Journal Article

Cross-talk between the Akt and NF-κB Signaling Pathways Inhibits MEHP-Induced Germ Cell Apoptosis

Rachel Rogers, Gregory Ouellet, Caitlin Brown, Ben Moyer, Teresa Rasoulpour and Mary Hixon

in Toxicological Sciences

Volume 106, issue 2, pages 497-508
Published in print December 2008 | ISSN: 1096-6080
Published online August 2008 | e-ISSN: 1096-0929 | DOI:
Cross-talk between the Akt and NF-κB Signaling Pathways Inhibits MEHP-Induced Germ Cell Apoptosis

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Phthalates are ubiquitous contaminants that target the testis during in utero and postnatal development. The PI3K/Akt and nuclear factor kappa B (NF-κB) signaling pathways have been implicated in germ cell survival following testicular injury. Here we observe that Akt kinase activity increases in the testes of postnatal day 28 wild-type mice following exposure to 500 mg/kg mono-(2-ethylhexyl) phthalate (MEHP), and that loss of Akt1 results in the premature onset of germ cell apoptosis. To further determine the basis for this sensitivity, we investigated the potential for cross-talk between the PI3K/Akt and NF-κB signaling pathways. We found a twofold increase in Akt1-dependent phosphorylation of the IκBα subunit following exposure to 500 mg/kg MEHP and decreased levels of the total IκBα protein. Examination of the expression of the NF-κB subunits, p50 and p65, in Akt1 wild-type testes following MEHP exposure revealed a twofold increase in p50 mRNA at 6 h. Interestingly, in Akt1-deficient testes, basal expression of both the p50 and p65 subunits was elevated 1.6- and 4-fold, respectively. This was due, at least in part, to increased levels of oxidative stress as measured by both superoxide anion formation and increased expression of SMAC/DIABLO, a proapoptotic mitochondrial protein. In wild-type testes, MEHP-induced Akt1-dependent transcription of the antiapoptotic mitochondrial target gene, Bcl-xL. Together, these results indicate that Akt1 plays a role in the initial protection of germ cells following MEHP-induced germ cell apoptosis and that this response is partially mediated by cross-talk with the NF-κB signaling pathway and an increased sensitivity to oxidative stress.

Keywords: Akt1; NF-κB; germ cell; Sertoli cell; phthalates; MEHP; oxidative stress

Journal Article.  7560 words.  Illustrated.

Subjects: Medical Toxicology ; Toxicology (Non-medical)

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