Intrauterine programming of ageing.
Ontology highlight
ABSTRACT:
SUBMITTER: Fernandez-Capetillo O
PROVIDER: S-EPMC2816621 | biostudies-other | 2010 Jan
REPOSITORIES: biostudies-other
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Project description:The type 2 diabetes epidemic and one of its predisposing factors, obesity, are major influences on global health and economic burden. It is accepted that genetics and the current environment contribute to this epidemic; however, in the last two decades, both human and animal studies have consolidated considerable evidence supporting the 'developmental programming' of these conditions, specifically by the intrauterine environment. Here, we review the various in utero exposures that are linked to offspring obesity and diabetes in later life, including epidemiological insights gained from natural historical events, such as the Dutch Hunger Winter, the Chinese famine and the more recent Quebec Ice Storm. We also describe the effects of gestational exposure to endocrine disruptors, maternal infection and smoking to the fetus in relation to metabolic programming. Causal evidence from animal studies, motivated by human observations, is also discussed, as well as some of the proposed underlying molecular mechanisms for developmental programming of obesity and type 2 diabetes, including epigenetics (e.g. DNA methylation and histone modifications) and microRNA interactions. Finally, we examine the effects of non-pharmacological interventions, such as improving maternal dietary habits and/or increasing physical activity, on the offspring epigenome and metabolic outcomes.
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Project description:The fetal brain is highly plastic and is not only receptive to but requires cues from its environment to develop properly. Based on an understanding of evolutionary biology, developmental plasticity, and life history theory, one can predict that stressors are an important environmental condition that may influence brain development. In fact, the available empirical evidence appears to support the notion that exposure to excess stress in intrauterine life has the potential to adversely affect short- and long-term neurodevelopmental outcomes with implications for altered susceptibility for mental health disorders in childhood and adult life. In this presentation, we provide a rationale for proposing that endocrine and inflammatory stress mediators are key candidate pathways for programming brain development. These mediators are responsive to a diverse set of intrauterine perturbations and alter key signaling pathways critical for brain development, including but not limited to mammalian target of rapamycin, Wnt (wingless), Sonic hedgehog, and reelin signaling. We suggest that recent advances in neuroimaging and other methods now afford us an unprecedented opportunity to advance our understanding of this important topic. Additionally, we provide empirical evidence from two recently published papers for fetal programming of human brain development. We conclude by suggesting some future directions for expanding this field of research.
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Project description:Ageing is a result of gradual and overall functional deteriorations across the body; however, it is unknown whether an individual tissue primarily works to mediate the ageing progress and control lifespan. Here we show that the hypothalamus is important for the development of whole-body ageing in mice, and that the underlying basis involves hypothalamic immunity mediated by I?B kinase-? (IKK-?), nuclear factor ?B (NF-?B) and related microglia-neuron immune crosstalk. Several interventional models were developed showing that ageing retardation and lifespan extension are achieved in mice by preventing ageing-related hypothalamic or brain IKK-? and NF-?B activation. Mechanistic studies further revealed that IKK-? and NF-?B inhibit gonadotropin-releasing hormone (GnRH) to mediate ageing-related hypothalamic GnRH decline, and GnRH treatment amends ageing-impaired neurogenesis and decelerates ageing. In conclusion, the hypothalamus has a programmatic role in ageing development via immune-neuroendocrine integration, and immune inhibition or GnRH restoration in the hypothalamus/brain represent two potential strategies for optimizing lifespan and combating ageing-related health problems.
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Project description:Purpose of reviewHerein, we summarize existent epidemiological studies relating adverse maternal metabolic environments of maternal obesity and gestational diabetes and placental DNA methylation.Recent findingsMultiple studies have evaluated associations between intrauterine exposure to gestational diabetes and/or maternal glucose levels and DNA methylation at candidate metabolic genes as well as in epigenome-wide studies. Some of the genomic regions more consistently associated include lipid-related genes (LPL and PPARGC1A), the major histocompatibility complex (MHC), and imprinted genes. Studies solely focused on maternal obesity influences on the placental epigenome are scarce. Understanding the placental mechanisms involved in fetal metabolic programming could lead to discovery of placental biomarkers at birth that predict later-life metabolic risk. Moving forward is important to standardize methods utilized in epigenetics research; consistent methodology can help interpret disparate findings. Larger studies with longitudinal follow-up are needed to address future challenges in fetal programming research.
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Project description:Epigenetic processes are primary candidates when searching for mechanisms that can stably modulate gene expression and metabolic pathways according to early life conditions. To test the effects of gestational diabetes mellitus (GDM) on the epigenome of the next generation, cord blood and placenta tissue were obtained from 88 newborns of mothers with dietetically treated GDM, 98 with insulin-dependent GDM, and 65 without GDM. Bisulfite pyrosequencing was used to compare the methylation levels of seven imprinted genes involved in prenatal and postnatal growth, four genes involved in energy metabolism, one anti-inflammatory gene, one tumor suppressor gene, one pluripotency gene, and two repetitive DNA families. The maternally imprinted MEST gene, the nonimprinted glucocorticoid receptor NR3C1 gene, and interspersed ALU repeats showed significantly decreased methylation levels (4-7 percentage points for MEST, 1-2 for NR3C1, and one for ALUs) in both GDM groups, compared with controls, in both analyzed tissues. Significantly decreased blood MEST methylation (3 percentage points) also was observed in adults with morbid obesity compared with normal-weight controls. Our results support the idea that intrauterine exposure to GDM has long-lasting effects on the epigenome of the offspring. Specifically, epigenetic malprogramming of MEST may contribute to obesity predisposition throughout life.
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Project description:Maternal stress during late pregnancy can lead to intrauterine hyperthermia affecting fetal hypothalamic-pituitary-adrenal axis development and function. This study aimed to characterize the impact of in utero heat stress on the postnatal offspring's adrenal gland transcriptome.
2023-06-21 | GSE235160 | GEO
Project description:BackgroundMaternal undernutrition programs fetal energy homeostasis and increases the risk of metabolic disorders later in life. This study aimed to identify the signs of hepatic metabolic programming in utero and during the juvenile phase after intrauterine undernutrition during midgestation.MethodsFifty-three pregnant goats were assigned to the control (100% of the maintenance requirement) or restricted (60% of the maintenance requirement from day 45 to day 100 of midgestation and realimentation thereafter) group to compare hepatic energy metabolism in the fetuses (day 100 of gestation) and kids (postnatal day 90).ResultsUndernutrition increased the glucagon concentration and hepatic hexokinase activity, decreased the body weight, liver weight and hepatic expression of G6PC, G6PD, and PGC1α mRNAs, and tended to decrease the hepatic glycogen content and ACOX1 mRNA level in the dams. Maternal undernutrition decreased the growth hormone (GH) and triglyceride concentrations, tended to decrease the body weight and hepatic hexokinase activity, increased the hepatic PCK1, PCK2 and PRKAA2 mRNAs levels and glucose-6-phosphatase activity, and tended to increase the hepatic PRKAB1 and CPT1α mRNAs levels in the male fetuses. In the restricted female fetuses, the hepatic hexokinase activity and G6PC mRNA level tended to be increased, but PKB1 mRNA expression was decreased and the ACACA, CPT1α, NR1H3 and STK11 mRNA levels tended to be decreased. Maternal undernutrition changed the hepatic metabolic profile and affected the metabolic pathway involved in amino acid, glycerophospholipid, bile acid, purine, and saccharide metabolism in the fetuses, but not the kids. Additionally, maternal undernutrition increased the concentrations of GH and cortisol, elevated the hepatic glucose-6-phosphate dehydrogenase activity, and tended to decrease the hepatic glycogen content in the male kids. No alterations in these variables were observed in the female kids.ConclusionsMaternal undernutrition affects the metabolic status in a sex- and stage-specific manner by changing the metabolic profile, expression of genes involved in glucose homeostasis and enzyme activities in the liver of the fetuses. The changes in the hormone levels in the male fetuses and kids, but not the female offspring, represent a potential sign of metabolic programming.
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Project description:The higher risk of adult neuropsychiatric diseases in individuals with low fetal birth weight may be related to brain-derived neurotrophic factor (BDNF) signaling pathway inhibition. Here, we investigated whether prenatal food restriction (PFR) induces neurobehavioral alterations in adult female offspring and explored the underlying intrauterine programming mechanism. Pregnant Wistar rats in the PFR group were fed 50% of the daily food intake of control rats from gestational day (GD) 11 to 20; some pregnant rats were sacrificed at GD20, and the remaining female pups had normal delivery and were fed a post-weaning high-fat diet (HFD) and half of them were exposed to an unpredictable chronic stress (UCS) from postnatal week (PW) 21. All adult female offspring were sacrificed at PW24. At GD20, PFR altered fetal hippocampal structure and function, increased glucocorticoid receptor (GR) expression, and decreased mineralocorticoid receptor (MR), BDNF and synaptic plasticity-related gene expressions. At PW24, PFR induced depression-like behavioral abnormalities in adult rat offspring fed an HFD. These rats exhibited depression- and anxiety-like behavioral changes after HFD/UCS. Furthermore, the hippocampal morphology of the PFR group showed abnormal changes in adult offspring fed an HFD and more serious damage after HFD/UCS. These changes were accompanied by increased serum corticosterone levels, elevated GR expression, and reduced expression of the BDNF signaling pathway and synaptic plasticity-related genes in the hippocampus. In conclusion, PFR may induce neurobehavioral abnormalities in adult offspring, especially those exposed to UCS, through high levels of glucocorticoids, which increase hippocampal GR expression and decrease BDNF expression.
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Project description:Fetal growth restriction (FGR) is a risk factor for obesity in adult life. Importantly, growth-restricted females are more prone to obesity than males. The mechanisms involved in this sexually dimorphic programming are not known. Previously, we have demonstrated that ambient hyperthermia (40° C) led to placental insufficiency and significant FGR, and the perirenal adipose tissue undergoes sexually dimorphic gene expression. We demonstrated that males undergo significant changes in gene expression with growth restriction. This was not the case in females. We have also demonstrated that the isolated preadipocytes from male FGR (MFGR) have reduced differentiation potential compared to control males & females and female FGR (FFGR). Thus, we hypothesized that growth restriction differentially programs gene expression and genetic pathways in perirenal preadipocytes, which reduces their differentiation potential in male fetuses in a sexually dimorphic manner. We created fetal growth restriction by exposing pregnant sheep to ambient hyperthermia. After isolating preadipocytes from perirenal adipose tissue, we differentiated them following published protocols. We examined the gene expression before and after differentiation from control male, control female, MFGR, and FFGR female. We also compared our data with other published studies in mouse and human preadipocytes. Our results demonstrate that a set of 21 genes altered with preadipocyte differentiation to mature adipocytes is common in adipose tissue from both sexes, humans, mice, and sheep, at different organismal ages (embryonic, fetal, and adult) and different sites (subcutaneous inguinal, pancreatic, perirenal). We also demonstrate that female FFGR fetuses demonstrate all these 21 genes altered similar to control males and females; however, MFGR fetuses have six genes (Dgat2, Fabp4, Lipe, Lrrfip1, Spred3, and Thrsp) that are not changed with preadipocyte differentiation to mature adipocyte. These genes may be responsible for reduced differentiation potential and obesity in FGR males compared to FGR females. Another important finding of the present study is that Lrrfip1, known to be associated with obesity, was upregulated with FGR and requires further investigation. Overall, our studies provide several target genes that may play a crucial role in reducing the risk of MFGR for obesity.
2024-12-12 | GSE278762 | GEO
Project description:Intrauterine growth restriction (IUGR) predisposes to chronic kidney disease via activation of proinflammatory pathways, and omega-3 PUFAs (n-3 PUFAs) have anti-inflammatory properties. In female rats, we investigated 1) how an elevated dietary n-3/n-6 PUFA ratio (1:1) during postnatal kidney development modifies kidney phospholipid (PL) and arachidonic acid (AA) metabolite content and 2) whether the diet counteracts adverse molecular protein signatures expected in IUGR kidneys. IUGR was induced by bilateral uterine vessel ligation or intrauterine stress through sham operation 3.5 days before term. Control (C) offspring were born after uncompromised pregnancy. On postnatal (P) days P2-P39, rats were fed control (n-3/n-6 PUFA ratio 1:20) or n-3 PUFA intervention diet (N3PUFA; ratio 1:1). Plasma parameters (P33), kidney cortex lipidomics and proteomics, as well as histology (P39) were studied. We found that the intervention diet tripled PL-DHA content (PC 40:6; P < 0.01) and lowered both PL-AA content (PC 38:4 and lyso-phosphatidylcholine 20:4; P < 0.05) and AA metabolites (HETEs, dihydroxyeicosatrienoic acids, and epoxyeicosatrienoic acids) to 25% in all offspring groups. After ligation, our network analysis of differentially expressed proteins identified an adverse molecular signature indicating inflammation and hypercoagulability. N3PUFA diet reversed 61 protein alterations (P < 0.05), thus mitigating adverse IUGR signatures. In conclusion, an elevated n-3/n-6 PUFA ratio in early diet strongly reduces proinflammatory PLs and mediators while increasing DHA-containing PLs regardless of prior intrauterine conditions. Counteracting a proinflammatory hypercoagulable protein signature in young adult IUGR individuals through early diet intervention may be a feasible strategy to prevent developmentally programmed kidney damage in later life.
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