API

Relationship: 1713

Title

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Apoptosis leads to testicular toxicity

Upstream event

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Apoptosis

Downstream event

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testicular toxicity

Key Event Relationship Overview

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AOPs Referencing Relationship

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Taxonomic Applicability

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Sex Applicability

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Life Stage Applicability

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Key Event Relationship Description

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In the mouse spermatocyte, spermatogenesis was inhibited by knockdown of Sucla2 via apoptosis (Huang). CD147 was reported to regulate apoptosis in mouse testis and spermatocyte cell line (GC-2 cells) via NFkB pathway (Wang).

Evidence Supporting this KER

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Biological Plausibility

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Apoptosis is a basic biological phenomenon in which the cells are controlled in the atrophy of various tissues and organs through the deletion and turnover, as well as in tumor regression (Kerr JFR et al).

Empirical Evidence

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MicroRNA-21 regulates the spermatogonial stem cell homeostasis, in which suppression of microRNA-21 with anti-miR-21 oligonucleotides led to apoptosis of spermatogonial stem cell-enriched germ cell cultures and the decrease in the number of spermatogonial stem cells (Niu Z et al).

Uncertainties and Inconsistencies

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Spermatogonial stem cell self-renewal and spermatocyte meiosis are regulated by Sertoli cell signaling, which suggests us that various pathways other than HDAC inhibition in spermatocytes or spermatogonia are involved in the spermatocyte deletion and testis atrophy/weight loss (Chen SR). It should be noted that the process of apoptosis is necessary for the meitosis of the stem cell differentiation in the testis, which remains in question for the regulation of spermatocyte deletion and testis atrophy/weight loss (Dym M).

Quantitative Understanding of the Linkage

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The ratio between self-renewal and differentiation of the spermatogonial stem cells is regulated by glial cell line-derived neurotrophic factor produced by Sertoli cells (de Rooij2001). The development of the spermatogenic cell lineage is strictly regulated with 12 epithelial stages, in which G1 arrest is involved (de Rooij1998).

Response-response Relationship

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Time-scale

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Known modulating factors

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Known Feedforward/Feedback loops influencing this KER

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Domain of Applicability

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Spermatogenesis was inhibited by knockdown of Sucla2 via apoptosis in the mouse spermatocyte (Mus musculus) (Huang). The suppression of microRNA-21 led to apoptosis of spermatogonial stem cell-enriched germ cell cultures and the decrease in the number of spermatogonial stem cells in mice (Mus musculus) (Niu Z et al).

References

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Huang S et al. (2016) Knockdown of Sucla2 decreases the viability of mouse spermatocytes by inducing apoptosis through injury of the mitochondrial function of cells. Folia Histochem Cytobiol 54: 134-142

Wang C et al. (2017) CD147 regulates extrinsic apoptosis in spermatocytes by modulating NFkB signaling pathways. Oncotarget 8: 3132-3143

Kerr JFR et al. (1972) Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer 26: 239-257

Niu Z et al. (2011) microRNA-21 regulates the self-renewal of mouse spermatogonial stem cells. Proc Natl Acad Sci 108: 12740-12745

Chen S and Liu Y. (2015) Regulation of spermatogonial stem cell self-renewal and spermatocyte meiosis by Sertoli cell signaling. Reproduction 149: R159-R167

Dym M. (1994) Spermatogonial stem cells of the testis. Proc Natl Acad Sci USA 91: 11287-11289

De Rooij DG et al. (2001) Proliferation and differentiation of spermatogonial stem cells. Reproduction 121: 347-354

De Rooij DG. (1998) Stem cells in the testis. Int J Exp Path 79: 67-80