Abstract
A low-protein diet applied during pregnancy in the rat results in intrauterine growth restricted (IUGR) fetuses. In humans, IUGR is associated with increased perinatal morbidity, higher incidence of neuro-developmental defects and increased risk of adult metabolic anomalies, such as diabetes and cardiovascular disease. Development and function of many organs are affected by environmental conditions such as those inducing fetal and early postnatal growth restriction. This phenomenon, termed “fetal programming” has been studied unconnectedly in some organs, but very few studies (if any) have investigated at the same time several organs, on a more comparative basis. However, it is quite probable that IUGR affects differentially most organ systems, with possible persistent changes in gene expression. In this study we address transcriptional alterations induced by IUGR in a multi-organ perspective, by systematic analysis of 20-days rat fetuses. We show that (1) expressional alterations are apparently stronger in organs functioning late in foetal or postnatal life than in organs that are functioning early (2) hierarchical classification of the deregulations put together kidney and placenta in one cluster, liver, lungs and heart in another; (3) the epigenetic machinery is set up especially in the placenta, while its alterations are rather mild in other organs; (4) the genes appear deregulated in chromosome clusters; (5) the altered expression cascades varies from organ to organ, with noticeably a very significant modification of the complement and coagulation cascades in the kidney; (6) we found a significant increase in TF binding site for HNF4 proteins specifically for liver genes that are down-regulated in IUGR, suggesting that this decrease is achieved through the action of HNF transcription factors, that are themselves transcriptionnally induced in the liver by IUGR (x 1.84 fold). Altogether, our study suggests that a combination of tissue-specific mechanisms contributes to bring about tissue-driven modifications of gene cascades. The question of these cascades being activated to adapt the organ to harsh environmental condition, or as an endpoint consequence is still raised.
Highlights
The period of intrauterine growth and development is one of the most vulnerable periods in the human life cycle
The notion of SGA (Small for Gestational Age) is defined by a birth weight below the 10th percentile at a given gestational age; it is currently used as an approximation for Intra-uterine growth restriction (IUGR); it mainly refers to measurements carried out at birth, rather than to a dynamic measure involving an in utero rupture of the growth curve
IUGR, especially when it is not associated to vascular causes, obviously embraces a very heterogeneous spectrum of diseases in humans, the great utility of animal models to understand the physiopathology of this disorder [8,9,10]
Summary
The period of intrauterine growth and development is one of the most vulnerable periods in the human life cycle. A low birth weight can be induced in pups when dams are fed a isocaloric low protein diet (half to one third of the normal protein content, according to the studies, i.e. 8–10% versus 18–22%) during pregnancy [11]. This model has been used in the present study, since it is probably one of the most commonly used, and is known for decades to induce multiple organ alterations [12,13,14]. The mechanisms inducing the various defects are imperfectly known, they could be basically caused by general defects in vascular architecture [18], reducing the placental nutrient transfer [19], or targets of placental hormones [20]
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