Inhibition of mitochondrial respiration by cationic rhodamines as a possible teratogenicity mechanism.
Exposure of mice to cationic rhodamines, Rh 123 and Rh 6G, has been found to be associated with developmental toxicity, while neutral rhodamines (e.g., Rh B) had no such effect. When mouse embryos from dams given ip injections of Rh 123, Rh 6G (15 mg/kg), or Rh B (30 mg/kg) on gestation Day (GD) 10 were examined, Rh 123, Rh 6G were present in embryonic tissue in fluorescent bodies within the average dimensions of mitochondria. Rh B was evenly distributed in the cytoplasm. With in vitro exposure of isolated mitochondria to rhodamines on GD 12, 3-4 times more Rh 123 was associated with mitochondria under energized conditions than under nonenergized conditions; the amount of Rh 6G associated with mitochondria was much less under either condition. Treatment of pregnant mice (ip) with Rh 123 (15 mg/kg/day) or Rh 6G (0.5 mg/kg/day) on GD 7-10 resulted in inhibition of state 3 respiration of embryonic mitochondria isolated on GD 12. When isolated embryonic mitochondria were exposed to the cationic rhodamines, inhibition of state 3 respiration was dose dependent. With 5 micrograms of Rh 123/mg mitochondrial protein, state 3 respiration decreased by 31%, while Rh 6G (1 microgram/mg) decreased state 3 respiration by 27%. In vivo exposure of maternal liver mitochondria to cationic rhodamines did not result in inhibition of respiration 2 days later, whereas in vitro results were similar to those for embryonic mitochondria. In vivo or in vitro exposure to Rh B had no effects on mitochondrial respiration. These results indicate that interference with embryonic energy metabolism is a possible mechanism by which cationic rhodamines exert adverse effects on embryogenesis.
Ranganathan
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S
Department of Biology, University of Alabama, Tuscaloosa 35487-0344.
Churchill
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PF
Hood
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RD
D000818:Animals; D002412:Cations; D004579:Electron Transport; D005260:Female; D005453:Fluorescence; D051379:Mice; D008815:Mice, Inbred Strains; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D010101:Oxygen Consumption / Q000187:drug effects*; D011247:Pregnancy; D012235:Rhodamines / Q000493:pharmacokinetics / Q000633:toxicity*; D013723:Teratogens; D014966:Xanthenes / Q000633:toxicity*
D002412:Cations; D012235:Rhodamines; D013723:Teratogens; D014966:Xanthenes