Measuring the methylome in clinical samples: improved processing of the Infinium Human Methylation450 BeadChip Array.

The Infinium Human Methylation450 BeadChip Array (TM) (Infinium 450K) is an important tool for studying epigenetic patterns associated with disease. This array offers a high-throughput, low cost alternative to more comprehensive sequencing-based methodologies. Here we compare data generated by interrogation of the same seven clinical samples by Infinium 450K and reduced representation bisulfite sequencing (RRBS).

PPTOX III: environmental stressors in the developmental origins of disease--evidence and mechanisms.

Fetal and early postnatal development constitutes the most vulnerable time period of human life in regard to adverse effects of environmental hazards. Subtle effects during development can lead to functional deficits and increased disease risk later in life. The hypothesis stating that environmental exposures leads to altered programming and, thereby, to increased susceptibility to disease or dysfunction later in life has garnered much support from both experimental and epidemiological studies.

Transcriptome changes affecting Hedgehog and cytokine signalling in the umbilical cord: implications for disease risk.

Background: Babies born at lower gestational ages or smaller birthweights have a greater risk of poorer health in later life. Both the causes of these sub-optimal birth outcomes and the mechanism by which the effects are transmitted over decades are the subject of extensive study. We investigated whether a transcriptomic signature of either birthweight or gestational age could be detected in umbilical cord RNA.

Developmental origins of non-communicable disease: implications for research and public health.

This White Paper highlights the developmental period as a plastic phase, which allows the organism to adapt to changes in the environment to maintain or improve reproductive capability in part through sustained health. Plasticity is more prominent prenatally and during early postnatal life, i.e.

Prenatal factors contribute to the emergence of kwashiorkor or marasmus in severe undernutrition: evidence for the predictive adaptation model.

Background: Severe acute malnutrition in childhood manifests as oedematous (kwashiorkor, marasmic kwashiorkor) and non-oedematous (marasmus) syndromes with very different prognoses. Kwashiorkor differs from marasmus in the patterns of protein, amino acid and lipid metabolism when patients are acutely ill as well as after rehabilitation to ideal weight for height. Metabolic patterns among marasmic patients define them as metabolically thrifty, while kwashiorkor patients function as metabolically profligate.

Match fitness: development, evolution, and behavior: comment on Frankenhuis and Del Giudice (2012).

The application of evolutionary thinking to human physical and psychological medicine suggests several pathways through which evolutionary processes affect risk of disease. Among these is the concept of mismatch between an individual and its environment, either because the environment has changed for the whole species (evolutionary novelty) or because the environment has changed for an individual during its lifetime (developmental mismatch). Here we set a discussion of maladaptation and mismatch as a cause of psychopathology (Frankenhuis & Del Giudice, 2012) in the broader framework of developmental plasticity and life history trade-offs.

Seven- to eight-year follow-up of the CoolCap trial of head cooling for neonatal encephalopathy.

Introduction: We sought to determine whether 18- to 22-mo neurodevelopmental outcomes predicted functional outcomes at 7-8 y for survivors of the CoolCap study of therapeutic hypothermia for neonates with hypoxic-ischemic encephalopathy.

Results: WeeFIM ratings were completed at 7-8 y of age on 62 (32 cooled; 30 standard care) of 135 surviving children who had had neurodevelopmental assessment at 18 mo. There was 1 refusal, 58 lost to follow-up, and 14 children whose centers declined to participate.

Evolutionary biology within medicine: a perspective of growing value.

Evolutionary biology provides an essential perspective on the determinants of health and disease, believe and . It needs to be further integrated into medical research and teaching

Epigenetics and metabolism in 2011: Epigenetics, the life-course and metabolic disease.

Clinical and experimental studies suggest that early life experiences, perhaps spanning multiple generations, affect lifelong risk of metabolic dysfunction through epigenetic mechanisms. Data published in 2011 suggest that epigenetic analysis could potentially have utility as a marker of early metabolic pathology and might enable early life prophylaxis.

Developmental origins of health and disease: moving from biological concepts to interventions and policy.

The rising incidence of noncommunicable diseases (NCDs), especially in young adults, presents great humanitarian and economic challenges to high-resource and, increasingly, to low-resource countries. No longer considered to be diseases of affluence, NCDs are exacerbated by urbanization and changes in social and lifestyle factors such as diet and family size. New research emphasizes the importance of early life factors in establishing the risk of NCDs through inadequate responses to later challenges, such as an obesogenic environment.

Progressive, transgenerational changes in offspring phenotype and epigenotype following nutritional transition.

Induction of altered phenotypes during development in response to environmental input involves epigenetic changes. Phenotypic traits can be passed between generations by a variety of mechanisms, including direct transmission of epigenetic states or by induction of epigenetic marks de novo in each generation. To distinguish between these possibilities we measured epigenetic marks over four generations in rats exposed to a sustained environmental challenge.

Developmental plasticity and epigenetic mechanisms underpinning metabolic and cardiovascular diseases.

The importance of developmental factors in influencing the risk of later-life disease has a strong evidence base derived from multiple epidemiological, clinical and experimental studies in animals and humans. During early life, an organism is able to adjust its phenotypic development in response to environmental cues. Such developmentally plastic responses evolved as a fitness-maximizing strategy to cope with variable environments.

Gene expression profiling in the Cynomolgus macaque Macaca fascicularis shows variation within the normal birth range.

Background: Although an adverse early-life environment has been linked to an increased risk of developing the metabolic syndrome, the molecular mechanisms underlying altered disease susceptibility as well as their relevance to humans are largely unknown. Importantly, emerging evidence suggests that these effects operate within the normal range of birth weights and involve mechanisms of developmental palsticity rather than pathology.

Method: To explore this further, we utilised a non-human primate model Macaca fascicularis (Cynomolgus macaque) which shares with humans the same progressive history of the metabolic syndrome.

Associations between DNA methylation of a glucocorticoid receptor promoter and acute stress responses in a large healthy adult population are largely explained by lifestyle and educational differences.

Background: Glucocorticoids are the key regulators of the biological stress response and act by binding to glucocorticoid receptors (GR). Expression of GR is altered by DNA methylation. Methylation patterns in GR promoters have been shown to be highly variable between individuals, but little is known about the functional consequences of this variation for the acute stress response.

Influence of birth weight on internalizing traits modulated by serotonergic genes.

Objective: Fetal growth predicts childhood behavioral problems associated with brain serotonergic systems. We hypothesized that allelic variations in genes involved in serotonergic function would moderate associations between birth weight (BW) and internalizing traits in childhood.

Methods: The Child Behavior Checklist was administered to 545 healthy Singaporean children at 8 to 12 years.

Myostatin promotes the wasting of human myoblast cultures through promoting ubiquitin-proteasome pathway-mediated loss of sarcomeric proteins.

Myostatin is a negative regulator of skeletal muscle growth and in fact acts as a potent inducer of "cachectic-like" muscle wasting in mice. The mechanism of action of myostatin in promoting muscle wasting has been predominantly studied in murine models. Despite numerous reports linking elevated levels of myostatin to human skeletal muscle wasting conditions, little is currently known about the signaling mechanism(s) through which myostatin promotes human skeletal muscle wasting.

Epigenetic epidemiology: the rebirth of soft inheritance.

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.

Losing the war against obesity: the need for a developmental perspective.

Developed countries are struggling to control epidemics of obesity and related chronic diseases; thus, we can expect only limited success from applying the current approaches to the developing world, which is experiencing an alarming increase in such disorders. This failure results in part from the fact that our focus on adult life-styles, although important, ignores data that suggest that biological and cultural factors operating early in life affect adult health status. To stem the rising obesity burden in developing countries, scientists and policy-makers must address obesity-promoting factors from early development to adulthood.

Human myostatin negatively regulates human myoblast growth and differentiation.

Myostatin, a member of the transforming growth factor-β superfamily, has been implicated in the potent negative regulation of myogenesis in murine models. However, little is known about the mechanism(s) through which human myostatin negatively regulates human skeletal muscle growth. Using human primary myoblasts and recombinant human myostatin protein, we show here that myostatin blocks human myoblast proliferation by regulating cell cycle progression through targeted upregulation of p21.

Epigenetic gene promoter methylation at birth is associated with child's later adiposity.

Objective: Fixed genomic variation explains only a small proportion of the risk of adiposity. In animal models, maternal diet alters offspring body composition, accompanied by epigenetic changes in metabolic control genes. Little is known about whether such processes operate in humans.

The role of developmental plasticity and epigenetics in human health.

Considerable epidemiological, experimental and clinical data have amassed showing that the risk of developing disease in later life is dependent on early life conditions, mainly operating within the normative range of developmental exposures. This relationship reflects plastic responses made by the developing organism as an evolved strategy to cope with immediate or predicted circumstances, to maximize fitness in the context of the range of environments potentially faced. There is now increasing evidence, both in animals and humans, that such developmental plasticity is mediated in part by epigenetic mechanisms.

How evolutionary principles improve the understanding of human health and disease.

An appreciation of the fundamental principles of evolutionary biology provides new insights into major diseases and enables an integrated understanding of human biology and medicine. However, there is a lack of awareness of their importance amongst physicians, medical researchers, and educators, all of whom tend to focus on the mechanistic (proximate) basis for disease, excluding consideration of evolutionary (ultimate) reasons. The key principles of evolutionary medicine are that selection acts on fitness, not health or longevity; that our evolutionary history does not cause disease, but rather impacts on our risk of disease in particular environments; and that we are now living in novel environments compared to those in which we evolved.

Developmental plasticity and developmental origins of non-communicable disease: theoretical considerations and epigenetic mechanisms.

There is now evidence that developmental influences have lifelong effects on cardiovascular and metabolic function and that elements of the heritable or familial component of susceptibility to cardiovascular disease, obesity and other non-communicable diseases (NCD) can be transmitted across generations by non-genomic means. In animals the developmental environment induces altered phenotypes through genetic, physiological (especially endocrine) and epigenetic mechanisms. The latter include DNA methylation, covalent modifications of histones and non-coding RNAs.

Developmental origins of health and disease: reducing the burden of chronic disease in the next generation.

Despite a wealth of underpinning experimental support, there has been considerable resistance to the concept that environmental factors acting early in life (usually in fetal life) have profound effects on vulnerability to disease later in life, often in adulthood. This has resulted in an unwillingness among public health decision makers to implement relatively simple approaches, based upon an understanding of developmental plasticity and intergenerational influences, to reducing the burden of disease particularly in low socioeconomic groups.