Biochemical basis for D,L,-beta-hydroxybutyrate-induced teratogenesis

Area of Science:

• Developmental biology
• Biochemistry
• Teratology

Background:

• D,L,-beta-hydroxybutyrate (BOHB) exposure can cause teratogenesis in neurulating mouse embryos.
• Previous studies linked BOHB-induced teratogenesis to pentose phosphate pathway (PPP) inhibition in 5-6 somite stage embryos.

Purpose of the Study:

• To investigate the biochemical mechanisms of BOHB-induced abnormalities in earlier (2-3 somite stage) mouse embryos.
• To assess the role of the PPP and de novo pyrimidine biosynthesis (PB) in BOHB teratogenesis.
• To evaluate the recovery potential of BOHB-exposed embryos.

Main Methods:

• Mouse embryos (2-3 somite stage) were exposed to 32 mM BOHB in vitro for 24 hours.
• Metabolic rates via PPP and PB, and BOHB utilization were measured.
• Embryos were transferred to control medium to assess recovery.
• D-ribose supplementation was tested for rescue effects.

Main Results:

• BOHB exposure resulted in 100% neural tube defects and decreased embryonic protein.
• No PPP inhibition was observed in 2-3 somite stage embryos, unlike in older embryos.
• BOHB significantly decreased PB (34.3%) in embryos, but not in the visceral yolk sac.
• D-ribose did not prevent BOHB-induced abnormalities.
• Recovered embryos showed an overshoot in pyrimidine biosynthesis (25.5%).

Conclusions:

• The mechanism of BOHB-induced teratogenesis differs between embryonic developmental stages.
• Pyrimidine biosynthesis inhibition, not PPP inhibition, is implicated in BOHB teratogenesis at the 2-3 somite stage.
• Embryonic recovery is possible, indicating plasticity in response to BOHB insult.