Role of Sertoli Cells in Injury‐Associated Testicular Germ Cell Apoptosis

Boekelheide, Kim; Fleming, Shawna L.; Johnson, Kamin J.; Patel, Sutchin R.; Schoenfeld, Heidi A.

doi:10.1111/j.1525-1373.2000.22513.x

Cited by 49 publications

(34 citation statements)

References 99 publications

(126 reference statements)

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“…Other death receptors and their ligands are know to be important in the testicular system as well. The death receptor DR5 and its ligand TRAIL have been described to be highly expressed in the testis of mice and rats [15][16][17][18][19]. We have observed that increases in the expression of DR5 and TRAIL occur in the testis of MEHP-exposed wild-type and gld mice [20], indicating the possibility that TRAIL/DR5 may also play a role in instigating germ cell apoptosis in the testis and providing the rationale for the present investigation.…”

Section: Introductionmentioning

confidence: 60%

“…To date, the cellular determinants of TRAIL sensitivity to cell death are not clearly recognized. Both DR5 and TRAIL are abundantly expressed in the testis [15][16][17][18][19]. Although we previously described the functional participation of Fas/FasL in the MEHP-induced instigation of germ cell apoptosis [16,21], this signaling pathway did not account completely for the observed cell death.…”

Section: Discussionmentioning

confidence: 88%

“…In previous studies, we have shown the functional participation of another death receptor ligand system, the Fas/FasL system, in inducing testicular germ cell apoptosis in rodents after exposure to the Sertoli cell toxicant MEHP [16,17,45]. A functional Fas/FasL signaling system, however, does not appear to be a requirement for physiological apoptosis in the testis as mice expressing mutant forms of these proteins or with a gene deficiency are still fertile and show normal spermatogenesis.…”

Section: Discussionmentioning

confidence: 91%

“…By 24 hours the change in germ cell morphology has also become evident as the cells eventually die and slough from the tubule. However, as discussed in prior literature [17,36], the Sertoli cell itself is rarely killed by the MEHP challenge, and paracrine contact between the two cells should remain in effect until apoptosis is complete.…”

Section: Discussionmentioning

confidence: 99%

“…Rather, specific populations of germ cells, the spermatocytes and early round spermatids, undergo apoptosis [15,16]. Since the functional capacity of the Sertoli cells is critical in orchestrating the complex process of spermatogenesis and maintaining the viability of the germ cells, it is hypothesized by our group and others [17], that Sertoli cells instigate apoptosis of germ cells as a mechanism to reduce the population of germ cells to match the reduced supportive capacity of the injured Sertoli cells.…”

Section: Introductionmentioning

confidence: 96%

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Testicular germ cell sensitivity to TRAIL-induced apoptosis is dependent upon p53 expression and is synergistically enhanced by DR5 agonistic antibody treatment

McKee¹,

Yang

Richburg

2006

Apoptosis

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The ability of the TRAIL/DR5 signaling pathway to induce apoptosis has generally been limited to tumor cells. Here we report that in primary testis explants, addition of TRAIL (0.5 mug/ml) caused a three-fold increase in germ cell apoptosis. Furthermore, exposure of C57BL/6 mice to the testicular toxicant, mono-(2-ethylhexyl) phthalate (MEHP), caused an increased p53 stability and elevated DR5 mRNA levels coincident with increases in the levels of apoptosis in spermatocytes. To further assess the mechanisms responsible for the sensitivity of germ cells to undergo TRAIL/DR5-mediated apoptosis, we used the germ cell lines GC-1spg and GC-2spd(ts) (a temperature sensitive spermatocyte-like cell line that allows for p53 nuclear localization at 32 degrees C but not 37 degrees C). Addition of TRAIL and the anti-DR5 monoclonal antibody, MD5-1, triggered a robust synergistic increase of apoptosis in p53 permissive GC-2 cells (32 degrees C) but not in GC-1 cells. In addition, DR5 levels on the plasma membrane of permissive cells were considerably enhanced concomitant with p53 expression and after MD5-1 treatment. These data represent the first indication that testicular germ cells, specifically spermatocytes, can undergo TRAIL-mediated apoptosis and the clinically relevant observation that pretreatment with a DR5 monoclonal antibody can greatly sensitize their apoptotic response to TRAIL.

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Section: Introductionmentioning

confidence: 60%

Section: Discussionmentioning

confidence: 88%

Section: Discussionmentioning

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 96%

See 3 more Smart Citations

Testicular germ cell sensitivity to TRAIL-induced apoptosis is dependent upon p53 expression and is synergistically enhanced by DR5 agonistic antibody treatment

McKee¹,

Yang

Richburg

2006

Apoptosis

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Apoptosis and blood–testis barrier during the first spermatogenic wave in the pubertal rat

Morales

Mohamed

Cavicchia

2007

The Anatomical Record

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This research explores the initial assembly of the blood-testis barrier (BTB) during puberty, when a massive physiological apoptosis in the first spermatogenic wave takes place. Fragments of testis from 14-to 20-dayold rats were studied by conventional transmission electron microscopic techniques. Lanthanum hydroxide was used as an intercellular tracer. Light microscopy was used to confirm apoptotic death when paraffin-embedded sections were studied by TUNEL analysis. When the seminiferous cords reached the zygotene-pachytene spermatocyte level, they exhibited abundant apoptotic figures, whereas the remaining segments showed sporadic apoptosis. We found a BTB not yet assembled in the cords with zygotene-pachytene spermatocytes and abundant apoptosis. The observed apoptosis frequency diminished drastically when BTB was organized, as confirmed by the use of the tracer. Our conclusion is that the massive apoptosis found in the zygotene-pachytene spermatocytes between days 14 and 20 coincides with an open BTB. The absence of BTB could be one of the factors causing massive apoptosis of zygotene-pachytene spermatocytes, at least within the time span analyzed. The zygotene-pachytene spermatocytes are left exposed in an open environment instead of being isolated in the adluminal compartment to which they are destined. Anat

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Cell death induced by zinc and cadmium is mediated by clusterin in cultured mouse seminiferous tubules

Kaisman-Elbaz

Sekler

Fishman

et al. 2009

Journal Cellular Physiology

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Sertoli cells, lining the walls of the seminiferous tubules, are in close contact with and regulate all aspects of the development of the germ cells. Clusterin, is a glycoprotein produced abundantly by Sertoli cells, and associated with either apoptosis or cell survival. Zinc is present in high concentrations in the testis and required for sperm development by an as yet unknown mechanism. Permeation of zinc into cells via voltage-gated calcium channels (VGCCs), however, is suggested to induce cell death. We examined the possibility that Zn(2+) acts via clusterin to regulate germ cell survival. Employing an ex vivo model of mouse testis, we have assessed the role of permeation of heavy metal ions on clusterin production and secretion. Up-regulation of clusterin expression and its secretion was observed after a short exposure to zinc or to cadmium under depolarizing conditions. Expression of zinc transporter-1 (ZnT-1), previously shown to regulate Zn(2+) influx, increased following prolonged application of zinc or cadmium to the explants and prevented clusterin up-regulation by subsequent exposure to these ions. Inhibition of the MAPK and PI3K pathways reduced the up-regulation of clusterin following the intracellular rise of Zn(2+) or Cd(2+). Neutralization of secreted clusterin by an antibody or attenuation of clusterin up-regulation by inhibition of Zn(2+) permeation via the LTCC, reduced cell death in cultured seminiferous tubule cells. Taken together, our results indicate that Zn(2+) and Cd(2+) influx induce expression and secretion of clusterin, thereby linking metal homeostasis and germ cell fate.

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Role of Sertoli Cells in Injury‐Associated Testicular Germ Cell Apoptosis

Cited by 49 publications

References 99 publications

Testicular germ cell sensitivity to TRAIL-induced apoptosis is dependent upon p53 expression and is synergistically enhanced by DR5 agonistic antibody treatment

Testicular germ cell sensitivity to TRAIL-induced apoptosis is dependent upon p53 expression and is synergistically enhanced by DR5 agonistic antibody treatment

Apoptosis and blood–testis barrier during the first spermatogenic wave in the pubertal rat

Cell death induced by zinc and cadmium is mediated by clusterin in cultured mouse seminiferous tubules

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