Early nutrition, epigenetics, and cardiovascular disease.

PURPOSE OF REVIEW: Here, we provide a summary of the current knowledge on the impact of early life nutrition on cardiovascular diseases that have emerged from studies in humans and experimental animal models. The involvement of epigenetic mechanisms in the Developmental Origins of Health and Disease will be discussed in relation to the implications for the heart and the cardiovascular system. RECENT FINDINGS: Environmental cues, such as parental diet and a suboptimal in utero environment can shape growth and development, causing long-lasting cardiometabolic perturbations. Increasing evidence suggest that these effects are mediated at the epigenomic level, and can be passed onto future generations. In the last decade, epigenetic mechanisms (DNA methylation, histone modifications) and RNA-based mechanisms (microRNAs, piRNAs, and tRNAs) have therefore emerged as potential candidates for mediating inheritance of cardiometabolic diseases. SUMMARY: The burden of obesity and associated cardiometabolic diseases is believed to arise through interaction between an individual's genetics and the environment. Moreover, the risk of developing poor cardiometabolic health in adulthood is defined by early life exposure to pathological cues and can be inherited by future generations, initiating a vicious cycle of transmission of disease. Elucidating the molecular triggers of such a process will help tackle and prevent the uncontrolled rise in obesity and cardiometabolic disease.Our research is supported by the Medical Research Council (MRC; MC_UU_12012/4) and the British Heart Foundation (FS/12/64/30001 and PG/14/20/30769).This is the author accepted manuscript. The final version is available from Wolters Kluwer via http://dx.doi.org/10.1097/MOL.0000000000000338

The Programming Power of the Placenta.

Size at birth is a critical determinant of life expectancy, and is dependent primarily on the placental supply of nutrients. However, the placenta is not just a passive organ for the materno-fetal transfer of nutrients and oxygen. Studies show that the placenta can adapt morphologically and functionally to optimize substrate supply, and thus fetal growth, under adverse intrauterine conditions. These adaptations help meet the fetal drive for growth, and their effectiveness will determine the amount and relative proportions of specific metabolic substrates supplied to the fetus at different stages of development. This flow of nutrients will ultimately program physiological systems at the gene, cell, tissue, organ, and system levels, and inadequacies can cause permanent structural and functional changes that lead to overt disease, particularly with increasing age. This review examines the environmental regulation of the placental phenotype with particular emphasis on the impact of maternal nutritional challenges and oxygen scarcity in mice, rats and guinea pigs. It also focuses on the effects of such conditions on fetal growth and the developmental programming of disease postnatally. A challenge for future research is to link placental structure and function with clinical phenotypes in the offspring.This is the final version of the article. It first appeared from Frontiers via https://doi.org/10.3389/fphys.2016.0003

Maternal obesity in females born small: pregnancy complications and offspring disease risk

Obesity is a major public health crisis, with 1.6 billion adults worldwide being classified as overweight or obese in 2014. Therefore, it is not surprising that the number of women who are overweight or obese at the time of conception is increasing. Obesity during pregnancy is associated with the development of gestational diabetes and preeclampsia. The developmental origins of health and disease hypothesis proposes that perturbations during critical stages of development can result in adverse fetal changes, which leads to an increased risk of developing diseases in adulthood. Of particular concern, children born to obese mothers are at a greater risk of developing cardiometabolic disease. One subset of the population who are predisposed to developing obesity are children born small for gestational age, which occurs in 10% of pregnancies worldwide. Epidemiological studies report that these growth restricted children have an increased susceptibility to type 2 diabetes, obesity and hypertension. Importantly during pregnancy, growth restricted females have a higher risk of developing cardiometabolic disease, indicating that they may have an exacerbated phenotype if they are also overweight or obese. Thus the development of early pregnancy interventions targeted to obese mothers may prevent their children from developing cardiometabolic disease in adulthood. This article is protected by copyright. All rights reserved

Programming of cardiovascular disease across the life-course.

Cardiovascular disease (CVD) is the leading cause of morbidity and mortality, affecting both developed and developing countries. Whilst it is well recognized that our risk of CVD can be determined by the interaction between our genetics and lifestyle, this only partly explains the variability at the population level. Based on these well-known risk factors, for many years, intervention and primary prevention strategies have focused on modifying lifestyle factors in adulthood. However, research shows that our risk of CVD can be pre-determined by our early life environment and this area of research is known as the Developmental Origins of Health and Disease. The aim of this review is to evaluate our current understanding of mechanisms underlying the programming of CVD. This article is part of a special issue entitled CV Aging.H.L. Blackmore is funded by the British Heart Foundation. S.E. Ozanne is a member of the MRC Metabolic Diseases Unit and funded by MRC grantMC_UU_12012/4.This is the accepted manuscript of a paper published in the Journal of Molecular and Cellular Cardiology (Blackmore HL, Ozanne SE, Journal of Molecular and Cellular Cardiology 2014, doi:10.1016/j.yjmcc.2014.12.006)

Maternal Obesity and the Fetal Origins of the Metabolic Syndrome

Over recent decades there has been a rapid rise in metabolic disorders throughout the world. Whilst lifestyle and societal habits have contributed to the obesity epidemic, there is now increasing evidence that the early developmental environment of an infant can play a pivotal role in the ‘programming’ of an adverse physiological phenotype in later life. Clinical evidence highlights that maternal over-nutrition and/or obesity during pregnancy presents not only adverse effects on maternal health, but also persistent and deleterious effects in the developing child. Animal models are providing essential information into the underlying cellular and molecular mechanisms that contribute to this adverse phenotype. The use of this information will aid our understanding of the programming signals related to maternal and paternal over-nutrition and the improved healthcare for both mother and infant

Long-Term Effects of the Periconception Period on Embryo Epigenetic Profile and Phenotype: The Role of Stress and How This Effect Is Mediated

Stress represents an unavoidable aspect of human life, and pathologies associated with dysregulation of stress mechanisms - particularly psychiatric disorders - represent a significant global health problem. While it has long been observed that levels of stress experienced in the periconception period may greatly affect the offspring's risk of psychiatric disorders, the mechanisms underlying these associations are not yet comprehensively understood. In order to address this question, this chapter will take a 'top-down' approach, by first defining stress and associated concepts, before exploring the mechanistic basis of the stress response in the form of the hypothalamic-pituitary-adrenal (HPA) axis, and how dysregulation of the HPA axis can impede our mental and physical health, primarily via imbalances in glucocorticoids (GCs) and their corresponding receptors (GRs) in the brain. The current extent of knowledge pertaining to the impact of stress on developmental programming and epigenetic inheritance is then extensively discussed, including the role of chromatin remodelling associated with specific HPA axis-related genes and the possible role of regulatory RNAs as messengers of environmental stress both in the intrauterine environment and across the germ line. Furthering our understanding of the role of stress on embryonic development is crucial if we are to increase our predictive power of disease risk and devise-effective treatments and intervention strategies

Early life origins of metabolic disease: Developmental programming of hypothalamic pathways controlling energy homeostasis.

A wealth of animal and human studies demonstrate that perinatal exposure to adverse metabolic conditions - be it maternal obesity, diabetes or under-nutrition - results in predisposition of offspring to develop obesity later in life. This mechanism is a contributing factor to the exponential rise in obesity rates. Increased weight gain in offspring exposed to maternal obesity is usually associated with hyperphagia, implicating altered central regulation of energy homeostasis as an underlying cause. Perinatal development of the hypothalamus (a brain region key to metabolic regulation) is plastic and sensitive to metabolic signals during this critical time window. Recent research in non-human primate and rodent models has demonstrated that exposure to adverse maternal environments impairs the development of hypothalamic structure and consequently function, potentially underpinning metabolic phenotypes in later life. This review summarizes our current knowledge of how adverse perinatal environments program hypothalamic development and explores the mechanisms that could mediate these effects.SEO receives funding from the British Heart Foundation and is a member of the MRC Metabolic Diseases Unit. LD is a Sir Henry Wellcome Post-Doctoral Fellow.This is the author accepted manuscript. The final version is available from Elsevier via http://dx.doi.org/10.1016/j.yfrne.2015.08.00

Fetal programming and lactation: modulating gene expression in response to undernutrition during intrauterine life

Adverse environmental conditions during intrauterine life, known as fetal programming, significantly contribute to the development of diseases in adulthood. Fetal programming induced by factors like maternal undernutrition leads to low birth weight and increases the risk of cardiometabolic diseases. Methods, We studied a rat model of maternal undernutrition during gestation (MUN) to investigate gene expression changes in cardiac tissue using RNA-sequencing of day 0–1 litters. Moreover, we analyzed the impact of lactation at day 21, in MUN model and cross-fostering experiments, on cardiac structure and function assessed by transthoracic echocardiography, and gene expression changes though qPCR. Results, Our analysis identified specific genes with altered expression in MUN rats at birth. Two of them, Agt and Pparg, stand out for being associated with cardiac hypertrophy and fibrosis. At the end of the lactation period, MUN males showed increased expression of Agt and decreased expression of Pparg, correlating with cardiac hypertrophy. Cross-fostering experiments revealed that lactation with control breastmilk mitigated these expression changes reducing cardiac hypertrophy in MUN males. Conclusions Our findings highlight the interplay between fetal programming, gene expression, and cardiac hypertrophy suggesting that lactation period is a potential intervention window to mitigate the effects of fetal programming. Impact Heart remodeling involves the alteration of several groups of genes and lactation period plays a key role in establishing gene expression modification caused by fetal programming. We could identify expression changes of relevant genes in cardiac tissue induced by undernutrition during fetal life We expose the contribution of the lactation period in modulating the expression of Agt and Pparg, relevant genes associated with cardiac hypertrophy. This evidence reveal lactation as a crucial intervention window for preventing or countering fetal programmingThis research was funded by Ministerio de Ciencia, Innovación y Universidades from Spain (grant number RTI2018-097504-B-I00), Instituto de Salud Carlos III (ISCIII) (grant number PI20/00306) with co-funding from the European Regional Development Fund (ERDF) “A way to build Europe”. R.G.B. was supported by the UAM and the MCNU FPU program (FPU19/01774) and A.S. by Universidad Francisco de Vitori