Embryonic development and mitochondrial function. III. Inhibition of respiration and ATP generation in rat embryos by thiamphenicol

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Abstract
Pregnant rats were injected s.c. with thiamphenicol (TAP) on days 10 and 11 of gestation. Embryos were removed on day 12 and mitochondrial energy parameters (respiration and ATP content), mitochondrial enzyme characteristics (cytochrome oxidase activity), as well as extramitochondrial growth indicators (dry weight, and DNA content) were measured. All those factors showed a dose‐dependent inhibition by TAP. Concentrations of TAP in the embryos (8 μ/g wet weight two to three hours after application of 100 mg/kg) were in the range necessary for reduction of mitochondrial protein synthesis in vitro, and well below the concentrations required for direct inhibition of mitochondrial (respiration) and extramitochondrial functions (replication). Cytochrome oxidase was most sensitive and inhibited by 50% at a dose of 10 mg TAP/kg/day. ATP was reduced by 50% and respiratory reserve (additional respiration in the presence of DNP) was inhibited by more than 90% at 100 mg TAP/kg/day using DNA as reference. Delayed and complete embryolethality resulted after injection of 125 mg TAP/kg/day, however, no malformations could be observed. When comparing the inhibition of mitochondrial functions induced by TAP with the inhibition of overall embryonic development, it appeared that respiration was the rate‐limiting step for the embryotoxic effects of TAP. Because of the non‐specificity of these effects, prenatal mortality rather than teratogenic effects was seen.