ToxSci Advance Access originally published online on August 28, 2008
Toxicological Sciences 2008 106(2):497-508; doi:10.1093/toxsci/kfn186
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Cross-talk between the Akt and NF-
B Signaling Pathways Inhibits MEHP-Induced Germ Cell Apoptosis
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* The Center for Environmental Studies
Department of Pathology and Laboratory Medicine, Brown University, Providence, Rhode Island 02912
1 To whom correspondence should be addressed at GE505, Department of Pathology and Laboratory Medicine, Brown University; Providence, RI 02912. Fax: (401) 863-9008. E-mail: Mary_Hixon{at}Brown.edu.
Received June 3, 2008; accepted August 25, 2008
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Abstract |
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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-
B) 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-B signaling pathways. We found a twofold increase in Akt1-dependent phosphorylation of the IB
subunit following exposure to 500 mg/kg MEHP and decreased levels of the total IB protein. Examination of the expression of the NF-B 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-B signaling pathway and an increased sensitivity to oxidative stress.
Key Words: Akt1; NF-B; germ cell; Sertoli cell; phthalates; MEHP; oxidative stress.