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Lillycrop K.A.,Institute of Developmental science | Burdge G.C.,University of Southampton
Journal of Nutrigenetics and Nutrigenomics | Year: 2011

Epigenetic processes which include DNA methylation, histone modification and miRNAs are integral in determining when and where specific genes are expressed. There is now increasing evidence that the epigenome is susceptible to a variety of environmental cues, such as nutrition, during specific periods of development. The changes induced by early-life nutrition may reflect an adaptive response of the foetus to environmental cues acting through the process of developmental plasticity. This may allow an organism to adjust its developmental programme resulting in long-term changes in its metabolism and physiology in order to be better matched to the future environment. However, when the future environment lies outside the anticipated range, metabolic and homoeostatic capacity will be mismatched with the environment and that individual will be at increased risk of developing a range of non-communicable diseases. Thus the environmental regulation of epigenetic processes is a central component in the developmental origins of non-communicable diseases and our understanding of these processes is, therefore, critical both for the identification of individuals at risk and for the development of new intervention strategies. Copyright © 2012 S. Karger AG, Basel.

Wallace J.M.,University of Aberdeen | Milne J.S.,University of Aberdeen | Green L.R.,Institute of Developmental science | Aitken R.P.,University of Aberdeen
Reproduction, Fertility and Development | Year: 2011

The relationship between impaired fetal nutrient supply and postnatal hypothalamicpituitaryadrenal (HPA) function was examined in ovine models of prenatal growth restriction (GR) caused by small placental size (SP) or by maternal undernutrition (UN). Adrenocorticotrophin (ACTH) and cortisol responses following corticotrophin-releasing hormone (CRH) plus arginine vasopressin (AVP) challenge were examined at 9, 18 and 24 months in growth-restricted (GR-SP) and normal birthweight (control) females (Experiment 1), and at 6 months in growth-restricted (GR-SP, GR-UN) and normal weight males and females (Experiment 2). In Experiment 1, GR-SP offspring were born early, were 40% lighter at birth and had higher fractional weight gains to weaning than control offspring. Baseline ACTH and cortisol were independent of GR and cortisol decreased with age. GR did not affect the HPA response to CRH+AVP challenge at any stage, but ACTH increased with age. In Experiment 2, birthweight was greater in control offspring than in GR-UN offspring, which had a higher birthweight again compared with GR-SP offspring. Only the latter group was born early and exhibited rapid catch-up growth to weaning. Neither nutritional route to GR altered HPA function at 6 months. Males grew faster than females and HPA responses after stimulation were lower in males. Together, the results of these studies demonstrate that postnatal HPA function in sheep is influenced by age and sex, but not by GR. © 2011 CSIRO.

Maiaru M.,University College London | Tochiki K.K.,University College London | Cox M.B.,University of Texas at El Paso | Annan L.V.,University College London | And 5 more authors.
Science Translational Medicine | Year: 2016

Polymorphisms in FKBP51 are associated with stress-related psychiatric disorders and influence the severity of pain symptoms experienced after trauma. We report that FKBP51 (FK506 binding protein 51) is crucial for the full development and maintenance of long-term pain states. Indeed, FKBP51 knockout mice, as well as mice in which silencing of FKBP51 is restricted to the spinal cord, showed reduced hypersensitivity in several persistent pain models in rodents. FKBP51 deletion did not compromise the detection of acute painful stimuli, a critical protective mechanism. Moreover, the intrathecal administration of the specific FKBP51 inhibitor SAFit2 reduced the severity of an established pain state, confirming the crucial role of spinal FKBP51 in nociceptive processing. Finally, glucocorticoid signaling, which is known to modulate persistent pain states in rodents, was impaired in FKBP51 knockout mice. This finding suggested that FKBP51 regulates chronic pain by modulation of glucocorticoid signaling. Thus, FKBP51 is a central mediator of chronic pain, likely in humans as well as rodents, and is a new pharmacologically tractable target for the treatment of long-term pain states.

Hanson M.A.,University of Southampton | Hanson M.A.,Institute of Developmental science | Low F.M.,University of Auckland | Gluckman P.D.,University of Auckland | Gluckman P.D.,Singapore Institute for Clinical science
Annals of Nutrition and Metabolism | Year: 2011

Non-communicable diseases (NCDs), such as cardiovascular disease and type 2 diabetes, constitute the main cause of death worldwide. Eighty percent of these deaths occur in low- and middle-income countries, especially as these countries undergo socio-economic improvement following reductions in the burden of infectious disease. The World Health Organization predicts a substantial increase in the incidence of NCDs over the next decade globally. NCDs are generally preventable, but current approaches are clearly inadequate. New initiatives are needed to implement such prevention, and there needs to be greater recognition that early-life interventions are likely to be the most efficacious. Devising appropriate prevention strategies necessitates an understanding of how the developmental environment influences risk. Progress in this field has been slow due to an excessive emphasis on fixed genomic variations (hard inheritance) as the major determinants of disease susceptibility. However, new evidence demonstrates the much greater importance of early-life developmental factors, involving epigenetic processes and 'soft' inheritance in modulating an individual's vulnerability to NCD. This also offers opportunities for novel epigenetic biomarkers of risk or interventions targeting epigenetic pathways to be devised for use in early life. This may pave the way to much more effective, customised interventions to promote health across the life course. Copyright © 2011 S. Karger AG, Basel.

Lillycrop K.A.,University of Southampton | Rodford J.,Institute of Developmental science | Garratt E.S.,Institute of Developmental science | Slater-Jefferies J.L.,Institute of Developmental science | And 4 more authors.
British Journal of Nutrition | Year: 2010

Feeding pregnant rats a protein-restricted (PR) diet induces altered expression of candidate genes in the liver of the adult offspring, which can be prevented by supplementation of the PR diet with folic acid (PRF). We investigated the effect of maternal nutrition during pregnancy on the liver transcriptome in their adult male offspring. Pregnant rats were fed control, PR or PRF diets. Male offspring were killed on day 84. The liver transcriptome was analysed by microarray (six livers per maternal dietary group) followed by post hoc analysis of relative mRNA levels and gene ontology. These results were confirmed for selected genes by real-time RT-PCR. There were 311 genes that differed significantly (≥1.5-fold change; P<0.05) between PR offspring (222 increased) and control offspring, while 191 genes differed significantly between PRF offspring (forty-five increased) compared with offspring of control dams. There were sixteen genes that were significantly altered in both PR and PRF offspring compared with controls. Ion transport, developmental process, and response to reactive oxygen species (RROS) and steroid hormone response (SHR) ontologies were altered in PR offspring. Folic acid supplementation prevented changes within RROS and SHR response pathways, but not in ion transport or developmental process. There was no effect of maternal PR on mRNA expression of imprinted genes. Insulin 1 and Pleckstrin homology-like domain family A member 2 were increased significantly in PRF compared with PR offspring. The present findings show that the pattern of induced changes in the adult liver transcriptome were dependent on maternal protein and folic acid intakes during pregnancy. © 2010 The Authors.

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