Undernutrition and hyperandrogenism during pregnancy: Role in programming of cardiovascular disease and infertility

Maternal nutritional status programs the development of several systems in female offspring, with effects that depend on the severity, duration, and window of development when the nutritional perturbation is imposed. On the basis of the developmental origins of health and disease concept, we hypothesize that gestational low caloric intake may induce maternal subclinical hyperandrogenism during early pregnancy and compromise cardiovascular health and fertility in the female offspring. To examine this possibility, a literature search for human and animal studies was conducted using two electronic databases, PubMed and Cochrane until April 2019 to address the following questions: (a) Do androgens have a developmental role in cardiovascular and ovarian development? (b) Is excess maternal testosterone linked to cardiovascular disease and infertility? and (c) Could early pregnancy undernutrition enhance maternal androgen production and compromise health and fertility in female offspring? The observations reviewed, establish a potential causative link between maternal undernutrition and subclinical hyperandrogenism with hypertension and reduced ovarian reserve in the progeny. Further studies in appropriate models are needed to better understand whether low energy intake and subclinical maternal hyperandrogenism during early pregnancy can negatively affect the health of the female offspring.     

Models of Intrauterine growth restriction and fetal programming in rabbits

Intrauterine growth restriction (IUGR) affects approximately 10% of human pregnancies globally and has immediate and life‐long consequences for offspring health. However, the mechanisms underlying the pathogenesis of IUGR and its association with later health and disease outcomes are poorly understood. To address these knowledge gaps, the use of experimental animals is critically important. Since the 50's different environmental, pharmacological, and surgical manipulations have been performed in the rabbit to improve our knowledge of the control of fetal growth, fetal responses to IUGR, and mechanisms by which offspring may be programmed by an adverse gestational environment. The purpose of this review is therefore to summarize the utility of the rabbit as a model for IUGR research. It first summarizes the knowledge of prenatal and postnatal development in the rabbit and how these events relate to developmental milestones in humans. It then describes the methods used to induce IUGR in rabbits and the knowledge gained about the mechanisms determining prenatal and postnatal outcomes of the offspring. Finally, it discusses the application of state of the art approaches in the rabbit, including high‐resolution ultrasound, magnetic resonance imaging, and gene targeting, to gain a deeper integrative understanding of the physiological and molecular events governing the development of IUGR. Overall, we hope to engage and inspire investigators to employ the rabbit as a model organism when studying pregnancy physiology so that we may advance our understanding of mechanisms underlying IUGR and its consequences in humans and other mammalian species.     

Fetal programming of neuropsychiatric disorders

Starting from the Developmental Origins of Health and Disease (DOHaD) hypotheses proposed by David Barker, namely fetal programming, in the past years, there is a growing evidence of the major role played by epigenetic factors during the intrauterine life and the perinatal period. Furthermore, it has been assessed that these factors can affect the health status in infancy and even in adulthood. In this review, we focus our attention on the fetal programming of the brain, analyzing the most recent literature concerning the epigenetic factors that can influence the development of neuropsychiatric disorders such as bipolar disorders, major depressive disorders, and schizophrenia. The perinatal epigenetic factors have been divided in two main groups: maternal factors and fetal factors. The maternal factors include diet, smoking, alcoholism, hypertension, malnutrition, trace elements, stress, diabetes, substance abuse, and exposure to environmental toxicants, while the fetal factors include hypoxia/asphyxia, placental insufficiency, prematurity, low birth weight, drugs administered to the mother or to the baby, and all factors causing intrauterine growth restriction. A better comprehension of the possible mechanisms underlying the pathogenesis of these diseases may help researchers and clinicians develop new diagnostic tools and treatments to offer these patients a tailored medical treatment strategy to improve their quality of life. Birth Defects Research (Part C) 108:207–223, 2016. © 2016 Wiley Periodicals, Inc.     

Microbial exposure during early human development primes fetal immune cells

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口腔微生物群和人体健康

口腔微生物群作为人体微生物群的重要组成部分,其与人体健康之间的关系已成为各领域研究的焦点。口腔微生物群种类繁多、组成复杂,涵盖了细菌、真菌、古细菌和病毒等。近年来的研究显示,口腔微生物群的组成和比例与人体健康密切相关,会影响口腔疾病如龋齿、牙周病的发生。同时口腔微生物也是全身系统性疾病如肺炎、肿瘤和糖尿病等发生的危险因素之一。大量研究认为,口腔微生物群组成的改变、口腔微生物群之间的相互作用对疾病的发生有协同促进作用。本文聚焦于口腔微生物群的组成相关研究、口腔微生物组的最新进展,并对其与人体健康之间的关系进行综述。     

Entangled lives: Implications of the developmental origins of health and disease hypothesis for bioarchaeology and the life course

Epidemiological research since the 1980s has highlighted the consequences of early life adversity, particularly during gestation and early infancy, for adult health (the “Barker hypothesis”). The fast‐evolving field of molecular epigenetics is providing explanatory mechanisms concerning phenotypic plasticity in response to developmental stressors and the accumulation of disease risk throughout life. In addition, there is now evidence for the heritability of poor health across generations via epigenetic modifications. This research has the potential to invoke a paradigmatic shift in how we interpret factors such as growth insults and immune response in past skeletal remains. It demonstrates that health cannot be understood in terms of immediate environmental circumstances alone. Furthermore, it requires both a theoretical and practical re‐evaluation of disease biographies and the life course more generally. Individual life courses can no longer be regarded as discrete, bounded, life histories, with clearly defined beginning and end points. If socioeconomic circumstances can have intergenerational effects, including disease susceptibility and growth stunting, then individual biographies should be viewed as nested or “embedded” within the lives of others. This commingling of life courses may prove problematic to unravel; nevertheless, this review aims to consider the potential consequences for bioarchaeological interpretations. These include a greater consideration of: the temporal power of human skeletons and a life course approach to past health; infant health and the implications for maternal well‐being; and the impact of non‐proximate stressors (e.g., early life and ancestral environments) on the presence of health indicators. Am J Phys Anthropol 158:530–540, 2015. © 2015 Wiley Periodicals, Inc.     

Sexual dimorphism in activation of placental autophagy in obese women with evidence for fetal programming from a placenta-specific mouse model

The incidence of maternal obesity and its co-morbidities (diabetes, cardiovascular disease) continues to increase at an alarming rate, with major public health implications. In utero exposure to maternal obesity has been associated with development of cardiovascular and metabolic diseases in the offspring as a result of developmental programming. The placenta regulates maternal-fetal metabolism and shows significant changes in its function with maternal obesity. Autophagy is a cell-survival process, which is responsible for the degradation of damaged organelles and misfolded proteins. Here we show an activation of autophagosomal formation and autophagosome-lysosome fusion in placentas of males but not females from overweight (OW) and obese (OB) women vs. normal weight (NW) women. However, total autophagic activity in these placentas appeared to be decreased as it showed an increase in SQSTM1/p62 and a decrease in lysosomal biogenesis. A mouse model with a targeted deletion of the essential autophagy gene Atg7 in placental tissue showed significant placental abnormalities comparable to those seen in human placenta with maternal obesity. These included a decrease in expression of mitochondrial genes and antioxidants, and decreased lysosomal biogenesis. Strikingly, the knockout mice were developmentally programmed as they showed an increased sensitivity to high-fat diet-induced obesity, hyperglycemia, hyperinsulinemia, increased adiposity, and cardiac remodeling. In summary, our results indicate a sexual dimorphism in placental autophagy in response to maternal obesity. We also show that autophagy plays an important role in placental function and that inhibition of placental autophagy programs the offspring to obesity, and to metabolic and cardiovascular diseases.     

Expression of fetal antigens in fetal and adult cells during long-term culture

Summary Expression of fetal antigens in early and late passages of tissue culture cells derived from C3H/HeN and C57BL/KaLw mouse fetal cells and from lung tissue of young C57BL/6N mice was investigated by the isotopic antiglobulin technique. The late passage lines of fetal cells had undergone “spontaneous” neoplastic transformation in culture. The antisera were produced by syngeneic immunization with 5000 R x-irradiated tissues from C3H/HeN and C57BL/6N fetuses of 1 to 2 weeks gestation. Fetal antigens were found to be retained even after 5 years in cell lines derived from fetal tissues In these lines no consistent change in fetal antigen expression could be correlated with neoplastic transformation. In contrast, the early passages of adult cells did not have detectable amounts of fetal antigens. However, fetal antigen(s) was demonstrated in cells of the late passages, and cells of both lines grew as sarcomas when next assayed 55 days later. In addition, fetal antigens were also present in established tumor lines in culture.     

Nutritional programming of adult disease

Intrauterine and early neonatal life is a period of physiological plasticity, during which environmental influences may produce long-term effects. Both undernutrition and overnutrition during this period have been shown to change disease risk in adulthood. These effects are influenced by the type, timing and duration of inappropriate nutrition and by the previous nutritional environment and may not be reflected in changes in body size. An understanding of the interaction between nutrient imbalance and alteration of gene expression is likely to be the key to optimising future health outcomes.     

The very low birth weight infant microbiome and childhood health

This review describes current understandings about the nature of the very low birth weight infant (VLBW) gut microbiome. VLBW infants often experience disruptive pregnancies and births, and prenatal factors can influence the maturity of the gut and immune system, and disturb microbial balance and succession. Many VLBWs experience rapid vaginal or Caesarean births. After birth these infants often have delays in enteral feeding, and many receive little or no mother's own milk. Furthermore the stressors of neonatal life in the hospital environment, common use of antibiotics, invasive procedures and maternal separation can contribute to dysbiosis. These infants experience gastrointestinal dysfunction, sepsis, transfusions, necrotizing enterocolitis, oxygen toxicity, and other pathophysiological consditions that affect the normal microbiota. The skin is susceptible to dysbiosis, due to its fragility and contact with NICU organisms. Dysbiosis in early life may resolve but little is known about the timing of the development of the signature gut microbiome in VLBWs. Dysbiosis has been associated with a number of physical and behavioral problems, including autism spectrum disorders, allergy and asthma, gastrointestinal disease, obesity, depression, and anxiety. Dysbiosis may be prevented or ameliorated in part by prenatal care, breast milk feeding, skin to skin contact, use of antibiotics only when necessary, and vigilance during infancy and early childhood. Birth Defects Research (Part C) 105:252–264, 2015. © 2015 Wiley Periodicals, Inc.     

Kidney development and the fetal programming of adult disease

Recent evidence, from both epidemiological and animal experimental studies, suggest that the very first environment, the intrauterine, is extremely important in determining the future health of the individual. Genetic and 'lifestyle' factors impinge on, and can exacerbate, a 'programming' effect of an adverse fetal environment. In this review, we present compelling evidence to suggest that one of the major organs affected by an unfavourable prenatal environment is the kidney. Many of the factors that can affect fetal renal development (i.e. exposure to excess glucocorticoids, insufficient vitamin A, protein/calorie malnutrition (in rats) and alterations in the intrarenal renin angiotensinogen system), also produce hypertension in the adult animal. When nephron number is compromised during kidney development, maladaptive functional changes occur and can lead, eventually, to hypertension and/or renal disease. Surprisingly, it is during the very earliest stages of kidney development that the vulnerability to these effects occurs.     

Growth plasticity of the embryonic and fetal heart

The developing mammalian heart responds to a variety of conditions, including changes in nutrient availability, blood oxygenation, hemodynamics, or tissue homeostasis, with impressive growth plasticity. This ensures the formation of a functional and normal sized organ by birth. During embryonic and fetal development the heart is exposed to various physiological and potentially pathological changes in the intrauterine environment which dramatically impact on normal cardiac function, tissue composition, and morphology. This paper summarizes the mechanisms employed by the embryonic and fetal heart to adapt to various intrauterine challenges to prevent or minimize postnatal consequences of impaired cardiac development. Future investigations of this growth plasticity might lead to new therapeutic strategies for the prevention of cardiac disease in postnatal life.     

人体微生态与健康和疾病

人体微生态是人体内的微生物生态群落,是存在于人体组织和体液中的共生和病原微生物的总和,也是近年来发现的"新器官",它在维持人体健康过程中扮演着重要角色。微生态与宿主间有着全面广泛的相互作用机制,微生态失衡与疾病的发生发展密切相关。本文概述了人体微生态与健康和疾病研究的重要意义,并对国内外研究进展作总结评述。     

Developmental trajectory of the healthy human gut microbiota during the first 5 years of life

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The association between birthweight and longevity in the rat is complex and modulated by maternal protein intake during fetal life

Maternal protein restriction in rat pregnancy has been suggested to reduce lifespan of the resulting offspring by inducing fetal growth retardation, followed by postnatal catch-up growth. We tested the hypothesis that lifespan could be programmed in both males and females by exposure to undernutrition at specific stages of fetal development. Protein restriction throughout gestation significantly reduced lifespan in both males and females. Low birthweight increased longevity, whilst rapid postnatal growth had a detrimental effect. There was no evidence that undernutrition programmed lifespan through oxidative processes in the major organs. Fetal programming is an important contributor to the ageing process.     

Growth,meat and feed efficiency traits of lambs born to ewes submitted to energy restriction during mid-gestation

The objective of this study was to evaluate the effects of the energy restriction of gestation of adult ewes from day 45 to day 115 on lamb live performance parameters, carcass and meat traits. In experiment I, dietary energy was restricted at 70% of the metabolizable energy (ME) requirements, after which ewes were re-fed ad libitum until lambing. In experiment II, dietary energy was restricted at 60% of the ME requirements, and ewes were re-fed to ME requirements until lambing. All ewes grazed together from the end of the restriction periods to weaning. Lambs were weaned and lot fed until slaughter. Feed intake, weight gain and feed efficiency were recorded, and body fat thickness and ribeye area (REA) were measured in the longissimus thoracis muscle. After slaughter, carcass weight and yield, fat depth, carcass and leg length, and frenched rack and leg weights and yields were determined. Muscle fiber type composition, Warner-Bratzler shear force, pH and color were determined in the longissimus lumborum muscle. In experiment I, energy restriction followed by ad libitum feeding affected lamb birth weight (P<0.05); however, no effects (P>0.05) were observed on later BW, REA, BF or carcass traits. Lambs born to non-restricted-fed ewes had higher (P<0.05) weight and yield of the frenched rack cut and their meat tended (P=0.11) to be tender compared with that of lambs from restricted ewes. The percentage of oxidative muscle fibers was lower for lambs born to non-restricted ewes (P<0.05); however, no effects of ewe treatment were observed on other muscle fiber types. For experiment II, energy restriction followed by ME requirements feeding, affected (P<0.01) pre-weaning live weight gain, weaning and final weights. Lambs from restricted ewes had higher (P<0.05) feed intake as % of leg weight and a trend to be less efficient (P=0.16) than lambs from unrestricted dams. Ribeye area and BF were not influenced by treatment. Treatment significantly affected slaughter weight, but had no effects on carcass yield and traits or on meat traits. The results obtained in both experiments indicate submitting ewes to energy restriction during gestation affects the performance of their progeny but the final outcome would depend on the ewe’s re-feeding level during late gestation and the capacity of the offspring to compensate the in utero restriction after birth.