Effects of in vivo and in vitro exposure to rhodamine dyes on mitochondrial function of mouse embryos.
Cationic rhodamines (Rh 123 and Rh 6G) can cause developmental toxicity in mice and inhibit embryonic mitochondrial respiration following in vivo or in vitro dye exposure. Rh B, a neutral rhodamine, fails to show such effects at comparable doses. To assess effects of rhodamines on development, F0F1ATPase activity and ADP translocation were measured on gestation day (GD) 12 in embryonic and adult mitochondria. ATP synthesis in embryonic mitochondria transplacentally exposed to Rh 123 (15 mg/kg/day) or Rh 6G (0.5 mg/kg/day) given to dams by i.p. injection from GD 7 to 10 were inhibited 39% and 49%, respectively. When isolated mitochondria were treated, dose-dependent inhibition was seen; at 5 micrograms of dye/mg mitochondrial protein, ATP synthesis was inhibited 65% and 81% by Rh 123 and Rh 6G, respectively. When F0F1ATPase activity was assessed, in vitro Rh 123 and Rh 6G exposures at levels up to 8 micrograms/mg mitochondrial protein resulted in enzyme inhibition, but at 10 micrograms/mg, ATPase activity was stimulated. Uncoupler-stimulated ATPase activity was also inhibited. ADP translocation was decreased by 19.1% and 37.7% by Rh 123 and Rh 6G, respectively, at dye concentrations of 20 micrograms/mg. Results of in vitro exposure of maternal liver mitochondria were similar to those for embryonic mitochondria, whereas liver from dams exposed in vivo on GD 7-10 was unaffected on GD 12. In vivo or in vitro treatment with Rh B did not affect any embryonic or maternal parameters. Such results support the hypothesis that inhibition of mitochondrial energy metabolism is a mechanism for the developmental toxicity of cationic rhodamines.
Ranganathan
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S
Department of Biology, University of Alabama, Tuscaloosa 35487-1927.
Hood
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RD
D000255:Adenosine Triphosphate / Q000096:biosynthesis; D000818:Animals; D005314:Embryonic and Fetal Development / Q000187:drug effects; D005260:Female; D005865:Gestational Age; D066298:In Vitro Techniques; D008431:Maternal-Fetal Exchange; D051379:Mice; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000378:metabolism; D000226:Mitochondrial ADP, ATP Translocases / Q000037:antagonists & inhibitors / Q000378:metabolism; D011247:Pregnancy; D006180:Proton-Translocating ATPases / Q000037:antagonists & inhibitors / Q000378:metabolism; D020112:Rhodamine 123; D012235:Rhodamines / Q000494:pharmacology / Q000633:toxicity*; D014966:Xanthenes / Q000633:toxicity*
D012235:Rhodamines; D014966:Xanthenes; C026188:rhodamine 6G; D020112:Rhodamine 123; D000255:Adenosine Triphosphate; D000226:Mitochondrial ADP, ATP Translocases; D006180:Proton-Translocating ATPases