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Association of adverse prenatal exposure burden with child psychopathology in the Adolescent Brain Cognitive Development
Numerous adverse prenatal exposures have been individually associated with risk for psychiatric illness in the offspring. However, such exposures frequently co-occur, raising questions about their cumulative impact. We evaluated effects of cumulative adverse prenatal exposure burden on psychopathology risk in school-aged children. Using baseline surveys from the U.S.-based Adolescent Brain and Cognitive Development (ABCD) Study (7,898 non-adopted, unrelated children from 21 sites, age 9-10, and their primary caregivers), we examined 8 retrospectively-reported adverse prenatal exposures in relation to caregiver-reported total and subscale Child Behavior Checklist (CBCL) scores. We also assessed cumulative effects of these factors on CBCL total as a continuous measure, as well as on odds of clinically significant psychopathology (CBCL total [greater than or equal to]60), in both the initial set and a separate ABCD sample comprising an additional 696 sibling pairs. Analyses were conducted before and after adjustment for 14 demographic and environmental covariates. In minimally and fully adjusted models, 6 exposures (unplanned pregnancy; maternal alcohol, marijuana, and tobacco use early in pregnancy; pregnancy complications; and birth complications) independently associated with significant but small increases in CBCL total score. Among these 6, none increased the odds of crossing the threshold for clinically significant symptoms by itself. However, odds of exceeding this threshold became significant with 2 exposures (OR = 1.86, 95% CI 1.47-2.36), and increased linearly with each level of exposure (OR = 1.39, 95% CI 1.31-1.47), up to 3.53-fold for [greater than or equal to]4 exposures versus none. Similar effects were observed in confirmatory analysis among siblings. Within sibling pairs, greater discordance for exposure load associated with greater CBCL total differences, suggesting that results were not confounded by unmeasured family-level effects. Children exposed to multiple common, adverse prenatal events showed dose-dependent increases in broad, clinically significant psychopathology at age 9-10. Fully prospective studies are needed to confirm and elaborate upon this pattern.
Journal Article
Your pregnancy week by week : what to expect from conception to birth
Professor Lesley Regan offer you allthe information and advice you need to make the right choices for you and your baby.
Book
Fetal brain lesions after subcutaneous inoculation of Zika virus in a pregnant nonhuman primate
New animal models of Zika virus (ZIKV) infection are imperative to accelerating efforts to treat or prevent disease in humans. Adams Waldorf
et al
. now report that ZIKV infection of a pregnant female pigtailed macaque caused brain lesions in the developing fetus, suggesting that this model may be useful for understanding ZIKV-associated congenital abnormalities in humans.
We describe the development of fetal brain lesions after Zika virus (ZIKV) inoculation in a pregnant pigtail macaque. Periventricular lesions developed within 10 d and evolved asymmetrically in the occipital–parietal lobes. Fetal autopsy revealed ZIKV in the brain and significant cerebral white matter hypoplasia, periventricular white matter gliosis, and axonal and ependymal injury. Our observation of ZIKV-associated fetal brain lesions in a nonhuman primate provides a model for therapeutic evaluation.
Journal Article
Ma! there's nothing to do here! : a word from your baby-in-waiting
A baby still waiting to be born describes the boredom of living in a small, cramped space where there are no toys and no one else can be \"it\" during a game of tag, then considers how life will change when Baby joins Pop and Ma in the outside world.
Book
Cells of the human intestinal tract mapped across space and time
The cellular landscape of the human intestinal tract is dynamic throughout life, developing in utero and changing in response to functional requirements and environmental exposures. Here, to comprehensively map cell lineages, we use single-cell RNA sequencing and antigen receptor analysis of almost half a million cells from up to 5 anatomical regions in the developing and up to 11 distinct anatomical regions in the healthy paediatric and adult human gut. This reveals the existence of transcriptionally distinct BEST4 epithelial cells throughout the human intestinal tract. Furthermore, we implicate IgG sensing as a function of intestinal tuft cells. We describe neural cell populations in the developing enteric nervous system, and predict cell-type-specific expression of genes associated with Hirschsprung’s disease. Finally, using a systems approach, we identify key cell players that drive the formation of secondary lymphoid tissue in early human development. We show that these programs are adopted in inflammatory bowel disease to recruit and retain immune cells at the site of inflammation. This catalogue of intestinal cells will provide new insights into cellular programs in development, homeostasis and disease.
Cells from embryonic, fetal, paediatric and adult human intestinal tissue are analysed at different locations along the intestinal tract to construct a single-cell atlas of the developing and adult human intestinal tract, encompassing all cell lineages.
Journal Article
The dance of life : the new science of how a single cell becomes a human being
\"Embryologist Magdalena Zernicka-Goetz has spent two decades unraveling the mysteries of fetal development. By studying embryonic mouse cells, she witnessed the embryo's ability to rid itself of abnormal cells as it prepared for implantation in the womb. When Zernicka-Goetz became pregnant at 44, she received a call that took her by surprise: a sample test of the cells in her own placenta indicated that the fetus had trisomy-2, a disastrous extra copy of the second chromosome, which increased the risk of miscarriage or serious birth defects. It seemed likely that the best choice was to have an abortion. But the plasticity of the embryonic mouse cells in her studies gave her hope; if mouse cells were able to course correct, then perhaps human cells were capable of similar resiliency. Six months later, she gave birth to a healthy baby boy, and the experience inspired her to begin a series of studies to test this hypothesis. Her subsequent experiments with early human embryos and artificial 'three parent' embryos were not only groundbreaking; they also proved that embryotic cells could be artificially nurtured through the trials and tribulations of their early development. To say that her work is controversial would be an understatement, but as Zernicka-Goetz notes, harm can arise as much from doing nothing as from taking risks. And with profound implications for stem cell research, infertility treatment, prenatal diagnostic testing, immunotherapy, and genetic engineering, not to mention women's reproductive health, the stakes have never been higher\"-- Provided by publisher.
Book
The maternal microbiome modulates fetal neurodevelopment in mice
‘Dysbiosis’ of the maternal gut microbiome, in response to challenges such as infection
1
, altered diet
2
and stress
3
during pregnancy, has been increasingly associated with abnormalities in brain function and behaviour of the offspring
4
. However, it is unclear whether the maternal gut microbiome influences neurodevelopment during critical prenatal periods and in the absence of environmental challenges. Here we investigate how depletion and selective reconstitution of the maternal gut microbiome influences fetal neurodevelopment in mice. Embryos from antibiotic-treated and germ-free dams exhibited reduced brain expression of genes related to axonogenesis, deficient thalamocortical axons and impaired outgrowth of thalamic axons in response to cell-extrinsic factors. Gnotobiotic colonization of microbiome-depleted dams with a limited consortium of bacteria prevented abnormalities in fetal brain gene expression and thalamocortical axonogenesis. Metabolomic profiling revealed that the maternal microbiome regulates numerous small molecules in the maternal serum and the brains of fetal offspring. Select microbiota-dependent metabolites promoted axon outgrowth from fetal thalamic explants. Moreover, maternal supplementation with these metabolites abrogated deficiencies in fetal thalamocortical axons. Manipulation of the maternal microbiome and microbial metabolites during pregnancy yielded adult offspring with altered tactile sensitivity in two aversive somatosensory behavioural tasks, but no overt differences in many other sensorimotor behaviours. Together, our findings show that the maternal gut microbiome promotes fetal thalamocortical axonogenesis, probably through signalling by microbially modulated metabolites to neurons in the developing brain.
Small molecules that arise from the maternal gut microbiome in pregnant dams promote fetal thalamocortical axonogenesis in their offspring.
Journal Article
Origins : how the nine months before birth shape the rest of our lives
A guide aiming to alleviate the anxiety that many women feel when they obsess over prenatal influences explores how fetuses are shaped in utero, separating the evidence from the hype, and examines the cultural mania that surrounds pregnancy today.
Book
Kidney organoids from human iPS cells contain multiple lineages and model human nephrogenesis
The kidney arises from two types of progenitors; here, the signalling conditions that induce the production of collecting ducts and functional nephrons from human pluripotent stem cells are determined, and organoids that recapitulate the functional regionalization of the kidney are produced.
Human kidney organoids with all renal components
The development of the human kidney in the embryo depends on two different stem cell types, one to generate collecting ducts and the other to generate functional nephrons. Melissa Little, Minoru Takasato and colleagues showed previously that human pluripotent stem cells (hPSCs) can differentiate into both types of progenitors. They have now identified the signalling conditions required to induce not only these structures but also the surrounding cell types including interstitium and blood vessels. Using this approach, they have grown kidney organoids that recapitulate the functional regionalization of the embryonic kidney. The tissue complexity and degree of functionalization achieved in these organoids are not on a par with a working kidney, but replicate the normal human embryonic kidney. Importantly, they provide evidence of their potential in screening drugs for toxicity, modelling genetic kidney disease or perhaps to provide specific kidney cell types for cellular therapy.
The human kidney contains up to 2 million epithelial nephrons responsible for blood filtration. Regenerating the kidney requires the induction of the more than 20 distinct cell types required for excretion and the regulation of pH, and electrolyte and fluid balance. We have previously described the simultaneous induction of progenitors for both collecting duct and nephrons via the directed differentiation of human pluripotent stem cells
1
. Paradoxically, although both are of intermediate mesoderm in origin, collecting duct and nephrons have distinct temporospatial origins. Here we identify the developmental mechanism regulating the preferential induction of collecting duct versus kidney mesenchyme progenitors. Using this knowledge, we have generated kidney organoids that contain nephrons associated with a collecting duct network surrounded by renal interstitium and endothelial cells. Within these organoids, individual nephrons segment into distal and proximal tubules, early loops of Henle, and glomeruli containing podocytes elaborating foot processes and undergoing vascularization. When transcription profiles of kidney organoids were compared to human fetal tissues, they showed highest congruence with first trimester human kidney. Furthermore, the proximal tubules endocytose dextran and differentially apoptose in response to cisplatin, a nephrotoxicant. Such kidney organoids represent powerful models of the human organ for future applications, including nephrotoxicity screening, disease modelling and as a source of cells for therapy.
Journal Article