Endoplasmic reticulum stress promotes blood-testis barrier impairment in mice with busulfan-induced oligospermia through PERK-eIF2α signaling pathway

Zhao, Jianan; Wang, Minxin; Wang, Yanan; Xu, Jinyu; Ma, Chenxu; Tang, Yu; Luo, Qianqian; Zhang, Hongqin; Xu, Feibo

doi:10.1016/j.tox.2022.153193

Cited by 10 publications

(7 citation statements)

References 45 publications

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“…This chemotherapeutic agent is regularly used prior to stem cell transplantation because of its preferential damages on type A spermatogonia 31 . Nevertheless, busulfan can also disrupt Sertoli cells and even reduce BTB protein expression 70 . Because Sertoli cells in recipient chicks might have been damaged by busulfan treatment, we assessed the effects of transplantation with crude testicular fractions in which somatic and germ cells are injected together.…”

Section: Discussionmentioning

confidence: 99%

Successful xenotransplantation of testicular cells following fractionated chemotherapy of recipient birds

Blank,

Kawaoku,

Rui

et al. 2024

Sci Rep

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An essential step in the success of germ cell transplantation is the preparation of the recipient’s testicular environment to increase the availability of stem cell niches. However, most methods for this purpose in birds face serious limitations such as partial germ cell depletion, high toxicity and mortality, or the need to use expensive technologies. Here, we validated a simple and practical technique of transferring quail testicular cells into chicken testes depleted of endogenous spermatozoa by fractioned chemotherapy (20 mg/kg/week busulfan for 5 weeks). This protocol resulted in a very low mortality of the treated day-old chicks and, despite maintenance of androgenic activity, sperm production was decreased by 84.3% at 25 weeks of age. NANOG immunostaining revealed that very few to no germ cells were present following treatment with 20 and 40 mg/kg, respectively. RT-qPCR data also showed that c-MYC and NANOG expression declined in these treatments, but GRFα1 and BID expressions remained unaltered among groups. After xenotransplantation, quail germ cells were immunodetected in chicken testes using a species-specific antibody (QCPN), and quail ovalbumin DNA was found in seminal samples collected from chicken recipients. Together, these data confirm that fractionated administration of busulfan in hatchlings is a practical, effective, and safe protocol to prepare recipient male birds capable of supporting xenogeneic spermatogenesis.

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Section: Discussionmentioning

confidence: 99%

Successful xenotransplantation of testicular cells following fractionated chemotherapy of recipient birds

Blank,

Kawaoku,

Rui

et al. 2024

Sci Rep

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“…Therefore, we treated the spotted sea bass testes with busulfan consecutively and observed a significant loss of germ cells and the appearance of large cavities, making them suitable for spermatogonia transplantation. Additionally, research indicates that busulfan can damage the BTB, thereby affecting spermatogenesis [50,51]. Consequently, the failure of colonization might be attributed to busulfan-induced BTB damage, which allows immune cells to infiltrate the seminiferous tubules, leading to acute immunological rejection responses.…”

Section: Discussionmentioning

confidence: 99%

Immune Rejection Mediated by prf1 and gzmb Affects the Colonization of Fat Greenling (Hexagrammos otakii) Spermatogonia in Heterotransplantation

Zhao,

Chen,

et al. 2024

IJMS

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Fish germ cell transplantation holds great potential for conserving endangered species, improving cultured fish breeds, and exploring reproductive techniques. However, low transplantation efficiency is a common issue in heterotransplantation. This study transplanted fat greenling (Hexagrammos otakii) spermatogonia into the testes of spotted sea bass (Lateolabrax maculatus) to investigate factors that might affect the colonization and fixation of heterologous transplanted germ cells. Results indicated that transplanted fat greenling spermatogonia cells were successfully detected in the early transplantation phase in spotted sea bass. Their numbers gradually decreased over time, and after 10 days post-transplantation, more than 90% of the transplanted cells underwent apoptosis. Transcriptome sequencing analysis of the testes of spotted sea bass and fat greenling spermatogonia on days 1 and 10 post-transplantation revealed that this apoptosis process involved many immune-related genes and their associated signaling pathways. Acute immune rejection marker genes prf1 and gzmb were detected in the spotted sea bass testes, while immune tolerance genes lck and zap-70 were expressed in the fat greenling spermatogonia. Additionally, differential expression of prf1 and gzmb genes was screened from spotted sea bass, with experimental evidence indicating that PRF1 and GZMB protein from spotted sea bass primarily induce apoptosis in transplanted fat greenling spermatogonia via the mitochondrial apoptosis pathway, at the protein level. This suggests that the difficulties in heterotransplantation are primarily related to acute immune rejection, with PRF1 and GZMB playing significant roles.

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“…Of note, previous investigations showed that busulfan induced ER stress in mouse testis and spermatogonial stem cells [54, 55], thus suggesting that this antineoplastic drug can trigger ER stress in different tissues. Moreover, busulfan was shown to induce oxidative stress in murine hepatocytes, as assessed by increased GSSG levels and lipid peroxidation [4].…”

Section: Discussionmentioning

confidence: 99%

Busulfan induces steatosis in HepaRG cells but not in primary human hepatocytes: Possible explanations and implication for the prediction of drug‐induced liver injury

Allard,

Bucher,

Ferron

et al. 2023

Fundamemntal Clinical Pharma

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BackgroundThe antineoplastic drug busulfan can induce different hepatic lesions including cholestasis and sinusoidal obstruction syndrome. However, hepatic steatosis has never been reported in patients.ObjectivesThis study aimed to determine whether busulfan could induce steatosis in primary human hepatocytes (PHH) and differentiated HepaRG cells.MethodsNeutral lipids were determined in PHH and HepaRG cells. Mechanistic investigations were performed in HepaRG cells by measuring metabolic fluxes linked to lipid homeostasis, reduced glutathione (GSH) levels, and expression of genes involved in lipid metabolism and endoplasmic reticulum (ER) stress. Analysis of two previous transcriptomic datasets was carried out.ResultsBusulfan induced lipid accumulation in HepaRG cells but not in six different batches of PHH. In HepaRG cells, busulfan impaired VLDL secretion, increased fatty acid uptake, and induced ER stress. Transcriptomic data analysis and decreased GSH levels suggested that busulfan‐induced steatosis might be linked to the high expression of glutathione S‐transferase (GST) isoenzyme A1, which is responsible for the formation of the hepatotoxic sulfonium cation conjugate. In keeping with this, the GST inhibitor ethacrynic acid and the chemical chaperone tauroursodeoxycholic acid alleviated busulfan‐induced lipid accumulation in HepaRG cells supporting the role of the sulfonium cation conjugate and ER stress in steatosis.ConclusionWhile the HepaRG cell line is an invaluable tool for pharmacotoxicological studies, it might not be always an appropriate model to predict and mechanistically investigate drug‐induced liver injury. Hence, we recommend carrying out toxicological investigations in both HepaRG cells and PHH to avoid drawing wrong conclusions on the potential hepatotoxicity of drugs and other xenobiotics.

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Endoplasmic reticulum stress promotes blood-testis barrier impairment in mice with busulfan-induced oligospermia through PERK-eIF2α signaling pathway

Cited by 10 publications

References 45 publications

Successful xenotransplantation of testicular cells following fractionated chemotherapy of recipient birds

Successful xenotransplantation of testicular cells following fractionated chemotherapy of recipient birds

Immune Rejection Mediated by prf1 and gzmb Affects the Colonization of Fat Greenling (Hexagrammos otakii) Spermatogonia in Heterotransplantation

Busulfan induces steatosis in HepaRG cells but not in primary human hepatocytes: Possible explanations and implication for the prediction of drug‐induced liver injury

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