title: The proteasome inhibitor bortezomib induces testicular toxicity by upregulation of oxidative stress, AMP-activated protein kinase (AMPK) activation and deregulation of germ cell development in adult murine testis.
abstract: Understanding how chemotherapeutic agents mediate testicular toxicity is crucial in light of compelling evidence that male infertility, one of the severe late side effects of intensive cancer treatment, occurs more often than they are expected to. Previous study demonstrated that bortezomib (BTZ), a 26S proteasome inhibitor used to treat refractory multiple myeloma (MM), exerts deleterious impacts on spermatogenesis in pubertal mice via unknown mechanisms. Here, we showed that intermittent treatment with BTZ resulted in fertility impairment in adult mice, evidenced by testicular atrophy, desquamation of immature germ cells and reduced caudal sperm storage. These deleterious effects may originate from the elevated apoptosis in distinct germ cells during the acute phase and the subsequent disruption of Sertoli-germ cell anchoring junctions (AJs) during the late recovery. Mechanistically, balance between AMP-activated protein kinase (AMPK) activation and Akt/ERK pathway appeared to be indispensable for AJ integrity during the late testicular recovery. Of particular interest, the upregulated testicular apoptosis and the following disturbance of Sertoli-germ cell interaction may both stem from the excessive oxidative stress elicited by BTZ exposure. We also provided the in vitro evidence that AMPK-dependent mechanisms counteract follicle-stimulating hormone (FSH) proliferative effects in BTZ-exposed Sertoli cells. Collectively, BTZ appeared to efficiently prevent germ cells from normal development via multiple mechanisms in adult mice. Employment of antioxidants and/or AMPK inhibitor may represent an attractive strategy of fertility preservation in male MM patients exposed to conventional BTZ therapy and warrants further investigation.
authors.affiliation: Department of Human Anatomy, Histology and Embryology, Fourth Military Medical University, Xi'an 710032, PR China.
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.affiliation: Department of Endocrinology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, PR China.
authors.forename: Jianfang
authors.initials: J
authors.lastname: Fu
authors.affiliation: Reproductive Medicine Center, Department of Gynecology and Obstetrics, Tangdu Hospital, Fourth Military Medical University, Xi'an 710038, PR China.
authors.forename: Shun
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Department of Human Anatomy, Histology and Embryology, Fourth Military Medical University, Xi'an 710032, PR China.
authors.forename: Jie
authors.initials: J
authors.lastname: Zhao
authors.affiliation: Department of Thoracic Surgery, Tangdu Hospital, Fourth Military Medical University, Xi'an 710038, PR China. Electronic address: xienianlin@126.com.
authors.forename: Nianlin
authors.initials: N
authors.lastname: Xie
authors.affiliation: Department of Gynaecology and Obstetrics, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, PR China. Electronic address: firstchair@fmmu.edu.cn.
authors.forename: Guoqing
authors.initials: G
authors.lastname: Cai
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects; D001897:Boronic Acids / Q000633:toxicity*; D000069286:Bortezomib; D004789:Enzyme Activation / Q000187:drug effects; D005298:Fertility / Q000187:drug effects; D005854:Germ Cells / Q000187:drug effects*; D012739:Gonadal Steroid Hormones / Q000097:blood; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018384:Oxidative Stress / Q000187:drug effects*; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects*; D011719:Pyrazines / Q000633:toxicity*; D012708:Sertoli Cells / Q000187:drug effects; D013091:Spermatogenesis / Q000187:drug effects; D013733:Testicular Diseases / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D013737:Testis / Q000187:drug effects / Q000473:pathology; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D001897:Boronic Acids; D012739:Gonadal Steroid Hormones; D011719:Pyrazines; D000069286:Bortezomib; D055372:AMP-Activated Protein Kinases; D046988:Proteasome Endopeptidase Complex
keywords: AMP-activated protein kinase; Anchoring junction; Apoptosis; Bortezomib; Oxidative stress; Testis