Bortezomib treatment causes long-term testicular dysfunction in young male mice

Abstract

BackgroundWith increased long-term survivors of childhood cancer patients, therapy-associated infertility has become one of the most common late side-effects and significantly affects their life-quality. Therefore, evaluation of anti-cancer agents on male reproduction and infertility prevention are urgently demanding. The proteasome inhibitor bortezomib has been launched in clinical trials for childhood cancers, however, its potential side effects on reproduction have so far been neither investigated experimentally nor reported in treated children. Thus the present study is designed to explore the impact of bortezomib on male reproductive function and to gain insights into how bortezomib exerts its adverse effects on man gonad, thereby providing pediatric oncologists relevant information.Methods35 day-old male mice were treated with one 11-day cycle of bortezomib and then sacrificed 2 days, 45 days, or 6 months later. A mating study was performed in the group followed for 6 months, and their pups were analyzed on postnatal day 50. Serum follicle-stimulating hormone (FSH) and testicular testosterone levels were measured. Testicular morphology was evaluated by light- and electron microscopy, and the underlying mechanisms and pathways of testis damage were investigated.ResultsTesticular damage was visible already 2 days after stopping bortezomib and increased in severity by day 45. Then 80% of seminiferous tubules exhibited hypospermatogenesis with arrest at the levels of spermatogonia, spermatocytes and round spermatids. Germ cells were specifically targeted by bortezomib as evidenced by increased apoptosis mediated through activation of p53 and caspases. Even six months after the bortezomib treatment, testis weight, sperm concentration and seminiferous tubule length remained at a decreased level, indicating that spermatogenesis and tubular outgrowth could not fully recover. Combined with persistently increased serum levels of FSH in these mice, our results demonstrate that bortezomib can have long-term effects on testicular function, although fertility of bortezomib-exposed males remained and their offspring looked healthy.ConclusionBortezomib treatment causes long-term gonadal dysfunction in male mice. Careful monitoring of gonadal function in male childhood cancer patients treated with bortezomib is thus strongly recommended.

(1 → 3)‐β‐ d ‐glucan enhances the toxicity induced by Bortezomib in rat testis

“…There are many antioxidants that reduce the production of ROS (Dallak, 2019 As the literature investigated, a few studies were related to the damage of the bortezomib on the testes. One of them is about the bortezomib toxicity on testes presented on young mice (Hou et al, 2014). The other showed the bortezomib-induced testes damage via increasing the AMP-activated protein kinase (AMPK) level in murine Sertoli cells (Li et al, 2015).…”

“…These results revealed that (1 → 3)-β-D-glucan and/or bortezomib treatment caused very serious structural defects in the testicular tissue that cause infertility due to breaking sperm maturation creating serious damage. Most of the previous studies also reported the testicular damage such as deformations in tubules, Leydig, and Sertoli cells due to chemotherapeutics (Hou et al, 2014;Karimi et al, 2018).…”

“…Proteasome eliminates aged, damaged, unfolded, and unnecessary proteins that are identified by ubiquitin and it is an important key for regulatory proteins found in many cell cytoplasms and nuclei (Kitajima et al, ). In recent studies, a few of them showed that the proteasome pathway also plays an important role in the testes for maintaining healthy sperm production (Hou et al, ). Bortezomib, a 20S proteasome complex inhibitor, known to act by disrupting various cell signaling pathways, thereby leading to cell cycle arrest, apoptosis, and inhibition of tumor growth (Jackson, Einsele, Moreau, & San Miguel, ).…”

“…In recent studies, a few of them showed that the proteasome pathway also plays an important role in the testes for maintaining healthy sperm production (Hou et al, 2014). Bortezomib, a 20S proteasome complex inhibitor, known to act by disrupting various cell signaling pathways, thereby leading to cell cycle arrest, apoptosis, and inhibition of tumor growth (Jackson, Einsele, Moreau, & San Miguel, 2005).…”

Preserving fertility in young patients with lymphoma: an overview

“…126 While little is known about the impact of biologic therapies, such as anti-20 monoclonal antibodies and proteasome inhibitors, on testicular function in humans, recent evidence in mice suggests that proteasome inhibitors may have longterm adverse effects on sperm concentrations, testicular weight, and Sertoli cell dysfunction, evidenced by persistently increased FSH levels. 127 Long-term studies in humans are needed, however, in order to delineate the effects of these therapies on future fertility.…”