Abstract
Background: Maternal malnutrition can lead to fetal growth restriction. This is often associated with organ sparing and long-lasting physiological dysfunctions during adulthood, although the underlying mechanisms are not yet well understood. Methods: Low protein (LP) dietary models in C57BL/6J mice were used to investigate the proximal effects of maternal malnutrition on fetal organ weights and organ sparing at embryonic day 18.5 (E18.5). Results: Maternal 8% LP diet induced strikingly different degrees of fetal growth restriction in different animal facilities, but adjustment of dietary protein content allowed similar fetal body masses to be obtained. A maternal LP diet that restricted fetal body mass by 40% did not decrease fetal brain mass to the same extent, reflecting positive growth sparing of this organ. Under these conditions, fetal pancreas and liver mass decreased by 60-70%, indicative of negative organ sparing. A series of dietary swaps between LP and standard diets showed that the liver is capable of efficient catch-up growth from as late as E14.5 whereas, after E10.5, the pancreas is not. Conclusions: This study highlights that the reproducibility of LP fetal growth restriction studies between laboratories can be improved by careful calibration of maternal dietary protein content. LP diets that induce 30-40% restriction of prenatal growth provide a good model for fetal organ sparing. For the liver, recovery of growth following protein restriction is efficient throughout fetal development but, for the pancreas, transient LP exposures spanning the progenitor expansion phase lead to an irreversible fetal growth deficit.
Highlights
Moderate nutrient deprivation during animal development results in viable undersized adults
Accurate masses were determined for the brain, liver and pancreas indicating that all organs from Low protein (LP) fetuses have significantly (p
Non-isometric decreases in organ weights at E18.5 are indicative that prenatal LP induces positive sparing of the brain (77% of STD value) but negative sparing of the liver (40% of STD value) and pancreas (32% of STD value), relative to the body (60% of STD value), which is defined as neutral sparing (Figure 2)
Summary
Moderate nutrient deprivation during animal development results in viable undersized adults. In humans and other mammals, intrauterine growth restriction (IUGR) limits the fetal supply of nutrients and oxygen such that overall growth is decreased but not all organs are affected (Barker & Osmond, 1986; Dobbing & Sands, 1971; Gruenwald, 1963) This non-isometric (asymmetric) scaling down of body parts reflects preferential utilization of scarce nutrient resources by certain tissues such as the brain at the expense of others, such as the liver and pancreas. A low protein (8%) maternal diet during pregnancy, followed by cross-fostering to a standard protein (20%) maternal diet at postnatal stages led to near normal weights at P21 for most organs, the spleen, heart and thymus were significantly larger (Chen et al, 2009) This and other studies raise the question of how the protein content of maternal diets during pregnancy affects C57BL/6 organ weights at earlier stages, prior to birth. Recovery of growth following protein restriction is efficient throughout fetal development but, for the pancreas, transient LP exposures spanning the progenitor expansion phase lead to an irreversible fetal growth deficit
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