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Disruption of iron homeostasis increases phosphine toxicity in Caenorhabditis elegans.

Toxicological sciences : an official journal of the Society of Toxicology (2006-12-19)
Ubon Cha'on, Nicholas Valmas, Patrick J Collins, Paul E B Reilly, Bruce D Hammock, Paul R Ebert
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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Ammonium iron(II) sulfate hexahydrate, ACS reagent, 99%
Sigma-Aldrich
Ammonium iron(II) sulfate hexahydrate, 99.997% trace metals basis
Sigma-Aldrich
Ammonium iron(II) sulfate hexahydrate, ReagentPlus®, ≥98%
Sigma-Aldrich
Ammonium iron(II) sulfate hexahydrate, BioUltra, ≥99.0% (RT)
Sigma-Aldrich
Ammonium iron(II) sulfate hexahydrate, BioXtra, ≥98%