2,5-Hexanedione-Induced Testicular Injury

Boekelheide, Kim; Fleming, Shawna L.; Allio, Theresa; Embree-Ku, Michelle; Hall, Susan J.; Johnson, Kamin J.; Kwon, Eun Ji; Patel, Sutchin R.; Rasoulpour, Reza J.; Schoenfeld, Heidi A.; Thompson, Stephanie

doi:10.1146/annurev.pharmtox.43.100901.135930

Cited by 62 publications

(52 citation statements)

References 103 publications

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“…In this study, we have employed a well known testicular toxin 2,5-hexanedione (2,5-HD), 2 which is a metabolite of the common industrial solvents n-hexane and methyl n-butyl ketone. Chronic exposure to 2,5-HD induces peripheral polyneuropathy and testicular injury (23). Using this toxin to induce spermatogenic cell apoptosis, we provide a new insight of a close relationship between Bcl-xS and Bcl-xL with intracellular Ca 2ϩ , where we demonstrate that increased intracellular Ca 2ϩ caused by exposure to 2,5-HD results in a shift toward a relative increase of Bcl-xS encoding isoform over the Bcl-xL isoform.…”

mentioning

confidence: 82%

Changes in Cytosolic Ca2+ Levels Regulate Bcl-xS and Bcl-xL Expression in Spermatogenic Cells during Apoptotic Death

Mishra

Pal

Shaha

2006

Journal of Biological Chemistry

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Bcl-x exists in two isoforms, the anti-apoptotic form Bcl-xL and the proapoptotic form Bcl-xS. The critical balance between the two forms appears to be important for cell survival; however, it is still not clear exactly how the vital balance is maintained. Using an in vitro spermatogenic cell apoptosis model, this study provides a new insight into the possible role of Ca 2؉ in regulating the Bcl-xS and Bcl-xL expression. 2,5-Hexanedione, a metabolite of the common industrial solvent n-hexane, caused a significant increase in reactive oxygen species followed by an enhancement of intracellular Ca 2؉ through the T-type Ca 2؉ channels. Consequent to the above changes, expression of Bcl-xS increased with a concomitant drop in Bcl-xL expression, thus altering the ratio of the two proteins. Impediment of Ca 2؉ influx by using a T-type Ca 2؉ channel blocker pimozide resulted in a decrease in Bcl-xS and an increase in Bcl-xL expression. This caused prevention of mitochondrial potential loss, reduction of caspase-3 activity, inhibition of DNA fragmentation, and increase in cell survival. Alternatively, Ca 2؉ ionophores caused an increase of Bcl-xS encoding isoform over the Bcl-xL-encoding isoform. Therefore, this study proposes a role for Ca 2؉ in regulation of Bcl-xS and Bcl-xL expression and ultimately cell fate.

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mentioning

confidence: 82%

Changes in Cytosolic Ca2+ Levels Regulate Bcl-xS and Bcl-xL Expression in Spermatogenic Cells during Apoptotic Death

Mishra

Pal

Shaha

2006

Journal of Biological Chemistry

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“…This animal model, similar to other drug models such as treatment of rats with environmental toxicant cadmium or other toxicants (e.g., carbendazim, 2,5-hexanedione, colchicine), is known to induce germ cell exfoliation from the testis. [55][56][57] It was noted that while spermatids near the tubule lumen at stage VI to early VIII were depleting from the epithelium, analogous to the release of sperm at spermiation, many step 19 spermatids remained entrapped deep inside the epithelium. 8 These step 19 spermatids were consistently found in the epithelium of stages IX, X, XI and XII tubules, until they were eventually engulfed and degraded by Sertoli cells.…”

Section: The Adjudin Modelmentioning

confidence: 99%

Transport of germ cells across the seminiferous epithelium during spermatogenesis—the involvement of both actin- and microtubule-based cytoskeletons

et al. 2016

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The transport of germ cells from the base of the seminiferous epithelium toward the luminal edge of the tubule lumen in the adluminal compartment during the epithelial cycle is an essential cellular event to support spermatogenesis. Thus, fully developed elongated spermatids (i.e., spermatozoa) can be released at spermiation in late stage VIII in rodents versus late stage II in humans. Earlier studies to examine the molecular mechanism(s) that support germ cell transport, most notably the transport of preleptotene spermatocytes across the blood-testis barrier (BTB), and the transport of elongating spermatids across the adluminal compartment during spermiogenesis, is focused on the adhesion protein complexes at the cell-cell interface. It is generally accepted that cell junctions at the Sertoli cell-cell interface at the BTB, including the actin-based tight junction (TJ), basal ectoplasmic specialization (basal ES, a testis-specific adherens junction) and gap junction (GJ), as well as the intermediate filament-based desmosome undergo constant remodeling to accommodate the transport of preleptotene spermatocytes across the barrier. On the other hand, similar junction dynamics (i.e., disassembly, reassembly and stabilization/maintenance) take place at the Sertoli-spermatid interface. Emerging evidence has shown that junction dynamics at the Sertoli cell-cell vs. Sertoli-germ cell interface are supported by the 2 intriguingly coordinated cytoskeletons, namely the F-actin-and microtubule (MT)-based cytoskeletons. Herein, we provide a brief summary and critically evaluate the recent findings. We also provide an updated hypothetical concept regarding germ cell transport in the testis utilizing the MT-conferred tracks and the MT-specific motor proteins. Furthermore, this cellular event is also supported by the F-actin-based cytoskeleton.

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“…2, 5-Hexanedione-induced seminiferous tubule atrophy appears to be caused by a direct affect of the toxicant on the Sertoli cell, impairing the ability of Sertoli cells to physiologically support germ cell maturation. 48 …”

Section: Seminiferous Epithelium Atrophymentioning

confidence: 99%

Testicular histopathology associated with disruption of the Sertoli cell cytoskeleton

Johnson

2014

Spermatogenesis

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2,5-Hexanedione-Induced Testicular Injury

Cited by 62 publications

References 103 publications

Changes in Cytosolic Ca2+ Levels Regulate Bcl-xS and Bcl-xL Expression in Spermatogenic Cells during Apoptotic Death

Changes in Cytosolic Ca2+ Levels Regulate Bcl-xS and Bcl-xL Expression in Spermatogenic Cells during Apoptotic Death

Transport of germ cells across the seminiferous epithelium during spermatogenesis—the involvement of both actin- and microtubule-based cytoskeletons

Testicular histopathology associated with disruption of the Sertoli cell cytoskeleton

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