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The urea cycle consist of five enzymatically controlled steps that are catalyzed by carbamyl phosphate synthetase, ornithine transcarbamylase, argininosuccinate synthetase, argininosuccinase, and arginase, respectively. The complete cycle is present in physiological meaningful levels in the liver of terrestrial vertebrates, and in man represents the sole mechanism for ammonia disposal. The formation of carbamyl phosphate and the synthesis of argininosuccinate are potential limiting steps in urea biosynthesis but substrate and not enzymes levels are rate-limiting under physiological conditions. In the adult, urea cycle enzymes change as a unit, and are largely influenced by dietary protein content. The urea cycle is closely linked to the citric acid cycle deriving one of its nitrogens through transamination of oxalacetate to form asparate and returns fumarate to that cycle. The biosynthesis of urea demands the expenditure of energy but less than 20% of the energy derived from metabolism of gluconeogenic amino acids is required for ureogenesis. Embryological development of the urea cycle in the tadpole and in mammalian fetal liver therefore permits use of amino acids as new sources of energy to meet oxidative demands for continuing growth.

Whole rat embryos were explanted at head-fold, late pre-somite stage (day 9.5 of gestation) and cultured in rat sera varyingly supplemented with glucose (3, 6, 9, or 12 mg/mL), D,L sodium beta-hydroxybutyrate (2, 4, 8, or 16 mM), or both (6 mg/mL D-glucose plus 8 mM beta-hydroxybutyrate). During 48 h culture, increasing glucose alone or beta-hydroxybutyrate alone effected growth retardation and faulty neural and extraneural organogenesis in dose-dependent fashion. Synergistic dysmorphogenic effects occurred when minimally teratogenic concentrations of glucose and beta-hydroxybutyrate were combined. Sera from diabetic animals containing somatomedin inhibitor bioactivity were also able to produce growth retardation and major developmental lesions in presence of amounts of glucose and ketones which of themselves were not teratogenic. Thus, aberrant fuels and fuel-related products can impair growth and organogenesis in early post-implantation embryo. Such fuel-mediated teratogenesis may be multifactorial and include possibilities for synergistic and additive interactions.

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