptohpeulpartioolnifeorfatcievlles caetltlasc,hbeudt taolstohethbeasaapl ompetomsbisr-apnoesoitfivteheceslelms iwniefererosutsrikepinitghleyliuremdu[7c–e1d1]w. hen compAadredditiwonitahllyth, we efinfoduinndgspirnevnioourmslyalthmaticaet [6102d].ays after BSF treatment (40 mg/kg), most germ cells
We identified the therapeutic effect of TJ107 on BSF-induced infertility
Summary
Busulfan (BSF; Myleran, 1,4-butanediol dimethanesulfonate) is an alkylating agent that primarily affects hematopoietic stem cells and results in bone marrow ablation. It is employed as an anti-cancer chemotherapeutic drug in childhood and adult chronic myelogenous leukemia before bone marrow transplantation. Previous studies have shown that BSF treatment at 100–150 mg/kg body weight is sufficient to induce myeloablation due to its toxic effect on these stem cells [1,2]. In the case of hematopoietic stem cells transplantation or graft-versus-host disease, the combination of BSF at 20–80 mg/kg/day for four days and cyclophosphamide at 100–200 mg/kg/day for two days is most commonly used for the thrombocytopenic effect and reduction in the number of leucocytes [3]. VInIEWmice, it has been demonstrated that a single dose of BSF d2 oefs1t2royed differentiating spermatogonia and possibly stem cells—with the exception of a small subpopulation of cells attacHhoewd etvoetrh, celibnaicsaalltrmeaetmmbenrtawneithofBtShFehsaesmbeiennifsehroowuns teopciathueseliguomna[d7a–l1d1y]s.fAundcdtiiotnio-anmalelnyo, rwrheefaound previadoneudsstlrayozytoehodastpdeairftfme6ri0aenditnaiaythsiunagmftasenprseBr[mS4F–a6tto]r.geIoanntmimaeiacnnet,d(i4tp0ohmsassigbb/leykegnst)e,dmmemocosetlnlssg—terarwmteidtchethltlhasetwaexescrieenpgdtlieeosndtrooosfyeeaodfs,mBanaSlFdl that not osnulbyptohpeulpartioolnifeorfatcievlles caetltlasc,hbeudt taolstohethbeasaapl ompetomsbisr-apnoesoitfivteheceslelms iwniefererosutsrikepinitghleyliuremdu[7c–e1d1]w. hen compAadredditiwonitahllyth, we efinfoduinndgspirnevnioourmslyalthmaticaet [6102d].ays after BSF treatment (40 mg/kg), most germ cells
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