Disruption of iron homeostasis increases phosphine toxicity in Caenorhabditis elegans

Cha'on, Ubon, Valmas, Nicholas, Collins, Patrick J., Reilly, Paul E. B., Hammock, Bruce D. and Ebert, Paul R. (2007) Disruption of iron homeostasis increases phosphine toxicity in Caenorhabditis elegans. Toxicological Sciences, 96 1: 194-201. doi:10.1093/toxsci/kfl187


Author Cha'on, Ubon
Valmas, Nicholas
Collins, Patrick J.
Reilly, Paul E. B.
Hammock, Bruce D.
Ebert, Paul R.
Title Disruption of iron homeostasis increases phosphine toxicity in Caenorhabditis elegans
Formatted title
Disruption of iron homeostasis increases phosphine toxicity in Caenorhabditis elegans
Journal name Toxicological Sciences   Check publisher's open access policy
ISSN 1096-6080
Publication date 2007-03
Sub-type Article (original research)
DOI 10.1093/toxsci/kfl187
Open Access Status Not Open Access
Volume 96
Issue 1
Start page 194
End page 201
Total pages 8
Place of publication Oxford, United Kingdom
Publisher Oxford University Press
Collection year 2008
Language eng
Subject 270102 Cell Metabolism
320504 Toxicology (incl. Clinical Toxicology)
C1
730118 Organs, diseases and abnormal conditions not elsewhere classified
780105 Biological sciences
Abstract The aim of this study is to identify the biochemical mechanism of phosphine toxicity and resistance, using Caenorhabditis elegans as a model organism. To date, the precise mode of phosphine action is unclear. In this report, we demonstrate the following dose-dependent actions of phosphine, in vitro: (1) reduction of ferric iron (Fe3+) to ferrous iron (Fe2+), (2) release of iron from horse ferritin, (3) and the peroxidation of lipid as a result of iron release from ferritin. Using in situ hybridization, we show that the ferritin genes of C. elegans, both ferritin-1 and ferritin-2, are expressed along the digestive tract with greatest expression at the proximal and distal ends. Basal expression of the ferritin-2 gene, as determined by quantitative PCR, is approximately 80 times that of ferritin-1. However, transcript levels of ferritin-1 are induced at least 20-fold in response to phosphine, whereas there is no change in the level of ferritin-2. This resembles the reported pattern of ferritin gene regulation by iron, suggesting that phosphine toxicity may be related to an increase in the level of free iron. Indeed, iron overload increases phosphine toxicity in C. elegans at least threefold. Moreover, we demonstrate that suppression of ferritin-2 gene expression by RNAi, significantly increases sensitivity to phosphine. This study identifies similarities between phosphine toxicity and iron overload and demonstrates that phosphine can trigger iron release from storage proteins, increasing lipid peroxidation, leading to cell injury and/or cell death.
Keyword Toxicology
phosphine
ferritin
iron overload
longevity
oxidative stress
C. elegans
Induced Oxidative Damage
Stored-product Insects
Lipid-peroxidation
In-vitro
Resistant Strains
Ferritin
Release
Oxygen
Mechanisms
Initiation
Q-Index Code C1
Q-Index Status Confirmed Code

 
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Created: Mon, 18 Feb 2008, 16:20:37 EST