Embryonic development and mitochondrial function. 2. Thiamphenicol induced embryotoxicity

Inhibition of mitochondrial protein synthesis in rat embryos during late organogenesis leads to impaired embryonic development. 1. Thiamphenicol (TAP), similar to chloramphenicol, inhibits in vivo the synthesis of cytochrome oxidase (cytox), which is partially synthesized by the mitochondrion. Subsequently, DNA synthesis and embryonic growth are affected. 2. Embryos on day 10 and 11, in contrast to embryos on day 9 of gestation, show a high sensitivity of mitochondrial protein synthesis, measured as cytox activity. From day 10 onwards, such an inhibition leads to pronounced impairment of DNA synthesis. The rat hemochorial placenta starts functioning on day 12 of gestation. Larger doses of TAP are required to inhibit cytox and DNA synthesis for treatment after placentation rather than before placentation. 3. Dose-response relationships differ depending on the date and duration of treatment. Application of TAP for 1 day requires 10-30 mg/kg TAP to inhibit cytox synthesis and 60-100 mg/kg to impair embryonic growth. Prolongation of treatment to 4 days (day 10-13) lowers the dose required for inhibition of DNA synthesis to 10 mg TAP/kg/day. This is lower than the human therapeutic dose. Larger doses lead to embryolethality. 4. The extent of inhibition of DNA synthesis provoked by inhibition of mitochondrial protein synthesis depends on a number of factors which include: different growth rates during organogenesis, the number of mitochondria present prior to treatment, availability of extramitochondrial ATP sources and placental permeability barrier.