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Oxidant Stress Responses in C. elegans

Farhang Payvar, Andrew DeMatteo, Tom Hazinski

Department of Pediatrics, Vanderbilt University Medical School, Nashville, TN, 37232

 

Worm Meeting, Los Angeles, June 2000

     We are intrigued by the genetic events triggered with hyperoxia and how they might differ from oxidative stress per se.  Hyperoxia can influence gene expression by transcriptional (JCI 96:2083-2089, 1995) and/or post-transcriptional mechanisms leading directly or indirectly to oxidant stress (OS).  In C. elegans, insulin-like signaling pathway regulates life span and sensitivity to OS.  For example, animals with mutations in DAF-2 (insulin-like receptor) or AGE-1 (PI3K) are relatively resistant to OS and have extended life span; mutations in DAF-16 (fork head transcription factor) suppress the phenotypes of daf-2 and age-1 mutants, suggesting that DAF-16 is target of negative regulation by upstream AGE-1 and DAF-2. 

     Two forms of OS-induction not previously explored in C. elegans were examined.  The wild type (N2) & mutant (daf-2, age-1, daf-16) animals were exposed to 3.5 days of sodium nitroprusside (NP), an OS inducer, in normoxic (21 % oxygen) or hyperoxic (95% oxygen) environments.  Survival rates were measured, and the LD50 for NP treatment with and without hyperoxia was calculated.

     Our results indicate that survival in wild-type animals is reduced by NP but not by hyperoxia.  However, hyperoxia increased the sensitivity to NP by ~ 3-fold.  This increase in NP sensitivity suggests that the genetic events mediating the effects of hyperoxia are, at least in part, distinct from those for NP in C. elegans, and that there is cross talk between hyperoxia and NP signaling pathways.  Moreover, response to NP, alone or in combination with hyperoxia is altered in several mutant C. elegans strains.  Consistent with the conventional DAF-16 pathway model, age-1 mutants are relatively NP-resistant, suggesting that AGE-1 is involved in NP signaling.  Unexpectedly, age-1 mutants retain their NP + hyperoxia phenotype, pointing to alternate players/pathways for transmission of hyperoxic signal.  Surprisingly, daf-2 mutants are hypersensitive to NP & have nearly lost their NP + hyperoxia-response phenotype.  These findings are consistent with the notion that NP + hyperoxia signals are relayed via DAF-2 to downstream molecules that are distinct from AGE-1.