Fuel-mediated teratogenesis: symmetric growth retardation in the rat fetus at term after a circumscribed exposure to D-mannose during organogenesis

Abstract

We previously infused the D-glucose epimer D-mannose into pregnant rats to deliver a brief metabolic insult to the early postimplantation conceptus. This insult caused developmental anomalies and growth retardation that were apparent in the embryos 2 days later. We now report the long-range effects on intrauterine development of such a circumscribed metabolic insult during organogenesis. Ten pregnant animals were infused with D-mannose for 12 hours during early neurulation (day 9.5 to 10 of development). Ten control animals were infused with equimolar D-glucose during this same time interval. Mannose infusions produced maternal plasma mananose concentrations in the embryotoxic range; glucose infusions caused only slight and transient hyperglycemia. Fetuses were removed at term and examined for evidence of developmental anomalies and growth retardation. None of 137 fetuses from the mannose group or 138 fetuses from the glucose group exhibited gross anomalies. However, an excess of resorbed conceptions in the mannose group (21 versus six in the glucose group; p less than 0.01) suggested some lethal toxicity from mannose exposure during embryogenesis. Among viable fetuses, the mean body weight of those from the mannose group was significantly reduced compared with those from the glucose group (5.62 +/- 0.04 versus 5.89 +/- 0.03 gm, respectively; p less than 0.001). Reductions of a similar magnitude were noted in the mean wet weight and protein content of fetal brains, hearts, livers, and kidneys from the mannose group (range, 3.4% to 7.1% below the glucose group), indicating a symmetric pattern of fetal growth retardation. In addition, analysis of fetal ossification sites after Alizarin Red S staining revealed a significant delay of skeletal development in the mannose group. These results indicate that a relatively brief metabolic insult to embryos during early organogenesis may cause lethal developmental anomalies as well as growth retardation and delayed skeletal development that are manifested in the fetus at term.