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.
Highlights
Human epidemiological studies have offered an array of evidence to support the theory that major disease states of adulthood are established in utero [1,2,3]
Animal models have played an important role in developing understanding of the processes underlying the programming theory, as they allow specific hypotheses to be tested during the critical windows of interest
Average birth weight of male pups was greater for Rowett Hooded Lister (RHL) neonates than Wistars (P,0.03), but again there
Summary
Human epidemiological studies have offered an array of evidence to support the theory that major disease states of adulthood are established in utero [1,2,3]. Whilst a range of human cohort studies have demonstrated associations between early life events and later disease risk, they are limited in their ability to demonstrate causality and cannot be used to investigate mechanisms, due to the impact of bias and confounding factors, and the lack of invasive measurements. A variety of small and large models have provided robust evidence to support an association between developmental insults and metabolic risk factors in later life. The observed commonality of phenotype between models following very diverse nutritional or hormonal insults suggests that a relatively small number of common changes are occurring in response to nutrient availability in utero, to influence fetal development and determine long-term disease risk. We propose that a small number of gatekeeper processes during development may underlie the nutritional programming observed in response to a range of insults
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