Factors influencing the induction of DNA single strand breaks in rats by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)

Z. Z. Wahba, Terence A Lawson, W. J. Murray, S. J. Stohs

Research output: Contribution to journalArticle

30 Citations (Scopus)

Abstract

The ability of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) to induce lipid peroxidation and DNA damage in rat hepatic nuclei was investigated. In addition, the role of iron in hepatic DNA damage was examined. Female Sprague-Dawley rats were treated with a single dose of 25-100 μg TCDD/kg orally, and sacrificed 3-14 days after treatment. Liver nuclei were isolated, and DNA single strand breaks (DNA-SSB) and lipid peroxidation were determined. Lipid peroxidation was assessed by measuring the content and production of thiobarbituric acid reactive substances (TBARS) while DNA-SSB were determined by the alkaline elution technique. The results demonstrate that TCDD dose and time-dependent increases in hepatic nuclear TBARS content and production occur in conjunction with an increase in DNA-SSB. The administration of the dithiolthione antioxidant oltipraz (30 mg/kg/day for 10 days) resulted in a significant decrease (47%) in the incidence of TCDD-induced DNA-SSB. Clofibrate administration (100 mg/kg/day for 12 days) and pair feeding had no effect on TCDD-induced DNA-SSB. The incubation of hepatic microsomes and mitochondria from TCDD-treated rats with nuclei from untreated animals for one hr at 37°C resulted in enhanced DNA damage which was abolished by the addition of 0.10 mM desferrioxamine (DFX). Incubation with cytosol had no significant effect. Incubation of 0.10 mM Fe2+ or Fe3+ with isolated hepatic nuclei from untreated rats produced significant increases in DNA-SSB, which were abolished by the addition of 0.10 mM DFX to the incubation medium. TCDD may produce an increased bioavailability of iron which leads to enhanced DNA single strand breaks and lipid peroxidation in hepatic nuclei.

Original languageEnglish (US)
Pages (from-to)57-69
Number of pages13
JournalToxicology
Volume58
Issue number1
DOIs
StatePublished - Jan 1 1989

Fingerprint

Single-Stranded DNA Breaks
Rats
Liver
DNA
Lipid Peroxidation
DNA Damage
Deferoxamine
Thiobarbituric Acid Reactive Substances
Lipids
Iron
Clofibrate
Microsomes
Polychlorinated Dibenzodioxins
1,4-dioxin
Cytosol
Biological Availability
Sprague Dawley Rats
Mitochondria
Antioxidants
Animals

Keywords

  • (DFX)
  • (DNA-SSB)
  • (TBARS)
  • (TCDD)
  • 2,3,7,8-Tetrachlorodibenzo-p-dioxin
  • Clofibrate
  • DNA single strand breaks
  • Desferrioxamine
  • Lipid peroxidation
  • Oltipraz
  • Thiobarbituric acid reactive substances

ASJC Scopus subject areas

  • Toxicology

Cite this

Factors influencing the induction of DNA single strand breaks in rats by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). / Wahba, Z. Z.; Lawson, Terence A; Murray, W. J.; Stohs, S. J.

In: Toxicology, Vol. 58, No. 1, 01.01.1989, p. 57-69.

Research output: Contribution to journalArticle

Wahba, Z. Z. ; Lawson, Terence A ; Murray, W. J. ; Stohs, S. J. / Factors influencing the induction of DNA single strand breaks in rats by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). In: Toxicology. 1989 ; Vol. 58, No. 1. pp. 57-69.
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abstract = "The ability of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) to induce lipid peroxidation and DNA damage in rat hepatic nuclei was investigated. In addition, the role of iron in hepatic DNA damage was examined. Female Sprague-Dawley rats were treated with a single dose of 25-100 μg TCDD/kg orally, and sacrificed 3-14 days after treatment. Liver nuclei were isolated, and DNA single strand breaks (DNA-SSB) and lipid peroxidation were determined. Lipid peroxidation was assessed by measuring the content and production of thiobarbituric acid reactive substances (TBARS) while DNA-SSB were determined by the alkaline elution technique. The results demonstrate that TCDD dose and time-dependent increases in hepatic nuclear TBARS content and production occur in conjunction with an increase in DNA-SSB. The administration of the dithiolthione antioxidant oltipraz (30 mg/kg/day for 10 days) resulted in a significant decrease (47{\%}) in the incidence of TCDD-induced DNA-SSB. Clofibrate administration (100 mg/kg/day for 12 days) and pair feeding had no effect on TCDD-induced DNA-SSB. The incubation of hepatic microsomes and mitochondria from TCDD-treated rats with nuclei from untreated animals for one hr at 37°C resulted in enhanced DNA damage which was abolished by the addition of 0.10 mM desferrioxamine (DFX). Incubation with cytosol had no significant effect. Incubation of 0.10 mM Fe2+ or Fe3+ with isolated hepatic nuclei from untreated rats produced significant increases in DNA-SSB, which were abolished by the addition of 0.10 mM DFX to the incubation medium. TCDD may produce an increased bioavailability of iron which leads to enhanced DNA single strand breaks and lipid peroxidation in hepatic nuclei.",
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