1. In the rat, hypertension is induced by fetal exposure to maternal low-protein diets. The effect on blood pressure of undernutrition before conception and during discrete periods in early, mid or late pregnancy was assessed using an 18% casein (control) diet and a 9% casein to apply mild protein restriction. 2. The offspring of rats fed 9% casein developed raised blood pressure by weaning age. Feeding a low-protein diet before conception was not a prerequisite for programming of hypertension. 3. Hypertension was observed in rats exposed to low protein during the following gestational periods: days 0-7, days 8-14 and days 15-22. Blood pressure increases elicited by these discrete periods of undernutrition were lower than those induced by feeding a low-protein diet throughout pregnancy. The effect in early gestation was significant only in male animals. Post-natal growth of male rats exposed to low-protein diets was accelerated, but kidneys were small in relation to body weight. 4. Biochemical indices of glucocorticoid action in liver, hippocampus, hypothalamus and lung were elevated in rats exposed to low-protein diets in utero. The apparent hypersensitivity to glucocorticoids was primarily associated with undernutrition in mid to late gestation. 5. Plasma renin activity was elevated in rats exposed to 9% casein over days 15-55 of gestation. Animals undernourished over days 0-7 and 8-14 produced pups with lower plasma angiotensin II concentrations at weaning. 6. Fetal exposure to maternal low-protein diets for any period in gestation may programme hypertension in the rat. Alterations to renal structure, renal hormone action or the hypothalamic-pituitary-adrenal axis may all play a role in the programming phenomenon, either independently or in concert.
"Interestingly, even when pregnant dams are placed on the low-protein diet for discrete periods lasting only 7 days (i.e., days 0–7, 8–14, or 15–22), the offspring exhibit signs of hypertension, albeit to a lesser degree than offspring of dams who consumed the diet throughout pregnancy . Furthermore, administration of a low-protein diet during the final week of pregnancy resulted in a more severe phenotype in the offspring than administration of the diet during early or mid-gestation . The administration of a synthetic glucocorticoid to pregnant rats in the final week of gestation has also been shown to program hypertension in the offspring . "
[Show abstract][Hide abstract] ABSTRACT: The placenta acts as a physiological barrier, preventing the transfer of maternal glucocorticoids to the developing fetus. This is accomplished via the oxidation, and subsequent inactivation, of endogenous glucocorticoids by the 11-
hydroxysteroid dehydrogenase type 2 enzyme (HSD2). Maternal protein restriction during pregnancy has been shown to result in a decrease in placental HSD2 expression and fetal glucocorticoid overexposure, especially late in gestation, resulting in low birth weight and “fetal programming” of the offspring. This dietary intervention impairs fetal growth and cardiovascular function in adult C57BL/6 offspring, but the impact on placental HSD2 has not been defined. The goal of the current study was to examine the effects of a maternal low-protein diet (18% versus 9% protein) on placental HSD2 gene expression and enzyme activity in mice during late gestation. In contrast to previous studies in rats, a maternal low-protein diet did not affect HSD2 protein or enzyme activity levels in the placentas of C57BL/6 mice and this was irrespective of the gender of the offspring. These data suggest that the effects of maternal protein restriction on adult phenotypes in C57BL/6 mice depend upon a mechanism that may be independent of placental HSD2 or possibly occurs earlier in gestation.
"After the birth of the offspring, the litter size in each cage was randomly adjusted to seven pups (four males, when possible) to ensure adequate and standardized nutrition until the pups were weaned . Offspring sex was assessed by measuring the anogenital distance . "
[Show abstract][Hide abstract] ABSTRACT: Maternal obesity induced by a high fat (HF) diet may program susceptibility in offspring, altering pancreatic development and causing later development of chronic degenerative diseases, such as obesity and diabetes. Female mice were fed standard chow (SC) or an HF diet for 8 weeks prior to mating and during the gestational and lactational periods. The male offspring were assessed at birth, at 10 days, and at 3 months of age. The body mass (BM) gain was 50% greater before pregnancy and 80% greater during pregnancy in HF dams than SC dams. Dams fed an HF diet showed higher oral glucose tolerance test (OGTT), blood pressure, serum corticosterone, and insulin levels than dams fed SC. At 10 days of age and at 3 mo old the HF offspring showed greater BM and higher blood glucose levels than the SC offspring. The mean diameter of the islets had increased by 37% in the SC offspring and by 155% in the HF offspring at 10 days of age. The islet mass ratio (IM/PM) was 88% greater in the HF offspring at 10 days of age, and 107% greater at 3 mo of age, compared to the values obtained at birth. The HF offspring had a beta cell mass (BCM)/PM ratio 54% lower than SC offspring at birth. However, HF offspring displayed a 146% increase in the BCM/PM ratio at 10 days of age, and 112% increase at 3 months of age than values at birth. A 3 mo of age, the HF offspring showed a greater OGTT and higher levels of than SC offspring. In conclusion, a maternal HF diet consumed during the preconceptional period and throughout the gestational and lactational periods in mice results in dramatic alterations in the pancreata of the offspring.
PLoS ONE 01/2013; 8(1):e55711. DOI:10.1371/journal.pone.0055711 · 3.23 Impact Factor
"Welham et al.,  concluded that protein restriction in pregnancy was associated with increased apoptosis of mesenchymal cells during metanephrogenesis, ultimately leading to a reduced glomerular endowment in the rat. Thus our study may have identified the fundamental driver of the tissue remodelling that is proposed to occur in response to maternal undernutrition (Langley-Evans & McMullen, 2010), for which evidence is readily available in the kidneys , pancreas  and brain ,  of the offspring of protein-restricted dams. "
[Show abstract][Hide abstract] ABSTRACT: Many mechanisms purport to explain how nutritional signals during early development are manifested as disease in the adult offspring. While these describe processes leading from nutritional insult to development of the actual pathology, the initial underlying cause of the programming effect remains elusive. To establish the primary drivers of programming, this study aimed to capture embryonic gene and protein changes in the whole embryo at the time of nutritional insult rather than downstream phenotypic effects. By using a cross-over design of two well established models of maternal protein and iron restriction we aimed to identify putative common “gatekeepers” which may drive nutritional programming.
Both protein and iron deficiency in utero reduced the nephron complement in adult male Wistar and Rowett Hooded Lister rats (P<0.05). This occurred in the absence of damage to the glomerular ultrastructure. Microarray, proteomic and pathway analyses identified diet-specific and strain-specific gatekeeper genes, proteins and processes which shared a common association with the regulation of the cell cycle, especially the G1/S and G2/M checkpoints, and cytoskeletal remodelling. A cell cycle-specific PCR array confirmed the down-regulation of cyclins with protein restriction and the up-regulation of apoptotic genes with iron deficiency.
The timing and experimental design of this study have been carefully controlled to isolate the common molecular mechanisms which may initiate the sequelae of events involved in nutritional programming of embryonic development. We propose that despite differences in the individual genes and proteins affected in each strain and with each diet, the general response to nutrient deficiency in utero is perturbation of the cell cycle, at the level of interaction with the cytoskeleton and the mitotic checkpoints, thereby diminishing control over the integrity of DNA which is allowed to replicate. These findings offer novel insight into the primary causes and mechanisms leading to the pathologies which have been identified by previous programming studies.
PLoS ONE 08/2011; 6(8):e23189. DOI:10.1371/journal.pone.0023189 · 3.23 Impact Factor
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