Fas- or FasL-deficient mice display an increased sensitivity to nitrobenzene-induced testicular germ cell apoptosis.
We have previously reported that the Fas/Apo-1/CD95-mediated apoptosis-inducing signaling system participates in the initiation of toxicant-induced testicular germ cell apoptosis. The contribution of Fas-mediated signaling is especially evident in the initiation of germ cell apoptosis after mono-(2-ethylhexyl)phthalate (MEHP)-induced Sertoli cell injury. In previous work, we demonstrated that the incidence of germ cell apoptosis after MEHP exposure is significantly reduced in B6.SMNC3H-Fas(gld,gld) (gld) mice that express a dysfunctional form of the FasL protein (the associated ligand that activates Fas). This has led to the hypothesis that activation of the Fas-mediated signaling pathway is a common mechanism for the initiation of germ cell apoptosis after toxicant-induced Sertoli cell injury. To test this hypothesis, we evaluated the sensitivity of testicular germ cells of wild-type, gld- and Fas-deficient CBA/KlJms-Tnfrsf6lpr-cg((lpr-cg)) (lpr(cg)) mice to undergo apoptosis after exposure to the Sertoli cell toxicant nitrobenzene (NB). Adult, 8-week-old gld mice treated with a single oral dose of NB (800 mg/kg) were observed to have a higher apoptotic index (AI; 66.1+/-1.3) 24 h after exposure as compared with the wild-type C57BL/6 (C57) mice (50.4+/-1.8). Similarly, 8-week-old lpr(cg) mice treated with NB displayed a higher AI 24 h after exposure (45.1+/-4.6) as compared with the wild-type CBA/KlJms (CBA) mice (32.1+/-3.8). Interestingly, exposure of both peri-pubertal 4-week-old C57 and gld mice showed a similar increase in the incidence of germ cell apoptosis after NB (600 mg/kg) exposure. Taken together, these findings indicate that Fas-mediated signaling is not required for NB-induced germ cell apoptosis and imply that a dysfunctional Fas signaling system sensitizes adult mice to NB-induced germ cell elimination.
Richburg
John H
JH
Division of Pharmacology and Toxicology, College of Pharmacy, The University of Texas at Austin, PHR 5.218D, Austin, TX 78712-1074, USA. john_richburg@mail.utexas.edu
Nañez
Adrian
A
D000375:Aging; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D004051:Diethylhexyl Phthalate / Q000031:analogs & derivatives* / Q000494:pharmacology; D053222:Fas Ligand Protein; D017353:Gene Deletion; D005786:Gene Expression Regulation; D008297:Male; D008562:Membrane Glycoproteins / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009578:Nitrobenzenes / Q000494:pharmacology* / Q000633:toxicity; D012708:Sertoli Cells / Q000187:drug effects / Q000473:pathology; D015398:Signal Transduction; D013094:Spermatozoa / Q000187:drug effects* / Q000473:pathology; D013737:Testis / Q000187:drug effects* / Q000473:pathology; D019014:fas Receptor / Q000235:genetics / Q000378:metabolism*
D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D008562:Membrane Glycoproteins; D009578:Nitrobenzenes; D019014:fas Receptor; D004051:Diethylhexyl Phthalate; C036077:nitrobenzene; C016599:mono-(2-ethylhexyl)phthalate