The toxicity and mechanisms of pyrotinib on male reproductive system
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ABSTRACT:
PROVIDER: PRJNA1233210 | ENA |
REPOSITORIES: ENA
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Project description:While Pyrotinib has proven effective in treating HER2-positive breast cancer, its impact on male patients is not well-studied. This research examines the potential toxicity of Pyrotinib on the male reproductive system using mouse Leydig cells. Our results indicate that 24 hours of Pyrotinib treatment significantly increased apoptosis and decreased cell viability. Clonogenic assays showed a marked reduction in colony formation, and flow cytometry analysis revealed that 67.2% of the treated cells were in the G1 phase, suggesting hindered progression into the S phase. Western blot analysis demonstrated an initial rise in phosphorylated AKT and ERK, which was followed by a notable decline in these phosphorylated proteins after extended treatment, indicating the involvement of specific pathways in the drug's effects. Transcriptome sequencing identified a downregulation of 197 genes due to Pyrotinib treatment, with these genes enriched in processes related to chromatin and mitosis, particularly in pathways linked to the cell cycle. These findings imply that Pyrotinib inhibits cell proliferation through various molecular mechanisms, underscoring the necessity for further research into its safety and effects on male reproductive health.
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Project description:Arsenic is a widespread metalloid in environment, whose exposure has been associated with a broad spectrum of toxic effects. However, a global view of arsenic-induced male reproductive toxicity is still lack, and the underlying mechanisms remain largely unclear. Our results revealed that arsenic exposure decreased testosterone level and reduced sperm quality in rats. By conducting an integrated proteomics and metabolomics analysis, the present study aims to investigate the global influence of arsenic exposure on the proteome and metabolome in rat testis. The abundance of 70 proteins (36 up-regulated and 34 down-regulated) and 13 metabolites (8 increased and 5 decreased) were found to be significantly altered by arsenic treatment. Among these, 19 proteins and 2 metabolites were specifically related to male reproductive system development and function, including spermatogenesis, sperm function and fertilization, fertility, internal genitalia development, and mating behavior. It is further proposed that arsenic mainly impaired spermatogenesis and fertilization via aberrant modulation of these male reproduction-related proteins and metabolites, which may be mediated by the ERK/AKT/NF-κB-dependent signaling pathway. Overall, these findings will aid our understanding of the mechanisms responsible for arsenic-induced male reproductive toxicity, and from such studies useful biomarkers indicative of arsenic exposure could be discovered.
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Project description:The testis, efferent ductules, epididymis, and vas deferens, constituting the majority of male reproductive tract, are the regions for testosterone production, spermatogenesis, and sperm maturation, storage and discharge, but whether these regions change during aging is unknown. Here, we addressed this by investigating the adult (3-month) and aged (18-month) transcriptomes from seven regions of male mouse reproductive tract：the testis, efferent ductules, initial segment, caput, corpus and cauda epididymis, and vas deferens. We identified various of region-specific genes across different regions of male mouse reproductive tract. Moreover, we identified region-dependent changes of transcripts at an anatomic resolution. This study provides a framework for futher studies on male reproducitve aging.
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Project description:Tripterygium glycoside tablet (TGT) is a common clinically used and effective non-steroidal immunosuppressant. However, its reproductive toxicity limits its application in pediatric immune diseases, warranting the study of the molecular mechanism behind its reproductive toxicity. In the present study, 4-week-old male SD mice were provided TGT through continuous gavage with a clinically equivalent dose of 12 mg/kg for 12 weeks. The reproductive toxicity of TGT was recorded, and its toxicity mechanism was verified through experimental validation and proteomics analyses. Our results demonstrated that TGT could significantly reduce the testosterone level in the serum as well as the concentration and survival rate of sperms. Pathological sections of the testis revealed that TGT could reduce spermatocytes at different levels and make the convoluted meridians vacuolated. Based on TMT-labeled quantitative mice testicular tissue proteomics, 34 differential proteins were screened, involving protein digestion and absorption, PPAR signaling pathway, PI3K-Akt, and other pathways, among which PI3K-Akt plays an important role in the study of reproductive injury. Western blotting results revealed that TGT could significantly downregulate the Col1A1, Col1A2, p-PI3K, and p-Akt expressions and inhibit the expression of proteins related to the PI3K-Akt signaling pathway. In summary, the clinically equivalent dose of TGT induced reproductive toxicity of 4-week-old male SD mice, possibly in relation to the inhibition of the PI3K-Akt pathway expression.
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