Pre- and postnatal methyl deficiency in the rat differentially alters glucose homeostasis.

BACKGROUND/AIMS: Early-life methyl-donor deficiency is implicated in growth restriction and later-life development of type 2 diabetes mellitus. We ascertained whether dietary methyl-donor deficiency in the mother during pregnancy or during postweaning growth in the rat would impair glucose homeostasis, insulin secretion and pancreatic endocrine development in young adults. METHODS: Effects of maternal methyl deficiency (90% deficiency in methionine, folate and choline) were compared with those of postweaning methyl deficiency and with control diets for effects on growth, impaired glucose tolerance, insulin secretion and pancreas development in offspring. Studies focussed on male offspring, which have been shown more susceptible to early-life influences on later disease development. RESULTS: Prenatal methyl deficiency delayed delivery, restricted birthweight by 22%, reduced litter size by 33% and increased offspring mortality to 23% shortly after birth. It reduced relative endocrine pancreatic mass in adult male offspring to 46% of endocrine mass in controls, but only mildly impaired their glucose tolerance and insulin secretion. In contrast, postweaning methyl deficiency restricted growth of male rats and reduced relative pancreatic endocrine mass (-40%), but improved their glucose tolerance, despite decreased insulin secretion. CONCLUSION: It is clear that the global undernutrition (UN) during pregnancy in rodents alters glucose metabolism in adult offspring. It has been hypothesised that alterations in epigenetic mechanisms may underlie this phenotype. However, removing all methyl donors during pregnancy, which are essential for epigenetic processes in development, did not cause any alteration in glucose metabolism in offspring as seen in the global UN model.

Altered placental lactogen and leptin expression in placentomes from bovine nuclear transfer pregnancies.

Appropriate growth, development, and function of the placenta is central to the success of nutrient partitioning between the mother, placenta, and fetus. Hormones such as placental lactogen (PL) and leptin are produced in the bovine placenta and play an important role in nutrient partitioning and regulation of placental and fetal growth. Nuclear transfer pregnancies are associated with a number of fetal and placental abnormalities, including increased placental growth and macrosomia, and hence represent a unique situation to gain insight into fetoplacental growth regulation. We have examined the expression of bovine PL (bPL) and leptin in placentomes of artificially inseminated (AI), in vitro produced (IVP), and nuclear transfer (NT) pregnancies at Days 50, 100, and 150 of gestation in the cow. Immunolocalization studies showed that spatial and temporal patterns of expression of bPL and leptin were markedly altered in the placentomes of NT pregnancies compared with AI or IVP controls. Concentrations of bPL in allantoic fluid, as determined by radioimmunoassay (RIA), were significantly higher (P < or = 0.001) in NT pregnancies (17.9 +/- 3.2 ng/ml; mean +/- SD) compared with AI (2.03 +/- 1.5 ng/ml), but not IVP (23.4 +/- 12.8 ng/ ml) pregnancies on Day 150 of gestation. In contrast, amniotic fluid levels of bPL were significantly decreased in NT pregnancies at Day 150 gestation. Leptin mRNA expression, as determined by real-time reverse transcription-PCR, was increased 2.4- to 3.0-fold in NT placentomes compared with AI controls at all gestational ages examined. We speculate that the observed dysregulation of expression of bPL and leptin in NT placentomes could contribute to aberrations in cell migration and invasion and subsequently to alterations in placental metabolism and transfer of nutrients to the fetus, thus leading to increased placental and fetal macrosomia in NT pregnancies.

Insulin-like growth factor-I and binding proteins 1, 2, and 3 in bovine nuclear transfer pregnancies.

In cloned pregnancies, placental deficiencies, including increased placentome size, reduced placentome number, and increased accumulation of allantoic fluid, have been associated with low cloning efficiency. To assess differences in paracrine and endocrine growth regulation in cloned versus normal bovine placentomes and pregnancies, we have examined the expression of insulin-like growth factor (IGF)-I and -II and their binding proteins (IGFBP)-1 through -3 in placentomes of artificially inseminated (AI), in vitro-produced (IVP), and nuclear transfer (NT) pregnancies at Days 50, 100, and 150 of gestation. Fetal, maternal, and binucleate cell counts in representative placentomes were performed on Days 50-150 of gestation in all three groups. Increased numbers of fetal, maternal, and binucleate cells were present in NT placentomes at all stages of gestation examined. Immunolocalization studies showed that spatial and temporal patterns of expression of IGFBP-2 and -3 were markedly altered in the placentomes of NT pregnancies compared to AI/IVP controls. Concentrations of IGF-I in fetal plasma, as determined by RIA, were significantly higher (P = 0.001) in NT pregnancies (mean +/- SEM, 30.3 +/- 2.3 ng/ml) compared with AI (19.1 +/- 5.5 ng/ml) or IVP (24.2 +/- 2.5 ng/ml) pregnancies on Day 150 of gestation. Allantoic fluid levels of IGFBP-1 were also increased in NT pregnancies. These findings suggest that endocrine and paracrine perturbations of the IGF axis may modulate placental dysfunction in NT pregnancies. Furthermore, increased cell numbers in NT placentomes likely have significant implications for fetomaternal communication and may contribute to the placental overgrowth observed in the NT placentomes.