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The developmental origin of health and disease highlights the importance of the period of the first 1000 days (from the conception to the 2 years of life). The process of the gut microbiota establishment is included in this time window. Various perinatal determinants, such as cesarean section delivery, type of feeding, antibiotics treatment, gestational age or environment, can affect the pattern of bacterial colonization and result in dysbiosis. The alteration of the early bacterial gut pattern can persist over several months and may have long-lasting functional effects with an impact on disease risk later in life. As for example, early gut dysbiosis has been involved in allergic diseases and obesity occurrence. Besides, while it was thought that the fetus developed under sterile conditions, recent data suggested the presence of a microbiota in utero, particularly in the placenta. Even if the origin of this microbiota and its eventual transfer to the infant are nowadays unknown, this placental microbiota could trigger immune responses in the fetus and would program the infant’s immune development during fetal life, earlier than previously considered. Moreover, several studies demonstrated a link between the composition of placental microbiota and some pathological conditions of the pregnancy. All these data show the evidence of relationships between the neonatal gut establishment and future health outcomes. Hence, the use of pre- and/or probiotics to prevent or repair any early dysbiosis is increasingly attractive to avoid long-term health consequences.
Barker et al. proposed that low birth weight predisposes to higher death rates in adult life. We previously confirmed this fact in a cohort of young adults who were born in a remote Australian Aboriginal community between 1956 and 1985. We now present data in these same people with four more years of follow-up and a greater number of deaths. The fates of participants were documented from age 15 years until death, start of dialysis, or until the end of 2010 and causes of death were derived from clinic narratives and dialysis records. Rates of natural deaths were compared by birth cohorts and birth weight, and hazard ratios were calculated using Cox proportional hazards methods, by birth weight and adjusted for birth cohort and sex. Over follow-up of 19,661 person-years, 61 people died of natural causes between age 15 and the censor date. Low birth weights (<2.5 kg) were associated with higher rates of natural death, with HR (95% CI) 1.76 (1.1–2.9, P=0.03), after adjustment for year of birth and sex. The effect was particularly prominent for deaths at <41 years of age, and with deaths from respiratory conditions/sepsis and unusual causes. A predisposing effect of low birth weight on adult deaths was confirmed. This phenomenon, occurring in the context of dramatically improved survivals of lower birth weight infants and children since the early 1960s, helps explain the current epidemic of chronic disease in Aboriginal people. Birth weights continue to improve, so excess deaths from this source should progressively be minimized.
Concerns have been raised about the health and development of children conceived by assisted reproductive technologies (ART) since 1978. Controversially, ART has been linked with adverse obstetric and perinatal outcomes, an increased risk of birth defects, cancers, and growth and development disorders. Emerging evidence suggests that ART treatment may also predispose individuals to an increased risk of chronic ageing related diseases such as obesity, type 2 diabetes and cardiovascular disease. This review will summarize the available evidence on the short-term and long-term health outcomes of ART singletons, as multiple pregnancies after multiple embryos transfer, are associated with low birth weight and preterm delivery, which can separately increase risk of adverse postnatal outcomes, and impact long-term health. We will also examine the potential factors that may contribute to these health risks, and discuss underlying mechanisms, including epigenetic changes that may occur during the preimplantation period and reprogram development in utero, and adult health, later in life. Lastly, this review will consider the future directions with the view to optimize the long-term health of ART children.
The significance of contact with microbes in early life for subsequent health has been the subject of intense research during the last 2 decades. Disturbances in the establishment of the indigenous intestinal microbiome caused by cesarean section delivery or antibiotic exposure in early life have been linked to the risk of immune-mediated and inflammatory conditions such as atopic disorders, inflammatory bowel disease and obesity later in life. Distinct microbial populations have recently been discovered at maternal sites including the amniotic cavity and breast milk, as well as meconium, which have previously been thought to be sterile. Our understanding of the impact of fetal microbial contact on health outcomes is still rudimentary. Breast milk is known to modulate immune and metabolic programming. The breast milk microbiome is hypothesized to guide infant gut colonization and is affected by maternal health status and mode of delivery. Immunomodulatory factors in breast milk interact with the maternal and infant gut microbiome and may mediate some of the health benefits associated with breastfeeding. The intimate connection between the mother and the fetus or the infant is a potential target for microbial therapeutic interventions aiming to support healthy microbial contact and protect against disease.
There has been a substantial body of evidence, which has shown that genetic variation is an important determinant of disease risk. However, there is now increasing evidence that alterations in epigenetic processes also play a role in determining susceptibility to disease. Epigenetic processes, which include DNA methylation, histone modifications and non-coding RNAs play a central role in regulating gene expression, determining when and where a gene is expressed as well as the level of gene expression. The epigenome is highly sensitive to a variety of environmental factors, especially in early life. One factor that has been shown consistently to alter the epigenome is maternal diet. This review will focus on how maternal diet can modify the epigenome of the offspring, producing different phenotypes and altered disease susceptibilities.
Early-life inorganic arsenic exposure influences not only child health and development but also health in later life. The adverse effects of arsenic may be mediated by epigenetic mechanisms, as there are indications that arsenic causes altered DNA methylation of cancer-related genes. The objective was to assess effects of arsenic on genome-wide DNA methylation in newborns. We studied 127 mothers and cord blood of their infants. Arsenic exposure in early and late pregnancy was assessed by concentrations of arsenic metabolites in maternal urine, measured by high performance liquid chromatography-inductively coupled plasma mass spectrometry. Genome-wide 5-methylcytosine methylation in mononuclear cells from cord blood was analyzed by Infinium HumanMethylation450K BeadChip. Urinary arsenic in early gestation was associated with cord blood DNA methylation (Kolmogorov–Smirnov test, P-value<10–15), with more pronounced effects in boys than in girls. In boys, 372 (74%) of the 500 top CpG sites showed lower methylation with increasing arsenic exposure (rS-values>−0.62), but in girls only 207 (41%) showed inverse correlation (rS-values>−0.54). Three CpG sites in boys (cg15255455, cg13659051 and cg17646418), but none in girls, were significantly correlated with arsenic after adjustment for multiple comparisons. The associations between arsenic and DNA methylation were robust in multivariable-adjusted linear regression models. Much weaker associations were observed with arsenic exposure in late compared with early gestation. Pathway analysis showed overrepresentation of affected cancer-related genes in boys, but not in girls. In conclusion, early prenatal arsenic exposure appears to decrease DNA methylation in boys. Associations between early exposure and DNA methylation might reflect interference with de novo DNA methylation.
It is now recognized that the quality of the fetal environment during early development is important in programming cardiovascular health and disease in later life. Fetal hypoxia is one of the most common consequences of complicated pregnancies worldwide. However, in contrast to the extensive research effort on pregnancy affected by maternal nutrition or maternal stress, the contribution of pregnancy affected by fetal chronic hypoxia to developmental programming is only recently becoming delineated and established. This review discusses the increasing body of evidence supporting the programming of cardiac susceptibility to ischaemia and reperfusion (I/R) injury, of endothelial dysfunction in peripheral resistance circulations, and of indices of the metabolic syndrome in adult offspring of hypoxic pregnancy. An additional focus of the review is the identification of plausible mechanisms and the implementation of maternal and early life interventions to protect against adverse programming.
Advances in understanding the molecular basis of behavior through epigenetic mechanisms could help explain the developmental origins of child mental health disorders. However, the application of epigenetic principles to the study of human behavior is a relatively new endeavor. In this paper we discuss the ‘Developmental Origins of Health and Disease’ including the role of fetal programming. We then review epigenetic principles related to fetal programming and the recent application of epigenetics to behavior. We focus on the neuroendocrine system and develop a simple heuristic stress-related model to illustrate how epigenetic changes in placental genes could predispose the infant to neurobehavioral profiles that interact with postnatal environmental factors potentially leading to mental health disorders. We then discuss from an ‘Evo-Devo’ perspective how some of these behaviors could also be adaptive. We suggest how elucidation of these mechanisms can help to better define risk and protective factors and populations at risk.
Maternal obesity during pregnancy is often characterized by fetal macrosomia but it can also result in fetal growth restriction in a subset of pregnancies. We hypothesized that mechanisms of this growth restriction may include adverse effects of maternal high fat (HF) intake on placental growth and function. Female rats (100 days old) were time-mated and randomly assigned to either a control (Con) or HF diet ad libitum throughout gestation. At E21, dams were killed; litter size and fetal and placental weights were recorded and maternal and fetal samples collected for further analyses. The HF diet resulted in a 54% increase in maternal body weight gain during gestation. In contrast, male and female fetal weights were reduced in HF pregnancies (P < 0.05), as were the weights of the junctional zone of the placenta (P = 0.013), whereas labyrinth zone weights were unaffected. The HF diet increased maternal and fetal plasma leptin levels (P < 0.05), but maternal and fetal insulin and fetal glucose levels were unaffected. Labyrinthine expression of PPARγ and total VEGFa mRNA, both markers of placental vascular development, were unaffected by consumption of the HF diet in placentas of male and female fetuses. Furthermore, maternal HF nutrition did not alter phosphorylated protein levels of either mammalian target of rapamycin or its downstream signaling factor eIF4E binding protein 1 (4E-BP1). These data show that in the rat, maternal HF nutrition results in fetal and placental junctional zone growth restriction, maternal and fetal hyperleptinemia but did not alter gene expression of markers of placental vascular development.
In the last decades, the developmental origins of health and disease (DOHaD) have emerged as a vigorous field combining experimental, clinical, epidemiological and public health research. Its goal is to understand how events in early life shape later morbidity risk, especially of non-communicable chronic diseases. As these diseases become the major cause of morbidity and mortality worldwide, research arising from DOHaD is likely to gain significance to public health and economic development. But action may be hindered by the lack of a firm mechanistic explanation and of a conceptual basis, especially regarding the evolutionary significance of the DOHaD phenomenon. In this article, we provide a succinct historical review of the research into the relationship between development and later disease, consider the evolutionary and developmental significance and discuss the underlying mechanisms of the DOHaD phenomenon. DOHaD should be viewed as a part of a broader biological mechanism of plasticity by which organisms, in response to cues such as nutrition or hormones, adapt their phenotype to environment. These responses may be divided into those for immediate benefit and those aimed at prediction of a future environment: disease occurs in the mismatch between predicted and realized future. The likely mechanisms that enable plasticity involve epigenetic processes, affecting the expression of genes associated with regulatory pathways. There is now evidence that epigenetic marks may be inherited and so contribute to non-genomic heritable disease risk. We end by discussing the global significance of the DOHaD phenomenon and its potential applications for public health purposes.