Role In Fetal Programming Research Articles

Employing Multi-Omics Analyses to Understand Changes during Kidney Development in Perinatal Interleukin-6 Animal Model.

Chronic kidney disease (CKD) is a leading cause of morbidity and mortality globally. Maternal obesity during pregnancy is linked to systemic inflammation and elevated levels of the pro-inflammatory cytokine interleukin-6 (IL-6). In our previous work, we demonstrated that increased maternal IL-6 during gestation impacts intrauterine development in mice. We hypothesized that IL-6-induced inflammation alters gene expression in the developing fetus. To test this, pregnant mice were administered IL-6 or saline during mid-gestation. Newborn mouse kidneys were analyzed using mRNA-seq, miRNA-seq and whole-genome bisulfite-seq (WGBS). A multi-omics approach was employed to quantify mRNA gene expression, miRNA expression and DNA methylation, using advanced bioinformatics and data integration techniques. Our analysis identified 19 key genes present in multiple omics datasets, regulated by epigenetics and miRNAs. We constructed a regulatory network for these genes, revealing disruptions in pathways such as Mannose type O-glycan biosynthesis, the cell cycle, apoptosis and FoxO signaling. Notably, the Atp7b gene was regulated by DNA methylation and miR-223 targeting, whereas the Man2a1 gene was controlled by DNA methylation affecting energy metabolism. These findings suggest that these genes may play a role in fetal programming, potentially leading to CKD later in life due to gestational inflammation.

Impact of Ionizing Radiation Exposure on Placental Function and Implications for Fetal Programming.

Accidental exposure to high-dose radiation while pregnant has shown significant negative effects on the developing fetus. One fetal organ which has been studied is the placenta. The placenta performs all essential functions for fetal development, including nutrition, respiration, waste excretion, endocrine communication, and immunological functions. Improper placental development can lead to complications during pregnancy, as well as the occurrence of intrauterine growth-restricted (IUGR) offspring. IUGR is one of the leading indicators of fetal programming, classified as an improper uterine environment leading to the predisposition of diseases within the offspring. With numerous studies examining fetal programming, there remains a significant gap in understanding the placenta's role in irradiation-induced fetal programming. This review aims to synthesize current knowledge on how irradiation affects placental function to guide future research directions. This review provides a comprehensive overview of placental biology, including its development, structure, and function, and summarizes the placenta's role in fetal programming, with a focus on the impact of radiation on placental biology. Taken together, this review demonstrates that fetal radiation exposure causes placental degradation and immune function dysregulation. Given the placenta's crucial role in fetal development, understanding its impact on irradiation-induced IUGR is essential.

Maternal-Periconceptional Vitamin B12 Deficiency in Wistar Rats Leads to Sex-Specific Programming for Cardiometabolic Disease Risk in the Next Generation

BackgroundMaternal vitamin B12 deficiency plays a vital role in fetal programming, as corroborated by previous studies on murine models and longitudinal human cohorts. ObjectivesThis study assessed the effects of diet-induced maternal vitamin B12 deficiency on F1 offspring in terms of cardiometabolic health and normalization of these effects by maternal-periconceptional vitamin B12 supplementation. MethodsA diet-induced maternal vitamin B12 deficient Wistar rat model was generated in which female rats were either fed a control AIN-76A diet (with 0.01 g/kg vitamin B12) or the same diet with vitamin B12 removed. Females from the vitamin B12-deficient group were mated with males on the control diet. A subset of vitamin B12-deficient females was repleted with vitamin B12 on day 1 of conception. The offspring in the F1 generation were assessed for changes in body composition, plasma biochemistry, and molecular changes in the liver. A multiomics approach was used to obtain a mechanistic insight into the changes in the offspring liver. ResultsWe showed that a 36% reduction in plasma vitamin B12 levels during pregnancy in F0 females can lead to continued vitamin B12 deficiency (60%–70% compared with control) in the F1 offspring and program them for cardiometabolic adversities. These adversities, such as high triglycerides and low high-density lipoprotein cholesterol, were seen only among F1 males but not females. DNA methylome analysis of the liver of F1 3-mo-old offspring highlights sexual dimorphism in the alteration of methylation status of genes critical to signaling processes. Proteomics and targeted metabolomics analysis confirm that sex-specific alterations occur through modulations in PPAR signaling and steroid hormone biosynthesis pathway. Repletion of deficient mothers with vitamin B12 at conception normalizes most of the molecular and biochemical changes. ConclusionsMaternal vitamin B12 deficiency has a programming effect on the next generation and increases the risk for cardiometabolic syndrome in a sex-specific manner. Normalization of the molecular risk markers on vitamin B12 supplementation indicates a causal role.

P07-002-23 Sucralose Consumption During Pregnancy Alters Birthweight, Insulin, and Markers of Systemic Inflammation in Neonates: Evidence of Sucralose Role in Fetal Programming

P07-002-23 Sucralose Consumption During Pregnancy Alters Birthweight, Insulin, and Markers of Systemic Inflammation in Neonates: Evidence of Sucralose Role in Fetal Programming

Insulin Resistance, Compensatory Hyperinsulinemia and its Role in Fetal Programming of Polycystic Ovarian Syndrome.

Insulin Resistance, Compensatory Hyperinsulinemia and its Role in Fetal Programming of Polycystic Ovarian Syndrome.

Oxidative stress as a shared mechanisms for different prenatal stressors: long-term effects on adolescent male and female mouse offspring

IntroductionStressful experiences in utero can produce physiological changes which become embedded biological traces affecting fetal brain development and ultimately leading to increased vulnerability for psychiatric disorders.ObjectivesWe hypothesized that stressors as diverse as maternal obesity and maternal psychophysical stress might disrupt fetal programming resulting in long-lasting effects on offspring brain development by acting through shared oxidative stress (OS)-mediated mechanisms.MethodsWe compared a mouse model (C57Bl/6N) of maternal high-fat diet (HFD) consumption (13 weeks, until delivery) to prenatal restraint stress (PNS) repeatedly administered during the last week of pregnancy. To counteract the negative effects of both stressors, the antioxidant N-acetyl-cysteine (NAC, 1 g/kg) was administered to female breeders for 8 weeks until delivery. Emotionality was assessed in adolescent male and female offspring through the elevated-plus-maze (EPM). Moreover, hippocampal gene expression levels of Brain-Derived-Neurotrophic-Factor (Bdnf ), Nuclear factor erythroid 2–related factor 2 (Nrf-2) and Kelch-like ECH-associated protein 1 (Keap-1) were measured, by qPCR, as markers of brain plasticity and antioxidant capacity.ResultsPrenatal exposure to both HFD and PNS enhanced behavioral disinhibition, increasing time spent in the open arms of the EPM and decreasing the frequency of risk-assessment behaviors, especially in female offspring. Moreover, both prenatal stressors led to decreased Bdnf (in females) and Nrf-2 levels, and disrupted Keap-1 levels. Prenatal NAC was able to counteract these effects on the brain.ConclusionsOur data support the hypothesis of a “funnel effect” model explaining how different prenatal stressors result in long-term negative effects on the adolescent offspring, increasing risk assessment behaviors and affecting brain plasticity and antioxidant defenses. The beneficial preventive effects of NAC suggest that OS may be a common mechanism, playing a pivotal role in fetal programming of mental disorders. ERANET-NEURON-JTC-2018-Mental Disorders-“EMBED” and Bando Ricerca Indipendente ISS 2021-2023; MOMINFLAM. Unique signatures underlying placental-fetal brain crosstalk in maternal obesity to F Cirulli.Disclosure of InterestNone Declared

213 from Conception to Birth: The Role of Minerals on Beef Cattle Fetal Programming

Abstract Fetal adaptations to nutrition in utero lead to long-term effects on fetal growth and postnatal performance. Although required in minute amounts, minerals play an essential role in fetal programming, likely through epigenetic mechanisms. Thus, changes in the embryonic and fetal epigenome modulate gene transcription and, consequently, the differentiation, growth, and development of cells and tissues. Despite the growing knowledge in nutritional epigenetics and gene expression, literature on the implications of minerals on the (epi)genome and fetal development is still scarce. Our research investigates fetal and postnatal offspring outcomes in response to maternal nutrition throughout the periconceptual period of pregnancy using a beef cattle model. We have reported placental adaptations through changes in gene expression in beef heifers supplemented with vitamins and minerals (113 g•heifer-1•d-1) during the first 83 days of pregnancy. We found coordinated crosstalk between fetal-maternal tissues and a fine-tuned regulation of placental genes involved with nutrient transport, tissue function and differentiation. Interestingly, the concentrations of minerals and amino acids in the allantoic and amniotic fluids and maternal serum were also affected. Furthermore, genes were differentially expressed in the fetal brain, liver, and muscle in response to the maternal diet. The nutrient-sensing PI3K-Akt signaling pathway was over-represented in muscle and cerebrum, whereas mineral and lipid metabolism were identified in the liver. A second study showed that providing supranutritional maternal selenium supplementation (105 mg of Se/wk as Se yeast) during different trimesters of gestation increased Se concentration in the whole blood and muscle of newborn calves. Likewise, calves born to dams supplemented in the last trimester had increased expression of myogenic genes. Altogether, these findings reinforce the implications of maternal nutrition during pregnancy on fetal programming. However, further studies are still required to understand the regulatory mechanisms and postnatal effects.

Epigenetics Beyond Fetal Growth Restriction: A Comprehensive Overview.

Fetal growth restriction is a pathological condition occurring when the fetus does not reach the genetically determined growth potential. The etiology of fetal growth restriction is expected to be multifactorial and include fetal, maternal, and placental factors, the latter being the most frequent cause of isolated fetal growth restriction. Severe fetal growth restriction has been related to both an increased risk of perinatal morbidity and mortality, and also a greater susceptibility to developing diseases (especially cardio-metabolic and neurologicaldisorders) later in life. In the last decade, emerging evidence has supported the hypothesis of the Developmental Origin of Health and Disease, which states that individual developmental 'programming' takes place via a delicate fine tuning of fetal genetic and epigenetic marks in response to a large variety of 'stressor' exposures during pregnancy. As the placenta is the maternal-fetal interface, it has a crucial role in fetal programming, such that any perturbation altering placental function interferes with both in-utero fetal growth and also with the adult life phenotype. Several epigenetic mechanisms have been highlighted in modulating the dynamic placental epigenome, including alterations in DNA methylation status, post-translational modification of histones, and non-coding RNAs. This review aims to provide a comprehensive and critical overview of the available literature on the epigenetic background of fetal growth restriction. A targeted research strategy was performed using PubMed, MEDLINE, Embase, and The Cochrane Library up to January 2022. A detailed and fully referenced synthesis of available literature following the Scale for the Assessment of Narrative Review Articles guidelines is provided. A variety of epigenetic marks predominantly interfering with placental development, function, and metabolism were found to be potentially associated with fetal growth restriction. Available evidence on the role of environmental exposures in shaping the placental epigenome and the fetal phenotype were also critically discussed. Because of the highly dynamic crosstalk between epigenetic mechanisms and the extra level of complexity in interpreting the final placental transcriptome, a full comprehension of these phenomenon is still lacking and advances in multi-omics approaches are urgently needed. Elucidating the role of epigenetics in the developmental origins of health and disease represents a new challenge for the coming years, with the goal of providing early interventions and prevention strategies and, hopefully, new treatment opportunities.

The role of fetal programming in human carcinogenesis - May the Barker hypothesis explain interindividual variability in susceptibility to cancer insurgence and progression?

The growing incidence of cancers is pushing oncologists to find out new explanations other than the somatic mutation theory, based on the accumulation of DNA mutations. In particular, the embryo-fetal exposure to an increasing number of environmental factors during gestation might represent a trigger able to influence the susceptibility of the newborn to develop cancer later in life. This idea agrees with the fetal programming theory, also known as the Barker hypothesis. Here the role of insulin-like growth factors, thymosin beta-4, and epigenome are discussed as mediators of cancer in prenatal human development. The role of epigenetic factors that during gestation increase the predisposition to develop cancer and the similarities in the gene expression (like MMP9, OPN, TP53 and CDKN2A) between embryonic development and cancer are key factors. Likewise, maternal obesity might be able to re-program embryo-fetal development with long-term changes, including an increased risk to develop neuroblastoma and acute leukemia. Birth weight alone and birth weight corrected for gestational age are proposed as important variables capable of predicting the vulnerability to develop cancers. According to the findings here reported, we hypothesize that cancer prevention should start during gestation by improving the quality of maternal diet. In conclusion, the Barker hypothesis should be applied to cancer as well. Therefore, the identification of the epigenetic factors of cancer appears mandatory, so that the cancer prevention might start in the womb before birth.

Prenatal Air Pollution Exposure and Placental DNA Methylation Changes: Implications on Fetal Development and Future Disease Susceptibility.

The Developmental Origins of Health and Disease (DOHaD) concept postulates that in utero exposures influence fetal programming and health in later life. Throughout pregnancy, the placenta plays a central role in fetal programming; it regulates the in utero environment and acts as a gatekeeper for nutrient and waste exchange between the mother and the fetus. Maternal exposure to air pollution, including heavy metals, can reach the placenta, where they alter DNA methylation patterns, leading to changes in placental function and fetal reprogramming. This review explores the current knowledge on placental DNA methylation changes associated with prenatal air pollution (including heavy metals) exposure and highlights its effects on fetal development and disease susceptibility. Prenatal exposure to air pollution and heavy metals was associated with altered placental DNA methylation at the global and promoter regions of genes involved in biological processes such as energy metabolism, circadian rhythm, DNA repair, inflammation, cell differentiation, and organ development. The altered placental methylation of these genes was, in some studies, associated with adverse birth outcomes such as low birth weight, small for gestational age, and decreased head circumference. Moreover, few studies indicate that DNA methylation changes in the placenta were sex-specific, and infants born with altered placental DNA methylation patterns were predisposed to developing neurobehavioral abnormalities, cancer, and atopic dermatitis. These findings highlight the importance of more effective and stricter environmental and public health policies to reduce air pollution and protect human health.

106 The Effects of Fetal Programming on Offspring Pancreas DNA Methylation

Abstract It has been well documented that fetal programming, caused by changes to the maternal environment during pregnancy, can impact the overall health and growth of the offspring in livestock and non-livestock species alike. These effects are observed in the F1 offspring as well as across subsequent generations; however, the mechanisms by which this occurs are still poorly understood. Epigenetics is one of the many mechanisms that is hypothesized to have a role in fetal programming and may be mediating the observed effects across multiple generations. It has been demonstrated by others that DNA methylation patterns can be altered by an individuals’ diet and that the pancreas is vulnerable to the effects of fetal programming. Therefore, we evaluated the effects of poor maternal nutrition during gestation on the pancreas tissue of lambs. We have demonstrated that maternal under- or overnutrition during gestation alters the DNA methylation patterns of the offspring pancreas tissue with these effects being diet dependent and sex specific. We have also begun evaluating the effects of maternal diet in murine models using whole-genome bisulfite sequencing to compare species differences and determine if there are any changes conserved across species. This will allow us to focus on a smaller number of critical factors in individuals as they age and across multiple generations in livestock species such as sheep and cattle. From these data we will be able to elucidate the role DNA methylation has in mediating the effects of maternal programming in the pancreas tissue.

Betamethasone administration during pregnancy is associated with placental epigenetic changes with implications for inflammation

BackgroundGlucocorticoids (GCs) play a pivotal role in fetal programming. Antenatal treatment with synthetic GCs (sGCs) in individuals in danger of preterm labor is common practice. Adverse short- and long-term effects of antenatal sGCs have been reported, but their effects on placental epigenetic characteristics have never been systematically studied in humans.ResultsWe tested the association between exposure to the sGC betamethasone (BET) and placental DNA methylation (DNAm) in 52 exposed cases and 84 gestational-age-matched controls. We fine-mapped associated loci using targeted bisulfite sequencing. The association of placental DNAm with gene expression and co-expression analysis on implicated genes was performed in an independent cohort including 494 placentas. Exposure to BET was significantly associated with lower placenta DNAm at an enhancer of FKBP5. FKBP5 (FK506-binding protein 51) is a co-chaperone that modulates glucocorticoid receptor activity. Lower DNAm at this enhancer site was associated with higher expression of FKBP5 and a co-expressed gene module. This module is enriched for genes associated with preeclampsia and involved in inflammation and immune response.ConclusionsOur findings suggest that BET exposure during pregnancy associates with few but lasting changes in placental DNAm and may promote a gene expression profile associated with placental dysfunction and increased inflammation. This may represent a pathway mediating GC-associated negative long-term consequences and health outcomes in offspring.

Lasting Effects of Low to Non-Lethal Radiation Exposure during Late Gestation on Offspring's Cardiac Metabolism and Oxidative Stress.

Ionizing radiation (IR) is known to cause fetal programming, but the physiological effects of low-dose IR are not fully understood. This study examined the effect of low (50 mGy) to non-lethal (300 and 1000 mGy) radiation exposure during late gestation on cardiac metabolism and oxidative stress in adult offspring. Pregnant C57BL/6J mice were exposed to 50, 300, or 1000 mGy of gamma radiation or Sham irradiation on gestational day 15. Sixteen weeks after birth, 18F-Fluorodeoxyglucose (FDG) uptake was examined in the offspring using Positron Emission Tomography imaging. Western blot was used to determine changes in oxidative stress, antioxidants, and insulin signaling related proteins. Male and female offspring from irradiated dams had lower body weights when compared to the Sham. 1000 mGy female offspring demonstrated a significant increase in 18F-FDG uptake, glycogen content, and oxidative stress. 300 and 1000 mGy female mice exhibited increased superoxide dismutase activity, decreased glutathione peroxidase activity, and decreased reduced/oxidized glutathione ratio. We conclude that non-lethal radiation during late gestation can alter glucose uptake and increase oxidative stress in female offspring. These data provide evidence that low doses of IR during the third trimester are not harmful but higher, non-lethal doses can alter cardiac metabolism later in life and sex may have a role in fetal programming.

Prenatal stress effects on offspring brain and behavior: Mediators, alterations and dysregulated epigenetic mechanisms

Prenatal environment significantly influences mammalian fetal development and adverse in utero conditions have life-long consequences for the offspring health. Research has revealed that a wide variety of prenatal stress factors lead to increased risk of vulnerability to neuropsychiatric disorders in the individuals. Multiple mediators are involved in stress transfer from mother to the developing fetus, with stress hormone cortisol being a chief player. Further, the developmental programming effects of prenatal stress have been observed in the form of alterations in the offspring brain at different levels. This review covers stress transfer mediators such as cortisol, serotonin, maternal cytokines, reactive oxygen species (ROS) and the maternal microbiota, and their role in fetal programming. Prenatal stress leads to alterations in the offspring brain at multiple levels, from molecular and cellular to structural. These alterations eventually result in lasting phenotypic alterations such as in the offspring behavior and cognition. Different brain alterations induced by prenatal stress such as in neural pruning processes, neural circuit formation, brain structural connectivity and epigenetic systems regulating neural gene expression are under focus in the second part of the review. The latter constitutes a key molecular mechanism involved in prenatal stress effects and has been discussed in more detail.

The Role of Magnesium in Pregnancy and in Fetal Programming of Adult Diseases

Magnesium is an essential trace metal and a necessary factor for multiple biochemical functions in humans. Its role in biology is fundamental in over 600 enzymatic reactions implicated in protein synthesis, mitochondrial functions, neuromuscular activity, bone formation, and immune system competence. Magnesium status is relevant in fetal development during gestation and in the newborn growth during the perinatal period. Moreover, magnesium is able to influence fetal programming and disease presentation in childhood or adulthood. The aim of this review is to focus on this metal homeostasis, analyzing its normal values, the causes of hypomagnesemia, the interaction with drugs and other conditions, and the diseases associated with magnesium value alteration during pregnancy, in order to study its role in fetal programming of adult diseases. The data here reported clearly indicated the existence of a connection between magnesium status and human pathology starting from intrauterine life and extending into childhood and adulthood.

Dysregulated hypothalamic-pituitary-adrenal axis function in healthy participants visually dependent in postural control

Background Adipocytokines may play a role in fetal programming of neurodevelopment. We aimed to investigate the associations between cord blood adipocytokine concentrations and children’s intelligence test scores.Methods We used data from two ongoing pregnancy cohorts in North America: the Maternal-Infant Research on Environmental Chemicals (MIREC, n = 429) and Health Outcomes and Measures of the Environment (HOME, n = 183) Studies. Umbilical cord blood adipocytokine concentrations were measured using enzyme-linked immunosorbent assays. We assessed children’s Intelligence Quotient (IQ) and its components using the Wechsler Preschool and Primary Scales of Intelligence-III or Wechsler Intelligence Scale for Children-IV. We used linear regression and linear mixed models to estimate associations between log2-transformed adipocytokine concentrations and children’s IQ after adjusting for sociodemographic, perinatal, and child factors.Results After adjusting for covariates, cord blood adiponectin was positively associated with children’s full-scale IQ scores at age 3 years in the MIREC Study (β = 1.4, 95% confidence interval [CI]: 0.2, 2.5) and at ages 5 and 8 years in the HOME Study (β = 1.7, CI: −0.1, 3.5). Adiponectin was positively associated with performance IQ in both studies (MIREC: β = 2.0, CI: 0.7, 3.3; HOME: β = 2.2, CI: 0.5, 3.9). Adiponectin was positively associated with working memory composite scores at age 8 in the HOME Study (β = 3.1, CI: 1.0, 5.2). Leptin was not associated with children’s IQ in either study.Conclusions Cord blood adiponectin was associated with higher full-scale and performance IQ and working memory composite scores in children. Future studies are needed to explore the mechanisms underlying these associations.

The body-oriented therapy has positive effect on executive abilities in children with attention deficit

Background Adipocytokines may play a role in fetal programming of neurodevelopment. We aimed to investigate the associations between cord blood adipocytokine concentrations and children’s intelligence test scores.Methods We used data from two ongoing pregnancy cohorts in North America: the Maternal-Infant Research on Environmental Chemicals (MIREC, n = 429) and Health Outcomes and Measures of the Environment (HOME, n = 183) Studies. Umbilical cord blood adipocytokine concentrations were measured using enzyme-linked immunosorbent assays. We assessed children’s Intelligence Quotient (IQ) and its components using the Wechsler Preschool and Primary Scales of Intelligence-III or Wechsler Intelligence Scale for Children-IV. We used linear regression and linear mixed models to estimate associations between log2-transformed adipocytokine concentrations and children’s IQ after adjusting for sociodemographic, perinatal, and child factors.Results After adjusting for covariates, cord blood adiponectin was positively associated with children’s full-scale IQ scores at age 3 years in the MIREC Study (β = 1.4, 95% confidence interval [CI]: 0.2, 2.5) and at ages 5 and 8 years in the HOME Study (β = 1.7, CI: −0.1, 3.5). Adiponectin was positively associated with performance IQ in both studies (MIREC: β = 2.0, CI: 0.7, 3.3; HOME: β = 2.2, CI: 0.5, 3.9). Adiponectin was positively associated with working memory composite scores at age 8 in the HOME Study (β = 3.1, CI: 1.0, 5.2). Leptin was not associated with children’s IQ in either study.Conclusions Cord blood adiponectin was associated with higher full-scale and performance IQ and working memory composite scores in children. Future studies are needed to explore the mechanisms underlying these associations.

Associations of cord blood leptin and adiponectin with children’s cognitive abilities

Background Adipocytokines may play a role in fetal programming of neurodevelopment. We aimed to investigate the associations between cord blood adipocytokine concentrations and children’s intelligence test scores.Methods We used data from two ongoing pregnancy cohorts in North America: the Maternal-Infant Research on Environmental Chemicals (MIREC, n = 429) and Health Outcomes and Measures of the Environment (HOME, n = 183) Studies. Umbilical cord blood adipocytokine concentrations were measured using enzyme-linked immunosorbent assays. We assessed children’s Intelligence Quotient (IQ) and its components using the Wechsler Preschool and Primary Scales of Intelligence-III or Wechsler Intelligence Scale for Children-IV. We used linear regression and linear mixed models to estimate associations between log2-transformed adipocytokine concentrations and children’s IQ after adjusting for sociodemographic, perinatal, and child factors.Results After adjusting for covariates, cord blood adiponectin was positively associated with children’s full-scale IQ scores at age 3 years in the MIREC Study (β = 1.4, 95% confidence interval [CI]: 0.2, 2.5) and at ages 5 and 8 years in the HOME Study (β = 1.7, CI: −0.1, 3.5). Adiponectin was positively associated with performance IQ in both studies (MIREC: β = 2.0, CI: 0.7, 3.3; HOME: β = 2.2, CI: 0.5, 3.9). Adiponectin was positively associated with working memory composite scores at age 8 in the HOME Study (β = 3.1, CI: 1.0, 5.2). Leptin was not associated with children’s IQ in either study.Conclusions Cord blood adiponectin was associated with higher full-scale and performance IQ and working memory composite scores in children. Future studies are needed to explore the mechanisms underlying these associations.

Implication of Oxidative Stress in Fetal Programming of Cardiovascular Disease.

Lifestyle and genetic background are well known risk factors of cardiovascular disease (CVD). A third contributing factor is suboptimal fetal development, due to nutrient or oxygen deprivation, placental insufficiency, or exposure to toxic substances. The fetus adapts to adverse intrauterine conditions to ensure survival; the immediate consequence is low birth weight (LBW) and the long-term effect is an increased susceptibility to develop CVD in adult life. This process is known as Developmental Origins of Health and Disease (DOHaD) or fetal programming of CVD. The influence of fetal life for the future cardiovascular health of the individual has been evidenced by numerous epidemiologic studies in populations suffering from starvation during intrauterine life. Furthermore, experimental animal models have provided support and enabled exploring the underlying mechanisms. Oxidative stress seems to play a central role in fetal programming of CVD, both in the response of the feto-placental unit to the suboptimal intrauterine environment and in the alterations of physiologic systems of cardiovascular control, ultimately leading to disease. This review aims to summarize current knowledge on the alterations in oxidative balance in response to fetal stress factors covering two aspects. Firstly, the evidence from human studies of the implication of oxidative stress in LBW induced by suboptimal conditions during intrauterine life, emphasizing the role of the placenta. In the second part we summarize data on specific redox alterations in key cardiovascular control organs induced by exposure to known stress factors in experimental animals and discuss the emerging role of the mitochondria.

Diet-induced obesity alters the maternal metabolome and early placenta transcriptome and decreases placenta vascularity in the mouse.

Maternal obesity is associated with an increased risk of obesity and metabolic disease in offspring. Increasing evidence suggests that the placenta plays an active role in fetal programming. In this study, we used a mouse model of diet-induced obesity to demonstrate that the abnormal metabolic milieu of maternal obesity sets the stage very early in pregnancy by altering the transcriptome of placenta progenitor cells in the preimplantation (trophectoderm [TE]) and early postimplantation (ectoplacental cone [EPC]) placenta precursors, which is associated with later changes in placenta development and function. Sphingolipid metabolism was markedly altered in the plasma of obese dams very early in pregnancy as was expression of genes related to sphingolipid processing in the early placenta. Upregulation of these pathways inhibits angiogenesis and causes endothelial dysfunction. The expression of many other genes related to angiogenesis and vascular development were disrupted in the TE and EPC. Other key changes in the maternal metabolome in obese dams that are likely to influence placenta and fetal development include a marked decrease in myo and chiro-inositol. These early metabolic and gene expression changes may contribute to phenotypic changes in the placenta, as we found that exposure to a high-fat diet decreased placenta microvessel density at both mid and late gestation. This is the first study to demonstrate that maternal obesity alters the transcriptome at the earliest stages of murine placenta development.