The honeybee syndrome: teratogenic effects of mannose during organogenesis in rat embryo culture.
The relevance of our present findings should not rest on the possible role of mannose as an important teratogen in man. Excessive exposure to mannose during pregnancy via dietary intake seems unlikely since mannose is absorbed poorly from the gastrointestinal tract and intestinal hydrolysis of mannosidic linkages may be minimal. Moreover, although some plasma mannose may be generated continuously from endogenous sources via the cleavage of mannose-6-phosphate by hepatic glucose-6-phosphatase or mannosidic linkages by other hydrolases, our ongoing surveys have not uncovered any specimens of plasma or amniotic fluid containing mannose in amounts which could compete effectively with prevailing levels of glucose. Although we are continuing to monitor clinical samples for unusual mannose levels, we believe that the major significance of our experiences with this hexose pertains to its applications as a physiological tool for evaluating the metabolic determinants of early organogenesis. Within the above context, our findings must be viewed in relation to the known features of energy metabolism in the embryo during the interval that we have studied (Fig. 9). The classic studies of Shepherd and colleagues, similar findings by others, and more recent experiments in our own laboratory have indicated that glycolysis constitutes the chief energy source for the post-implantation embryo prior to the establishment of the yolk sac circulation on day 10 1/2. Almost all of the assimilated glucose goes to lactic acid, mitochondrial electron transfer is poorly developed, and oxidative metabolism via the Krebs' cycle is minimal. Meaningful Krebs' cycle activity does not become operative until day 10 1/2 and full expression is not found until the establishment of the allantoic circulation on day 11 (Fig. 9). The present experiences with mannose provide the first documentation of how precariously development is balanced during that transitory 9 1/2-10 1/2 day phase of organogenesis when glycolysis predominates. We have shown that even minor perturbations of glycolytic flux during that interval can result in major dysmorphogenic sequelae. Thus, the proposition by Kalter and Warkany that "any meaningful attempt to reduce infant mortality further will have to address the still unresolved causes of congenital malformations" prompts our speculation that major congenital lesions may result from relatively minor disturbances in glycolysis occurring prior to oxidative maturation in the embryo unit. Such effects on glycolysis during this vulnerable phase of embryogenesis could provide a common basis for the teratogenic actions of many unrelated and as yet unidentified agents.(ABSTRACT TRUNCATED AT 400 WORDS)