Busulfan administration produces toxic effects on epididymal morphology and inhibits the expression of ZO-1 and vimentin in the mouse epididymis

Fang, Fang; Ni, Ke; Cai, Yang; Zhao, Qian; Shang, Jin; Zhang, Xiaoke; Shen, Shuai

doi:10.1042/bsr20171059

Cited by 24 publications

(17 citation statements)

References 58 publications

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“…However, corroborating with a previous report (Fang et al, 2017), tDFI assay revealed that busulfan caused a high level of DNA damage in epididymal spermatozoa in the rats. There was also heightened sperm DNA damage due to oxidation, as evident by a significant rise in 8OHdG levels.…”

Section: Discussionsupporting

confidence: 92%

Kolaviron, a flavonoid‐rich extract ameliorates busulfan‐induced chemo‐brain and testicular damage in male rats through inhibition of oxidative stress, inflammatory, and apoptotic pathways

Tesi

Ben‐Azu

Mega

et al. 2022

Journal of Food Biochemistry

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Previous reports revealed that increased oxidative stress with up-regulated inflammatory proteins and apoptotic factors have serious implications in busulfan-induced chemo-brain and testicular damages. Hence, we investigated the potential reversal effects of kolaviron (KV), a neuro-active extract rich in flavonoids with proven antioxido-inflammatory and anti-apoptotic properties, on busulfan-induced oxidative damage, inflammatory proteins, and apoptosis in the brains and testes of male rats. In the treatment-regimen, animals in groups 1 and 2 had saline (10 ml/kg/p.o./day) and dimethyl sulfoxide (DMSO; 10 ml/kg/p.o./day), group 3 received KV extract (200 mg/ kg/p.o./day), group 4 was given busulfan (50 mg/kg/p.o./day) and animals in group 5 were pretreated with busulfan (50 mg/kg/p.o./day) successively for 56 days in addition to KV extract (200 mg/kg/p.o./day) from days 29-56. Non-spatial memory function was valuated with a novel-object recognition memory test. Thereafter, testicular and brain oxidative/antioxidant status, proinflammatory-and apoptotic-related proteins, testicular enzymatic markers were evaluated respectively. Kolaviron extract improved cognitive function by increasing exploration of novel-object of busulfantreated rats. Kolaviron extract reversed busulfan-mediated increased malondialdehyde, 8-hydroxy-2′-deoxyguanosine, and decreased superoxide dismutase, catalase, glutathione, and glutathione-peroxidase in brains and testes as well as the testicular enzyme markers. Increased brain and testicular weights, and TNFα, IL-1β, and NFκβ productions due to busulfan administration were also reduced by the extract.The reduced testicular B-cell lymphoma-2, sperm mitochondrial cytochrome-C, and membrane potential, increased DNA fragmentation, caspases -3 and -9 levels were also profoundly reversed by KV. Additionally, KV extract ameliorated busulfaninduced testicular histopathological changes in rats. Conclusively, KV extract reverses busulfan-induced neuroendopathobiological derangements via oxidative stress inhibition, down-regulation of inflammatory and apoptotic mediators in rats' brains and testes.

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Section: Discussionsupporting

confidence: 92%

Kolaviron, a flavonoid‐rich extract ameliorates busulfan‐induced chemo‐brain and testicular damage in male rats through inhibition of oxidative stress, inflammatory, and apoptotic pathways

Tesi

Ben‐Azu

Mega

et al. 2022

Journal of Food Biochemistry

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“…The tight junction protein ZO-1 regulated cell proliferation and gene expression (Georgiadis et al, 2010). Occludin was associated with the formation of epididymal tight junctions (Long et al, 2017;Fang et al, 2017). Vim provided physical support to the BTB and mainly contributed to controlling cell shape changes and cell mechanisms.…”

Section: Discussionmentioning

confidence: 99%

Effects of intragastric administration of La<sub>2</sub>O<sub>3</sub> nanoparticles on mouse testes

et al. 2020

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Lanthanum oxide (La 2 O 3) nanoparticles (NPs) have been widely used in photoelectric and catalytic applications. However, their exposure and reproductive toxicity is unknown. In this study, the effect of the intragastric administration of two different-sized La 2 O 3 particles in the testes of mice for 60 days was investigated. Although the body weight of mice treated or not treated with La 2 O 3 NPs was not different and La 2 O 3 NPs were distributed in the organs including the testis, liver, kidney, spleen, heart and brain. La 2 O 3 NPs accumulate more than micro-sized La 2 O 3 (MPs) in mice testes. The histopathological evaluation showed that moderate reproductive toxicity induced by La 2 O 3 NPs in the testicle tissues. Furthermore, increased MDA, 8-OHdG levels and decreased SOD activities were detected in the La 2 O 3 NP-treated groups. Moreover, qRT-PCR and western blotting data indicated that La 2 O 3 NPs affecting the blood-testis barrier (BTB)-related genes in mice testes. Taken together, these findings suggested that La 2 O 3 NPs activated inflammation responses and cross the BTB in the murine testes. This study provided useful information for risk analysis and regulation of La 2 O 3 NPs by administrative agencies.

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Section: Discussionmentioning

confidence: 99%

“…In our study, we used busulfan as a positive control. Busulfan is a common alkylating drug for chronic myeloid leukemia that is widely used before the transplantation of hematopoietic stem cells 31,32 and has been categorized in a high‐risk group in previous studies. We used two doses of NCL1: a high dose of 3.0 mg/kg, and a low dose of 1.0 mg/kg,the latter was previously reported by us as a therapeutic dose 12 .…”

Section: Discussionmentioning

confidence: 99%

Selective lysine‐specific demethylase 1 inhibitor, NCL1, could cause testicular toxicity via the regulation of apoptosis

et al. 2020

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Background Recent studies have shown that epigenetic alterations, such as those involving lysine‐specific demethylase 1 (LSD1), lead to oncogenic activation and highlight such alterations as therapeutic targets. However, studies evaluating the effect of LSD1 inhibitors on male fertility are lacking. Objectives We analyzed the potential toxicity of a new selective LSD1 inhibitor, N‐[(1S)‐3‐[3‐(trans‐2‐aminocyclopropyl)phenoxy]‐1‐(benzylcarbamoyl)propyl] benzamide (NCL1), in testes. Materials and methods Human testicular samples were immunohistochemically analyzed. Six‐week‐old male C57BL/6J mice were injected intraperitoneally with dimethyl sulfoxide vehicle (n = 15), or 1.0 (n = 15) or 3.0 (n = 15) mg/kg NCL1 biweekly. After five weeks, toxicity and gene expression were analyzed in testicular samples by ingenuity pathway analysis (IPA) using RNA sequence data and quantitative reverse transcriptase (qRT)–PCR; hormonal damage was analyzed in blood samples. NCL1 treated GC‐1, TM3, and TM4 cell lines were analyzed by cell viability, chromatin immunoprecipitation, flow cytometry, and Western blot assays. Results LSD1 was mainly expressed in human Sertoli and germ cells, with LSD1 levels significantly decreased in a progressive meiosis‐dependent manner; germ cells showed similar expression patterns in normal spermatogenesis and early/late maturation arrest. Histological examination revealed significantly increased levels of abnormal seminiferous tubules in 3.0 mg/kg NCL1–treated mice compared to control, with increased cellular detachment, sloughing, vacuolization, eosinophilic changes, and TUNEL‐positive cells. IPA and qRT–PCR revealed NCL1 treatment down‐regulated LSD1 activity. NCL1 also reduced total serum testosterone levels. Western blots of mouse testicular samples revealed NCL1 induced a marked elevation in cleaved caspases 3, 7, and 8, and connexin 43 proteins. NCL1 treatment significantly reduced GC‐1, but not TM3 and TM4, cell viability in a dose‐dependent manner. In flow cytometry analysis, NCL1 induced apoptosis in GC‐1 cells. Conclusions High‐dose NCL1 treatment targeting LSD1 caused dysfunctional spermatogenesis and induced caspase‐dependent apoptosis. This suggests the LSD1 inhibitor may cause testicular toxicity via the regulation of apoptosis.

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Busulfan administration produces toxic effects on epididymal morphology and inhibits the expression of ZO-1 and vimentin in the mouse epididymis

Cited by 24 publications

References 58 publications

Kolaviron, a flavonoid‐rich extract ameliorates busulfan‐induced chemo‐brain and testicular damage in male rats through inhibition of oxidative stress, inflammatory, and apoptotic pathways

Kolaviron, a flavonoid‐rich extract ameliorates busulfan‐induced chemo‐brain and testicular damage in male rats through inhibition of oxidative stress, inflammatory, and apoptotic pathways

Effects of intragastric administration of La<sub>2</sub>O<sub>3</sub> nanoparticles on mouse testes

Selective lysine‐specific demethylase 1 inhibitor, NCL1, could cause testicular toxicity via the regulation of apoptosis

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