Disruption of iron homeostasis increases phosphine toxicity in caenorhabditis elegans

Ubon Cha'on, Nicholas Valmas, Patrick J. Collins, Paul E B Reilly, Bruce D. Hammock, Paul R. Ebert

Research output: Contribution to journalArticle

19 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)194-201
Number of pages8
JournalToxicological Sciences
Volume96
Issue number1
DOIs
StatePublished - Mar 15 2007

Fingerprint

phosphine
Caenorhabditis elegans
Ferritins
Toxicity
Homeostasis
Iron
Iron Overload
Gene expression
Lipid Peroxidation
Genes

Keywords

  • C. elegans
  • Ferritin
  • Iron overload
  • Longevity
  • Oxidative stress
  • Phosphine

ASJC Scopus subject areas

  • Toxicology

Cite this

Cha'on, U., Valmas, N., Collins, P. J., Reilly, P. E. B., Hammock, B. D., & Ebert, P. R. (2007). Disruption of iron homeostasis increases phosphine toxicity in caenorhabditis elegans. Toxicological Sciences, 96(1), 194-201. https://doi.org/10.1093/toxsci/kfl187

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.; Ebert, Paul R.

In: Toxicological Sciences, Vol. 96, No. 1, 15.03.2007, p. 194-201.

Research output: Contribution to journalArticle

Cha'on, U, Valmas, N, Collins, PJ, Reilly, PEB, Hammock, BD & Ebert, PR 2007, 'Disruption of iron homeostasis increases phosphine toxicity in caenorhabditis elegans', Toxicological Sciences, vol. 96, no. 1, pp. 194-201. https://doi.org/10.1093/toxsci/kfl187
Cha'on U, Valmas N, Collins PJ, Reilly PEB, Hammock BD, Ebert PR. Disruption of iron homeostasis increases phosphine toxicity in caenorhabditis elegans. Toxicological Sciences. 2007 Mar 15;96(1):194-201. https://doi.org/10.1093/toxsci/kfl187
Cha'on, Ubon ; Valmas, Nicholas ; Collins, Patrick J. ; Reilly, Paul E B ; Hammock, Bruce D. ; Ebert, Paul R. / Disruption of iron homeostasis increases phosphine toxicity in caenorhabditis elegans. In: Toxicological Sciences. 2007 ; Vol. 96, No. 1. pp. 194-201.
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