The effect of traditional medicine on busulfan- and/or irradiation-induced aspermatogenesis

• Project/Area Number: 15K08937
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: General internal medicine(including psychosomatic medicine)
• Research Institution: Tokai University (2017-2018); Tokyo Medical University (2015-2016)
• Principal Investigator: QU Ning 東海大学, 医学部, 講師 (70527952)
• Co-Investigator(Kenkyū-buntansha): 伊藤 正裕 東京医科大学, 医学部, 主任教授 (00232471) ; 善本 隆之 東京医科大学, 医学部, 教授 (80202406)
• Project Period (FY): 2015-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2015: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 精子形成 / 抗癌治療 / 漢方薬 / 抗がん剤 / 精巣 / 液性因子 / 細胞因子 / 放射線 / セルトリ細胞 / マウス / 抗癌剤 / マクロファージ

Outline of Final Research Achievements

Sterility is a frequent side effect in men after cancer treatment such as alkylating agents and irradiation. However, there is little information about therapy on male infertility after cancer treatment. We determined the Goshajinkigan, an oriental medicine, can recover the spermatogenesis in cancer-treatment induced infertility. Male mice were received busulfan or irradiation and then fed on the Goshajinkigan-including diet. Although the damages of spermatogenesis and the testicular immunology after busulfan- or irradiation-treatment are different, Goshajinkigan can completely cure the severe aspermatogenesis after busulfan- or irradiation-treatment in mice. The results suggest that the supplementation of TJ107 exerts a therapeutic effect on cancer-treatment induced testicular dysfunction. Furthermore, Hachimijiogan and/or Hochuekkito were already determined in busulfan-treatment induced aspermatogenesis in mice and showed the different therapeutic effect on reproductive toxicities.

Academic Significance and Societal Importance of the Research Achievements

化学療法や放射線療法による精子形成障害に対する治療は、薬剤に頼る以外に選択肢が無く、ホルモン製剤、代謝改善剤、酵素剤、 そしてビタミン製剤が併用されている。その治療効果は低く、精子形成障害は難治性慢性疾患となっている。本研究で、抗癌剤投与或いは放射線照射後のマウス精子形成障害に対して、牛車腎気丸と八味地黄丸・補中益気湯が有効な治療効果を示すことを見出した。さらに抗癌治療による精子形成障害の改善作用機序への液性因子・精巣内細胞の関与を明らかにし、抗癌治療後の男性不妊症に対する漢方治療の学術的基盤を作ることが期待される。

Research Products

• [Journal Article] Effects of Chemotherapy and Radiotherapy on Spermatogenesis: The Role of Testicular Immunology (2019)
  • Author(s): Qu Ning、Itoh Masahiro、Sakabe Kou
  • Journal Title: International Journal of Molecular Sciences Volume: 20 Issue: 4 Pages: 957-957
  • DOI: 10.3390/ijms20040957
  • Peer Reviewed / Open Access
• [Journal Article] Gosha-Jinki-Gan Recovers Spermatogenesis in Mice with Busulfan-Induced Aspermatogenesis (2018)
  • Author(s): Qu N, Kuramasu M, Hirayanagi Y, Nagahori K, Hayashi S, Ogawa Y, Terayama H, Suyama K, Naito M, Sakabe K, Itoh M
  • Journal Title: Int J Mol Sci Volume: 19(9) Issue: 9 Pages: 2606-2606
  • DOI: 10.3390/ijms19092606
  • Peer Reviewed / Open Access
• [Journal Article] Male infertility after anticancer treatment and oriental medicine therapy -----Gosha-jinki-gan recovers the intact spermatogenesis in busulfan-induced aspermatogenesis in mice. (2017)
  • Author(s): Qu N, Itoh M, Terayama H, Suyama K, Sakabe K
  • Journal Title: Jpn J Clin Ecol. Volume: 26(2) Pages: 85-90
  • Peer Reviewed / Open Access
• [Journal Article] Anatomical etiology of “pseudo-sciatica” from superior cluneal nerve entrapment: a laboratory investigation (2017)
  • Author(s): Konno T, Aota Y, Kuniya H, Saito T, Qu N, Hayashi S, Kawata S, Itoh M
  • Journal Title: J Pain Res. Volume: 10 Pages: 2539-2545
  • DOI: 10.2147/jpr.s142115
  • Peer Reviewed / Open Access
• [Journal Article] Pathological effect of arterial ischaemia and venous congestion on rat testes (2017)
  • Author(s): Hirai S, Hatayama N, Naito M, Nagahori K, Kawata S, Hayashi S, Qu N, Terayama H, Shoji S, Itoh M
  • Journal Title: Sci Rep. Volume: 14;7(1) Issue: 1 Pages: 5422-5422
  • DOI: 10.1038/s41598-017-05880-2
  • Peer Reviewed / Open Access
• [Journal Article] Anatomical study of middle cluneal nerve entrapment. (2017)
  • Author(s): Konno T, Aota Y, Saito T, Qu N, Hayashi S, Kawata S, Itoh M.
  • Journal Title: J Pain Res. Volume: 13;10 Pages: 1431-1435
  • DOI: 10.2147/jpr.s135382
  • Peer Reviewed / Open Access
• [Journal Article] Induction of experimental autoimmune orchitis by immunization with xenogenic testicular germ cells in mice. (2017)
  • Author(s): Qu N, Terayama H, Hirayanagi Y, Kuramasu M, Ogawa Y, Hayashi S, Hirai S, Naito M, Itoh M.
  • Journal Title: J Reprod Immunol. Volume: 121 Pages: 11-16
  • DOI: 10.1016/j.jri.2017.04.006
  • Peer Reviewed / Open Access
• [Journal Article] Development of heterotopic transplantation of the testis with the epididymis to evaluate an aspect of testicular immunology in rats (2017)
  • Author(s): Yi K, Hatayama N, Hirai S, Qu N, Hayashi S, Kawata S, Nagahori K, Naito M, Itoh M.
  • Journal Title: PLoS One Volume: 12(5) Issue: 5 Pages: e0177067-e0177067
  • DOI: 10.1371/journal.pone.0177067
  • NAID: 120006591011
  • Peer Reviewed / Open Access
• [Journal Article] Specific autoantigens identified by sera obtained from mice that are immunized with testicular germ cells alone. (2016)
  • Author(s): Terayama H, Hirai S, Naito M, Qu N, Katagiri C, Nagahori K, Hayashi S, Sasaki H, Moriya S, Hiramoto M, Miyazawa K, Hatayama N, Li ZL, Sakabe K, Matsushita M, Itoh M.
  • Journal Title: Sci Rep. Volume: 18 Issue: 1 Pages: 35599-35599
  • DOI: 10.1038/srep35599
  • Peer Reviewed / Open Access
• [Journal Article] Busulfan pretreatment for transplantation of rat spermatogonia differentially affects immune and reproductive systems in male recipient mice. (2015)
  • Author(s): Hirayanagi Y, Qu N, Hirai S, Naito M, Terayama H, Hayashi S, Hatayama N, Kuramasu M, Ogawa Y, Itoh M.
  • Journal Title: Anat Sci Int. Volume: 90 Issue: 4 Pages: 264-274
  • DOI: 10.1007/s12565-014-0261-y
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Low-dose exposure to di-(2-ethylhexyl) phthalate (DEHP) increases susceptibility to testicular autoimmunity in mice. (2015)
  • Author(s): Hirai S, Naito M, Kuramasu M, Ogawa Y, Terayama H, Qu N, Hatayama N, Hayashi S, Itoh M.
  • Journal Title: Reproductive Biology Volume: 15(3) Issue: 3 Pages: 163-171
  • DOI: 10.1016/j.repbio.2015.06.004
  • Peer Reviewed
• [Journal Article] Scimitar vein descending from the right inferior lobe to the inferior vena cava beneath the diaphragm: a rare case. (2015)
  • Author(s): Hayashi S, Hirai S, Naito M, Kawata S, Qu N, Hatayama N, Terayama H, Moriyama H, Itoh M.
  • Journal Title: Anatomical Science International Volume: 90(2) Issue: 2 Pages: 123-125
  • DOI: 10.1007/s12565-014-0230-5
  • Peer Reviewed
• [Journal Article] 炎症疾患におけるTh17関連サイトカインIL-17，IL-22，IL-23の役割 (2015)
  • Author(s): 徐明利、曲 寧、溝口出、古澤純一、千葉祐規乃、伊藤正裕、善本隆之
  • Journal Title: 炎症と免疫 Volume: Vol.23, No.2 Pages: 66-72
• [Presentation] The different effect of traditional medicine alone or in combination on busulfan-induced aspermatogenesis (2019)
  • Author(s): 曲寧, 倉升三幸, 永堀健太, 小川夕輝, 寺山隼人, 伊藤正裕, 坂部貢
  • Organizer: 第124回日本解剖学会学術大会（新潟）
• [Presentation] Gosha-jinki-gan recover the intact spermatogenesis in busulfan-induced immunotoxicology and aspermatogenesis in mice (2018)
  • Author(s): 曲寧、伊藤正裕、平栁淑惠、寺山隼人、坂部貢
  • Organizer: American-Sino Joint Meeting of Reproductive Immunology (ASRI-CSI2018）
  • Int'l Joint Research
• [Presentation] Goshajinkigan recover the intact spermatogenesis in busulfan-induced aspermatogenesis in mice (2017)
  • Author(s): Ning Qu, Miyuki Kuramasu, Kenta Nagahori, Yoshie Hirayanagi, Shogo Hayashi, Yuki Ogawa, and Masahiro Itoh
  • Organizer: 第122回日本解剖学会総会・全国学術集会
  • Place of Presentation: 長崎
  • Year and Date: 2017-03-28
• [Presentation] Gosha-jinki-gan recover the intact spermatogenesis in busulfan-induced aspermatogenesis in mice (2017)
  • Author(s): Ning Qu, Miyuki Kuramasu, Kenta Nagahori, Shogo Hayashi, Yuki Ogawa, Hayato Terayama, Kou Sakabe and Masahiro Itoh
  • Organizer: 日本アンドロロジー学会第37回学術大会
• [Presentation] ブスルファン処置後の精巣免疫毒性と精子形成障害における牛車腎気丸の治療効果 (2017)
  • Author(s): 曲寧、伊藤正裕、寺山隼人、 永堀健太、 倉升三幸、 小川夕輝、坂部貢
  • Organizer: 第24回日本免疫毒性学会学術年会
• [Presentation] ブスルファン処置マウスの精子形成障害における牛車腎気丸の治療効果 (2017)
  • Author(s): 曲寧, 永堀健太, 寺山隼人, 倉升三幸, 小川夕輝, 坂部貢, 伊藤正裕
  • Organizer: 第26回日本臨床環境医学会学術集会
• [Presentation] ブスルファン処置マウスの精子形成障害における牛車腎気丸の治療効果―病態生理学的考察 (2017)
  • Author(s): 曲寧, 伊藤正裕, 寺山隼人, 坂部貢
  • Organizer: 第27回日本病態生理学会大会
• [Presentation] 放射線処置マウスの精子形成傷害における牛車腎気丸の治療効果 (2016)
  • Author(s): 曲 寧, 高橋 薫平 , 永堀 健太 , 倉升 三幸 , 平栁 淑恵 , 平井 宗一 , 林 省吾 , 宮宗 秀伸 , 李 忠連 , 小川 夕輝 , 伊藤 正裕
  • Organizer: 第31回日本生殖免疫学会学術集会
  • Place of Presentation: 兵庫
  • Year and Date: 2016-12-02
• [Presentation] EAO血清抗体に特異的に反応する自己抗原タンパク質の同定 (2016)
  • Author(s): 永堀 健太, 平井 宗一 , 寺山 隼人 , 倉升 三幸 , 曲 寧 , 宮宗 秀伸 , 李 忠連 , 小川 夕輝 , 林 省吾 , 伊藤 正裕
  • Organizer: 第31回日本生殖免疫学会学術集会
  • Place of Presentation: 兵庫
  • Year and Date: 2016-12-02
• [Presentation] 精巣におけるマクロファージの免疫寛容機構 (2016)
  • Author(s): 曲 寧,寺山 隼人, 平井 宗一, 林 省吾、畑山 直之,倉升 三幸, 小川 夕輝, 坂部 貢, 伊藤 正裕
  • Organizer: 第121回日本解剖学会・全国学術集会
  • Place of Presentation: 福島
  • Year and Date: 2016-03-28
  • Invited
• [Presentation] ラットにおける異所性精巣移植の試み (2016)
  • Author(s): 畑山 直之,曲 寧,林 省吾,平井 宗一,、倉升 三幸, 永堀 健太,小川 夕輝, 伊藤 正裕
  • Organizer: 第121回日本解剖学会・全国学術集会
  • Place of Presentation: 福島
  • Year and Date: 2016-03-28
  • Invited