A potential mechanism of DL-beta-hydroxybutyrate-induced malformations in mouse embryos.
DL-beta-Hydroxybutyrate (DL-BOHB) is teratogenic to rodent embryos in culture, but the biochemical mechanism(s) responsible for the induction of malformations has not been elucidated. Thus, to delineate a potential mechanism, the interaction of the ketone body with embryonic glucose metabolism was investigated. Mouse embryos were exposed in whole embryo culture to DL-BOHB or each isomer separately during the period of neurulation. The results demonstrate that DL-BOHB inhibits glucose oxidation by the pentose phosphate pathway (PPP) with no concomitant effect on Krebs cycle or glycolysis. Furthermore, decreased rates of embryonic uridine monophosphate and DNA synthesis were produced by DL-BOHB, whereas orotate synthesis was unaffected, thereby suggesting that the availability of ribose moieties synthesized by the PPP was compromised. This hypothesis was supported by the observation that addition of ribose to DL-BOHB-containing medium reduced the incidence of ketone body-induced neural tube defects and maintained the rates of DNA synthesis at control levels. Furthermore, these biochemical alterations are due to the synergistic effects of the D and L isomers and may be related to changes in redox states.
D020155:3-Hydroxybutyric Acid; D015120:6-Aminonicotinamide / Q000494:pharmacology; D000014:Abnormalities, Drug-Induced / Q000209:etiology* / Q000378:metabolism; D000090:Acetoacetates / Q000494:pharmacology; D000818:Animals; D001696:Biomechanical Phenomena; D004247:DNA / Q000096:biosynthesis; D004622:Embryo, Mammalian / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D006885:Hydroxybutyrates / Q000506:poisoning*; D051379:Mice; D009436:Neural Tube Defects / Q000139:chemically induced / Q000517:prevention & control; D010084:Oxidation-Reduction; D010428:Pentosephosphates / Q000378:metabolism; D012266:Ribose / Q000494:pharmacology; D014542:Uridine Monophosphate / Q000096:biosynthesis; D015017:Yolk Sac / Q000098:blood supply
D000090:Acetoacetates; D006885:Hydroxybutyrates; D010428:Pentosephosphates; D015120:6-Aminonicotinamide; C016635:acetoacetic acid; D012266:Ribose; D004247:DNA; D014542:Uridine Monophosphate; D005947:Glucose; D020155:3-Hydroxybutyric Acid