Asymmetric development of mitochondrial activity in rat embryos as a determinant of the defect patterns induced by exposure to hypoxia, hyperoxia, and redox cyclers in vitro.
Previous study has shown that midorganogenesis-stage rat embryos exposed to strong redox cyclers under moderate hypoxia in vitro develop severe necrotic defects on the right side. Similar effects can be produced by exposure to severe hypoxia alone. Studies presented here indicate that exposure to severe but survivable hyperoxia induces comparable necrotic degeneration on the left sides of all embryos. We hypothesize that the basis of these axially asymmetric defects is relatively precocious mitochondrial maturity on the left side of the embryo. In order to investigate this hypothesis, we compared mitochondrial oxygen utilization (NADH oxidase activities) on either side of rat embryos between days 11 and 14 of gestation. Activities were consistently higher on the left side during this period and significantly higher on day 11. We also found that the asymmetric embryotoxicity induced by niridazole, a strong redox cycler, could be attenuated by prior culture under hyperoxic conditions. We propose that mitochondrial immaturity on the right results in inadequate energy generation under hypoxic conditions, either directly or as a result of redox cycling. On the other hand, necrosis associated with hyperoxic conditions results from "leakage" of superoxide from functionally mature mitochondria on the left side.
Fantel
A G
AG
Department of Pediatrics, University of Washington, Seattle 98195.
Person
R E
RE
Burroughs-Gleim
C
C
Shepard
T H
TH
Juchau
M R
MR
Mackler
B
B
D000014:Abnormalities, Drug-Induced / Q000473:pathology*; D000818:Animals; D046508:Culture Techniques; D004622:Embryo, Mammalian / Q000187:drug effects*; D005314:Embryonic and Fetal Development / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects* / Q000201:enzymology; D009097:Multienzyme Complexes / Q000187:drug effects / Q000378:metabolism; D009247:NADH, NADPH Oxidoreductases / Q000187:drug effects / Q000378:metabolism; D009560:Niridazole / Q000633:toxicity; D010084:Oxidation-Reduction; D010100:Oxygen / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains
D009097:Multienzyme Complexes; C023107:NADH oxidase; D009247:NADH, NADPH Oxidoreductases; D009560:Niridazole; D010100:Oxygen