Prenatal programming of neuroendocrine reproductive function

It is now well recognized that the gestational environment can have long-lasting effects not only on the life span and health span of an individual but also, through potential epigenetic changes, on future generations. This article reviews the “prenatal programming” of the neuroendocrine systems that regulate reproduction, with a specific focus on the lessons learned using ovine models. The review examines the critical roles played by steroids in normal reproductive development before considering the effects of prenatal exposure to exogenous steroid hormones including androgens and estrogens, the effects of maternal nutrition and stress during gestation, and the effects of exogenous chemicals such as alcohol and environment chemicals. In so doing, it becomes evident that, to maximize fitness, the regulation of reproduction has evolved to be responsive to many different internal and external cues and that the GnRH neurosecretory system expresses a degree of plasticity throughout life. During fetal life, however, the system is particularly sensitive to change and at this time, the GnRH neurosecretory system can be “shaped” both to achieve normal sexually differentiated function but also in ways that may adversely affect or even prevent “normal function”. The exact mechanisms through which these programmed changes are brought about remain largely uncharacterized but are likely to differ depending on the factor, the timing of exposure to that factor, and the species. It would appear, however, that some afferent systems to the GnRH neurons such as kisspeptin, may be critical in this regard as it would appear to be sensitive to a wide variety of factors that can program reproductive function. Finally, it has been noted that the prenatal programming of neuroendocrine reproductive function can be associated with epigenetic changes, which would suggest that in addition to direct effects on the exposed offspring, prenatal programming could have transgenerational effects on reproductive potential

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)

Metabolic and Expression Changes Associated with a Mouse Model of Intrauterine Growth Restriction (IUGR)

Intrauterine growth restriction (IUGR) is a pregnancy condition where fetal growth is suboptimal, resulting in an infant born small for gestational age (\u3c10th percentile) and is associated with metabolic disorders such as type 2 diabetes in adulthood. This study aims to understand tissue-specific adaptations to fetal undernutrition which predispose the individual to metabolic disorders in adulthood. A model of growth restriction in mice was established using 70% of maternal ad libitum total food (g) (E6.5-birth). At weaning, male offspring received standard chow or a HFHS diet. Body weight and random blood glucose levels were measured at 6 months. To assess metabolism at 6 or 7 months, glucose tolerance, pyruvate challenge and hepatic portal vein insulin challenge tests were administered and serum peptide markers for obesity and diabetes were measured. Metabolic cages were also used at 2 and 7 months to measure activity, food intake and respiratory exchange ratios (RERs). Adult liver, adipose and skeletal muscle and fetal liver was collected for RNA sequencing. Maternal nutrient restricted (MNR) offspring were growth restricted with disproportionately smaller fetal livers. 19% of standard chow-fed MNR offspring became glucose intolerant. On an isocaloric high-fat high-sugar diet no differences in MNR growth or glucose metabolism were detected. However, RERs were reduced at all timepoints in MNR on a HFHS relative to MNR on standard chow. Differences in transcription of genes involved in hypoxia signalling were detected and HIF-2a and HIF-3a proteins were increased in fetal liver of MNR offspring. Genes differentially expressed in the fetus were not differentially expressed at 6 months. Gene expression of metabolically regulatory transcripts in liver, adipose and skeletal muscle did not differ in all MNR and glucose intolerant MNR relative to controls. This model results in a susceptible and non-susceptible population of maternal nutrient restricted offspring and supports the concept of hypoxia signalling contributing to fetal adaptations. Understanding adaptations in hepatic hypoxia signalling in response to fetal undernutrition and how they vary in susceptible and unsusceptible populations will provide insight into how fetal nutrition can influence adult metabolism

Maternal nutritional status, C1 metabolism and offspring DNA methylation: a review of current evidence in human subjects.

: Evidence is growing for the long-term effects of environmental factors during early-life on later disease susceptibility. It is believed that epigenetic mechanisms (changes in gene function not mediated by DNA sequence alteration), particularly DNA methylation, play a role in these processes. This paper reviews the current state of knowledge of the involvement of C1 metabolism and methyl donors and cofactors in maternal diet-induced DNA methylation changes in utero as an epigenetic mechanism. Methyl groups for DNA methylation are mostly derived from the diet and supplied through C1 metabolism by way of choline, betaine, methionine or folate, with involvement of riboflavin and vitamins B6 and B12 as cofactors. Mouse models have shown that epigenetic features, for example DNA methylation, can be altered by periconceptional nutritional interventions such as folate supplementation, thereby changing offspring phenotype. Evidence of early nutrient-induced epigenetic change in human subjects is scant, but it is known that during pregnancy C1 metabolism has to cope with high fetal demands for folate and choline needed for neural tube closure and normal development. Retrospective studies investigating the effect of famine or season during pregnancy indicate that variation in early environmental exposure in utero leads to differences in DNA methylation of offspring. This may affect gene expression in the offspring. Further research is needed to examine the real impact of maternal nutrient availability on DNA methylation in the developing fetus

Effects of Protein Deficiency on Perinatal and Postnatal Health Outcomes

There are a variety of environmental insults that can occur during pregnancy which cause low birth weight and poor fetal health outcomes. One such insult is maternal malnutrition, which can be further narrowed down to a low protein diet during gestation. Studies show that perinatal protein deficiencies can impair proper organ growth and development, leading to long-term metabolic dysfunction. Understanding the molecular mechanisms that underlie how this deficiency leads to adverse developmental outcomes is essential for establishing better therapeuticstrategies that may alleviate or prevent diseases in later life. This chapter reviews how perinatal protein restriction in humans and animals leads to metabolic disease, and it identifies the mechanisms that have been elucidated, to date. These include alterations in transcriptional and epigenetic mechanisms, as well as indirect means such as endoplasmic reticulum (ER) stress and oxidative stress. Furthermore, nutritional and pharmaceutical interventions are highlighted to illustrate that the plasticity of the underdeveloped organs during perinatal life can be exploited to prevent onset of long-term metabolic disease

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 role of prenatal factors in cognitive decline and dementia

Worldwide, people are living longer and the number of people living with dementia is rising. Several lifestyle factors have been identified as risk factors for premature aging, cognitive decline and dementia, including smoking, obesity and reduced social contact. As the majority of brain development occurs prenatally and brain size, structure and function are shaped by the conditions during the prenatal period, prenatal factors may also play a role.In this thesis we therefore aimed to investigate prenatal factors in relation to the later risk for cognitive decline, dementia and mortality. We systematically reviewed the evidence for the prenatal origins of dementia as well directly assessed the relationship between prenatal undernutrition and later risk for cognitive decline, dementia and mortality by using observational data from the Dutch famine birth cohort as well as Dutch registry data.Although much remains unclear regarding causal pathways and differences between the sexes, and not all studies in this thesis found evidence for increased cognitive decline and dementia after prenatal undernutrition, the overall findings in this thesis suggest that prenatal factors may play an important role in the aging process. Our findings further emphasize that prenatal exposure to war and hunger may result in negative health outcomes in the developing child decades later. For the health of future generations it is thus essential to protect unborn children and their parents in conditions of adversity. In addition, it would be of great importance to investigate how we can improve the health trajectories of those already exposed to adverse conditions in utero

Of Mouse And Methyl: An Investigation Of Methyl Donors, Methylation And Methyltransferases In The Pfc

Gaining excessive weight during pregnancy occurs in over 50% of pregnancies in the United States. This excessive weight gain can lead to development of Large for Gestational Age (LGA) babies, or babies born in the top 10% for weight class at birth. LGA babies have increased risk for neurological disorders, including autism, schizophrenia and ADHD. Our lab models excessive gestational weight gain and LGA in a mouse model by feeding dams a 60% high fat (HF) diet throughout gestation and lactation. At weaning all offspring are fed control diet for the remainder of life. HF offspring have increased preference for palatable foods, increased learning and motivation deficits, disrupted gene expression in reward system neurocircuitry and both global- and promoter-specific DNA hypomethylation within the prefrontal cortex (PFC). Dietary methyl donor nutrient supplementation (MS) during pregnancy has been shown to ameliorate some of these phenotypes in HF offspring as well as alter DNA methylation patterns. Because the PFC continues developing postnatally, we were interested in understanding whether MS given during early postnatal life (3-6 weeks) would also ameliorate behavioral and molecular phenotypes. Also, because HF offspring exhibit DNA hypomethylation throughout the brain, we were interested in whether DNA methyltransferase (DNMT) function could mediate these changes. Utilizing operant behavior training, gene and protein expression analysis and mass spectrometry we were able to answer these questions. We determined that early life MS can counteract deficits in motivation and learning in female offspring. Also that MS alters the concentrations of folate and methionine intermediates and gene expression directly after supplementation in the PFC tissue of male and female offspring. Finally, we determined that perinatal HF diet alters overall DNMT activity within the PFC without altering DNMT1 or DNMT3a expression in adult male and female offspring. This work adds to our understanding that long-term behavior and disease risk can be influenced by both maternal and early life diet. Therefore, it is important to continue study the mechanistic links between excessive gestational weight gain, perinatal HF diet exposure and MS to make better dietary recommendations that may combat disease risk