AJP - Endocrinology and Metabolism, Vol 253, Issue 1 E72-E80, Copyright © 1987 by American Physiological Society
A potential mechanism of DL-beta-hydroxybutyrate-induced malformations in mouse embryos
E. S. Hunter 3rd, T. W. Sadler and R. E. Wynn
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.
