Altered dietary ratio of folic acid and vitamin B12 during pregnancy influences the expression of imprinted H19/IGF2 locus in C57BL/6 mice

Maternal folic acid and vitamin B12 (B12) status during pregnancy influence fetal growth. This study elucidated the effect of altered dietary ratio of folic acid and B12 on the regulation of H19/IGF2 locus in C57BL/6 mice. Female mice were fed diets with 9 combinations of folic acid and B12 for 4 weeks. They were mated and the offspring born (F1) were continued on the same diet for 6 weeks post-weaning and were allowed to mate. The placenta and fetal (F2) tissues were collected at day 20 of gestation. H19 overexpression observed under dietary deficiency of folate combined with normal B12 (BNFD) was associated with an increased expression of miR-675 in maternal and fetal tissues. Insulin-like growth factor 2 (IGF2), expression was decreased under folic acid deficient conditions combined with normal, deficient or over-supplemented state of B12 (BNFD, BDFD, BOFD) in fetal tissues along with B12 deficiency combined with normal folic acid (BDFN) in the placenta. The altered expression of imprinted genes under folic acid deficient conditions was related to decreased serum levels of folate and body weight (F1). Hypermethylation observed at the H19 differentially methylated region (DMR) (in BNFD) might be responsible for the decreased expression of IGF2 in female fetal tissues. IGF2 DMR2 was found to be hypomethylated and associated with low serum B12 levels with B12 deficiency in fetal tissues. Results suggest that the altered dietary ratio of folic acid and B12 affects the in-utero development of the fetus in association with altered epigenetic regulation of H19/IGF2 locus.

Maternal B cell signaling orchestrates fetal development in mice

B cell participation in early embryo/fetal development and the underlying molecular pathways have not been explored. To understand whether maternal B cell absence or impaired signaling interferes with placental and fetal growth, we paired CD19-deficient (CD19−/-) mice, females with B cell-specific MyD88 (BMyD88−/-) or IL-10 (BIL-10−/-) deficiency as well as WT and MyD88−/- controls on C57Bl/6 background with BALB/c males. Pregnancies were followed by ultrasound and Doppler measurements. Implantation number was reduced in BMyD88−/- and MyD88−/- mice. Loss of MyD88 or B cell-specific deletion of MyD88 or IL-10 resulted in decreased implantation areas at gestation days (gd)5, 8 and 10, accompanied by reduced placental thickness, diameter and areas at gd10. Uterine artery resistance was enhanced in BIL-10−/- dams at gd10. Challenge with 0.4mg LPS/kg BW at gd16 revealed that BMyD88−/-, BIL-10−/- and CD19−/- mothers delivered preterm while controls maintained their pregnancy. B cell specific MyD88 and IL-10 expression is essential for appropriate in utero development. IL-10+B cells are involved in uterine blood flow regulation during pregnancy. Finally, B cell-specific CD19, MyD88 and IL-10 expression influences susceptibility towards preterm birth.

Biological and Clinical Significance of Mosaicism in Human Preimplantation Embryos

Applications and indications of assisted reproduction technology are expanding, but every new approach is under scrutiny and thorough consideration. Recently, groups of assisted reproduction experts have presented data that support the clinical use of mosaic preimplantation embryos at the blastocyst stage, previously excluded from transfer. In the light of published contemporary studies, with or without clinical outcomes, there is growing evidence that mosaic embryos have the capacity for further in utero development and live birth. Our in-depth discussion will enable readers to better comprehend current developments. This expansion into the spectrum of ART practices requires further evidence and further theoretical documentation, basic research, and ethical support. Therefore, if strict criteria for selecting competent mosaic preimplantation embryos for further transfer, implantation, fetal growth, and healthy birth are applied, fewer embryos will be excluded, and more live births will be achieved. Our review aims to discuss the recent literature on the transfer of mosaic preimplantation embryos. It also highlights controversies as far as the clinical utilization of preimplantation embryos concerns. Finally, it provides the appropriate background to elucidate and highlight cellular and genetic aspects of this novel direction.

Disruption of paternal circadian rhythm affects metabolic health in male offspring via nongerm cell factors

Circadian rhythm synchronizes each body function with the environment and regulates physiology. Disruption of normal circadian rhythm alters organismal physiology and increases disease risk. Recent epidemiological data and studies in model organisms have shown that maternal circadian disruption is important for offspring health and adult phenotypes. Less is known about the role of paternal circadian rhythm for offspring health. Here, we disrupted circadian rhythm in male mice by night-restricted feeding and showed that paternal circadian disruption at conception is important for offspring feeding behavior, metabolic health, and oscillatory transcription. Mechanistically, our data suggest that the effect of paternal circadian disruption is not transferred to the offspring via the germ cells but initiated by corticosterone-based parental communication at conception and programmed during in utero development through a state of fetal growth restriction. These findings indicate paternal circadian health at conception as a newly identified determinant of offspring phenotypes.

Impact of prenatal maternal cytokine exposure on sex differences in brain circuitry regulating stress in offspring 45 years later

Stress is associated with numerous chronic diseases, beginning in fetal development with in utero exposures (prenatal stress) impacting offspring’s risk for disorders later in life. In previous studies, we demonstrated adverse maternal in utero immune activity on sex differences in offspring neurodevelopment at age seven and adult risk for major depression and psychoses. Here, we hypothesized that in utero exposure to maternal proinflammatory cytokines has sex-dependent effects on specific brain circuitry regulating stress and immune function in the offspring that are retained across the lifespan. Using a unique prenatal cohort, we tested this hypothesis in 80 adult offspring, equally divided by sex, followed from in utero development to midlife. Functional MRI results showed that exposure to proinflammatory cytokines in utero was significantly associated with sex differences in brain activity and connectivity during response to negative stressful stimuli 45 y later. Lower maternal TNF-α levels were significantly associated with higher hypothalamic activity in both sexes and higher functional connectivity between hypothalamus and anterior cingulate only in men. Higher prenatal levels of IL-6 were significantly associated with higher hippocampal activity in women alone. When examined in relation to the anti-inflammatory effects of IL-10, the ratio TNF-α:IL-10 was associated with sex-dependent effects on hippocampal activity and functional connectivity with the hypothalamus. Collectively, results suggested that adverse levels of maternal in utero proinflammatory cytokines and the balance of pro- to anti-inflammatory cytokines impact brain development of offspring in a sexually dimorphic manner that persists across the lifespan.

The First Prior: from Co-Embodiment to Co-Homeostasis in Early Life

The idea that whatever we perceive now is influenced by whatever we perceived before lies at the core of Predictive Processing (PP) theories in philosophy and computational neuroscience. If this is so, then it becomes crucial to look at how perception, cognition and actions get off the ground from square one, in utero. Here we examine how humans self-regulate their homeostatic bodily states and build their most basic self- and world-model, literally through others’ bodies, in utero. Indeed, one basic yet overlooked aspect of current embodied and PP approaches is that brains (and minds), and human bodies, first develop within another human body. Crucially, while not all humans will have the experience of being pregnant or carrying a baby, the experience of being carried and growing within another person’s body is universal. Specifically, we define in utero development as a process co-embodiment and co-homeostasis, and highlight their close relationship. We show that the case of pregnancy offers a clear and fundamental example of co-embodiment, building upon theoretical and empirical work tackling the emergence of perceptual experiences in utero. We focus on pregnancy, a case where two individuating organisms literally grasp/ grip one into each other. Contrary to the common view of the foetus being passively ‘contained’ and solipsistically ‘trapped’ in the solitude of the womb, we will present evidence speaking in favour of an active and bidirectional co-regulation between the two living bodies, what we will call co-homeostasis. The co-embodiment and co-homeostasis theses will lay the preliminary ground for introducing a predictive processing reading of in utero development of perceptual experiences.We conclude that when it comes to understanding the nature of predictive perceptions, the infant is father to the human - to paraphrase the famous Wordsworth metaphor.

Neonatal lamb mortality: major risk factors and the potential ameliorative role of melatonin

High incidences of pre-weaning mortality continue to limit global sheep production, constituting a major economic and welfare concern. Despite significant advances in genetics, nutrition, and management, the proportion of lamb deaths has remained stable at 15–20% over the past four decades. There is mounting evidence that melatonin can improve outcomes in compromised ovine pregnancies via enhanced uterine bloodflow and neonatal neuroprotection. This review provides an overview of the major risk factors and underlying mechanisms involved in perinatal lamb mortality and discusses the potential of melatonin treatment as a remedial strategy. Supplementing pregnant ewes with melatonin enhances uterine bloodflow and fetal oxygenation, and potentially birthweight and neonatal thermogenic capacity. Melatonin freely crosses the ovine placenta and blood-brain barrier and provides neuroprotection to the fetal lamb during periods of chronic and acute hypoxia throughout gestation, with improved behavioural outcomes in hypoxic neonates. The current literature provides strong evidence that maternal melatonin treatment improves outcomes for lambs which experience compromised in utero development or prolonged parturition, though to date this has not been investigated in livestock production systems. As such there is a clear basis for continued research into the effects of maternal melatonin supplementation during gestation on pre-weaning survival under extensive production conditions.

3D Brain Organoids: Studying Brain Development and Disease Outside the Embryo

Scientists have been fascinated by the human brain for centuries, yet knowledge of the cellular and molecular events that build the human brain during embryogenesis and of how abnormalities in this process lead to neurological disease remains very superficial. In particular, the lack of experimental models for a process that largely occurs during human in utero development, and is therefore poorly accessible for study, has hindered progress in mechanistic understanding. Advances in stem cell–derived models of human organogenesis, in the form of three-dimensional organoid cultures, and transformative new analytic technologies have opened new experimental pathways for investigation of aspects of development, evolution, and pathology of the human brain. Here, we consider the biology of brain organoids, compared and contrasted with the endogenous human brain, and highlight experimental strategies to use organoids to pioneer new understanding of human brain pathology.

Of Mice and Men: The Effect of Maternal Protein Restriction on Offspring’s Kidney Health. Are Studies on Rodents Applicable to Chronic Kidney Disease Patients? A Narrative Review

In the almost 30 years that have passed since the postulation of the “Developmental Origins of Health and Disease” theory, it has been clearly demonstrated that a mother’s dietary habits during pregnancy have potential consequences for her offspring that go far beyond in utero development. Protein malnutrition during pregnancy, for instance, can cause severe alterations ranging from intrauterine growth retardation to organ damage and increased susceptibility to hypertension, diabetes mellitus, cardiovascular diseases and chronic kidney disease (CKD) later in life both in experimental animals and humans. Conversely, a balanced mild protein restriction in patients affected by CKD has been shown to mitigate the biochemical derangements associated with kidney disease and even slow its progression. The first reports on the management of pregnant CKD women with a moderately protein-restricted plant-based diet appeared in the literature a few years ago. Today, this approach is still being debated, as is the optimal source of protein during gestation in CKD. The aim of this report is to critically review the available literature on the topic, focusing on the similarities and differences between animal and clinical studies.