2,3,7,8-Tetrachlorodibenzo-p-dioxin-induced oxidative stress in female rats.
Oxidative stress may play a role in the toxic manifestations of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Therefore, the time-dependent effects of 100 micrograms TCDD/kg on various indices of oxidative stress including lipid peroxidation. DNA damage, membrane fluidity, calcium homeostasis, nonprotein sulfhydryl content, and NADPH content of hepatic subcellular fractions of female rats were followed for 12 days. Increases in lipid peroxidation of 400-500% occurred in mitochondrial and microsomal membranes and nuclei, with maximum increases occurring 5-6 days post-treatment. Decreases in the nonprotein sulfhydryl content of mitochondrial and microsomal fractions of approximately 80% were observed by Day 12 posttreatment. Membrane fluidity gradually decreased following administration of TCDD, with decreases of 30-40% being observed in mitochondria, microsomes, and plasma membranes. A sharp increase in the incidence of hepatic nuclear DNA single strand breaks was observed 3 days after treatment with an increase of approximately 600% by Day 9. Following the administration of TCDD, increases of 70-80% occurred in the calcium content of mitochondria and microsomes. An 18% increase in cytosolic calcium was present 12 days after the administration of TCDD. Cytosol and mitochondria both exhibited an initial increase in NADPH content following administration of TCDD, but by Day 12 both had decreased to approximately two-thirds of control values. The results clearly demonstrate that TCDD administration induces an oxidative stress in rat liver. The most pronounced effects were observed in membrane lipid peroxidation and DNA damage with gradual changes being observed in calcium and nonprotein sulfhydryl contents and membrane fluidity.
Stohs
S J
SJ
Department of Pharmaceutical Sciences, School of Pharmacy and Allied Health, Creighton University, Omaha, Nebraska 68178.
Shara
M A
MA
Alsharif
N Z
NZ
Wahba
Z Z
ZZ
al-Bayati
Z A
ZA
D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002118:Calcium / Q000032:analysis; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D004249:DNA Damage; D005260:Female; D015227:Lipid Peroxidation / Q000187:drug effects; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008560:Membrane Fluidity / Q000187:drug effects; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D008930:Mitochondria, Liver / Q000187:drug effects / Q000378:metabolism; D009929:Organ Size / Q000187:drug effects; D010084:Oxidation-Reduction; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity*; D051381:Rats; D011919:Rats, Inbred Strains
D000072317:Polychlorinated Dibenzodioxins; D002118:Calcium