Unveiling the Threat of Maternal Advanced Glycation End Products to Fetal Muscle: Palmitoleic Acid to the Rescue.

Advanced glycation end products (AGEs) accumulate in the plasma of pregnant women with hyperglycemia, potentially inducing oxidative stress and fetal developmental abnormalities. Although intrauterine hyperglycemia has been implicated in excessive fetal growth, the effects of maternal AGEs on fetal development remain unclear. We evaluated the differentiation regulators and cellular signaling in the skeletal muscles of infants born to control mothers (ICM), diabetic mothers (IDM), and diabetic mothers supplemented with either cis-palmitoleic acid (CPA) or trans-palmitoleic acid (TPA). Cell viability, reactive oxygen species levels, and myotube formation were assessed in AGE-exposed C2C12 cells to explore potential mitigation by CPA and TPA. Elevated receptors for AGE expression and decreased Akt and AMPK phosphorylation were evident in rat skeletal muscles in IDM. Maternal palmitoleic acid supplementation alleviated insulin resistance by downregulating RAGE expression and enhancing Akt phosphorylation. The exposure of the C2C12 cells to AGEs reduced cell viability and myotube formation and elevated reactive oxygen species levels, which were attenuated by CPA or TPA supplementation. This suggests that maternal hyperglycemia and plasma AGEs may contribute to skeletal muscle disorders in offspring, which are mitigated by palmitoleic acid supplementation. Hence, the maternal intake of palmitoleic acid during pregnancy may have implications for fetal health.

Intrauterine developmental origin, programming mechanism, and prevention strategy of fetal-originated hypercholesterolemia.

There is increasing evidence that hypercholesterolemia has an intrauterine developmental origin. However, the pathogenesis of fetal-originated is still lacking in a theoretical system, which makes its clinical early prevention and treatment difficult. It has been found that an adverse environment during pregnancy (e.g., xenobiotic exposure) may lead to changes in fetal blood cholesterol levels through changing maternal cholesterol metabolic function and/or placental cholesterol transport function and may also directly affect the liver cholesterol metabolic function of the offspring in utero and continue after birth. Adverse environmental conditions during pregnancy may also raise maternal glucocorticoid levels and promote the placental glucocorticoid barrier opening, leading to fetal overexposure to maternal glucocorticoids. Intrauterine high-glucocorticoid exposure can alter the liver cholesterol metabolism of offspring, resulting in an increased susceptibility to hypercholesterolemia after birth. Abnormal epigenetic modifications are involved in the intrauterine programming mechanism of fetal-originated hypercholesterolemia. Some interventions targeted at pregnant mothers or offspring in early life have been proposed to effectively prevent and treat the development of fetal-originated hypercholesterolemia. In this paper, the recent research progress on fetal-originated hypercholesterolemia was reviewed, with emphasis on intrauterine maternal glucocorticoid programming mechanisms, in order to provide a theoretical basis for its early clinical warning, prevention, and treatment.

Meconium Transferrin and Ferritin as Markers of Homeostasis in the Developing Fetus.

The molecular mechanisms regulating homeostasis in the developing fetus have not been satisfactorily elucidated. Meconium contains substances accumulated in the fetal intestines. Measurements of transferrin and ferritin concentrations in meconium and assessment of transferrin-ferritin relationships could enhance knowledge about specific processes of the intrauterine period involving the two proteins and their effects on the development and growth of the fetus. Transferrin and ferritin concentrations were measured by ELISA in the homogenates of first meconium portions from 125 neonates. Higher birth weight was associated with lower ferritin concentrations in meconium (r = -0.22, p = 0.015). In neonates with a birth weight of more than 3750 g, there was a positive correlation between transferrin and ferritin concentrations (r = 0.51, p = 0.003). With meconium transferrin concentrations above 43.52 µg/g, a negative correlation between transferrin and ferritin was established (r = -0.37, p = 0.036), while with transferrin concentrations below 43.52 µg/g, the correlations between the birth weight and the meconium transferrin and ferritin concentrations were negative (r = -0.61, p < 0.001 and r = -0.43, p = 0.017, respectively). Measurements of transferrin and ferritin in meconium specimens create a new use for these common biomarkers to improve our understanding of the effects of homeostasis in utero on the fetal development and growth. Establishing reference ranges of meconium transferrin and ferritin concentrations and their association with the clinical parameters during pregnancy could aid in the assessment of the impact of intrauterine life on the health status of the neonate and its adaptation to extrauterine life.

Expression of aldose reductase in mouse endometrial epithelial cells and its role in sperm capacitation.

The survival, motility and capacitation of sperm in the female reproductive tract are important prerequisites for fertilization. The uterus is the main location for sperm capacitation. One of the most important physiological functions of the endometrial epithelium is to create a suitable uterine environment under the regulation of ovarian hormones, to ensure sperm capacitation. The composition of uterine fluid directly affects sperm capacitation. Fructose is an important component of semen that supports sperm viability and motility. Aldose reductase, a rate-limiting enzyme in the polyol pathway, metabolizes sorbitol and fructose, thereby supplying cells with necessary energy for functional activities. Existing studies have reported the presence aldose reductase in the endometrium, leading us to hypothesize that its expression in endometrial epithelium might promote sperm capacitation by maintaining the uterine environment. Yet, the mechanism of regulation has not been clarified. In this study, we investigated the expression of aldose reductase in mouse endometrial epithelium and its potential role in sperm capacitation. We initially investigated the periodic characteristics of glucose, fructose and sorbitol in uterine fluid. We then studied the temporal and spatial characteristics of aldose reductase in the endometrial epithelium. Next, we examined the effect of aldose reductase on glucose, fructose and sorbitol in uterine fluid. Finally, we explored the effect of aldose reductase on sperm capacitation and fertilization. The results showed that glucose and fructose content in uterine fluid and the expression of aldose reductase fluctuated periodically during physiological periods. Inhibition of aldose reductase in the endometrial epithelium interfered with sperm capacitation and fertilization by reducing the fructose levels in the uterine fluid. To conclude, the aldose reductase-mediated polyol pathway in endometrial epithelial cells is essential to maintain an appropriate fructose environment in the uterine fluid for sperm capacitation and fertilization.

The Uterine Environment and Childhood Obesity Risk: Mechanisms and Predictions.

PURPOSE OF REVIEW: Childhood obesity is a growing health problem in many populations, hence the urgent need to unravel the underlying mechanisms. Some evidence suggests that exposure to suboptimal intrauterine environments can program foetal metabolic health, with adverse consequences in later life, including susceptibility to childhood obesity. FINDINGS: Factors such as high and low foetal birth weight, excessive gestational-weight-gain, maternal stress and smoking are all associated with increased risk of childhood obesity in observational studies. Animal models, where both genetic background and the postnatal environment can be carefully controlled, suggest that several different mechanisms, including epigenetic changes, dysregulation of adipose tissue development and programming of appetite, may be key drivers of developmental programming of childhood obesity. However, the influence of genetics and the post-natal environment are much more difficult to disentangle as independent effects in human studies, which are also complicated by low follow-up rates. Suboptimal intrauterine environments interact with maternal and foetal genetics and with the postnatal environment to contribute to the risk of childhood obesity. Maternal metabolic challenges, for example obesity and insulin resistance, contribute to the risk of foetal overgrowth and subsequent adiposity in childhood. To protect the long-term health of populations, research focusing on effective means of identifying and intervening in the transgenerational cycle of childhood obesity is required.

Pre- and Postnatal Determinants Shaping the Microbiome of the Newborn in the Opinion of Pregnant Women from Silesia (Poland).

Pre- and postnatal factors influence the formation of the newborn's microbiome as early as birth and the intrauterine period has a substantial impact on the composition of the baby's gastrointestinal microbiota and its subsequent development. This study intends to measure pregnant women's knowledge of the importance of microbiota for the health of the newborn. The sample was selected based on defined inclusion and exclusion criteria. The assessment of women's knowledge was assessed by the Kolmogorov-Smirnov and Kruskal-Wallis statistical tests. This study population comprised 291 adult pregnant women with a mean age of 28.4 ± 4.7 years. A total of 34% (n = 99), 35% (n = 101), and 31.3% (n = 91) were at the 1-3 trimester, respectively. The results showed that 36.4% of the women were aware that the intrauterine period changes the makeup of the gastrointestinal microbiota, whereas 5.8% exhibited awareness of the composition of the child's normal gut microbiota. Most of the women surveyed-(72.1%)-know that colonization of the tract occurs as early as the birth period. Women with student status (those who will pursue higher education in the future) and those who had given birth to the most children exhibited higher levels of knowledge.

Maternal and fetal origins of offspring blood pressure: statistical analysis using genetic correlation and genetic risk score-based Mendelian randomization.

BACKGROUND: Epidemiological studies demonstrated that adverse in utero environment was associated with increased risk of offspring high blood pressure, by using birthweight as the proxy of maternal intrauterine exposure; however, the nature of such association remains less understood. METHODS: With maternal/fetal-specific summary statistics of birthweight (n = 297 356 for own birthweight and n = 210 248 for offspring birthweight) and summary statistics of blood pressure [i.e. systolic blood pressure (SBP), diastolic blood pressure (DBP) and pulse pressure (PP)] (n = 757 601), we evaluated the genetic correlation between fetal-specific birthweight and blood pressure using cross-trait linkage disequilibrium score regression, and next detected pleiotropic genes for them with a pleiotropy mapping method called mixture-adjusted intersect-union pleiotropy test. Furthermore, we conducted a genetic risk score (GRS)-based Mendelian randomization analysis in parent-offspring pairs (n = 6031) of the UK Biobank cohort, to assess the causal relation between maternal-specific GRS and blood pressure conditioning on fetal genotypes. RESULTS: We found fetal-specific birthweight had a negative genetic correlation with DBP (ρ^g = -0.174, P = 1.68 × 10-10), SBP (ρ^g = -0.198, P = 8.09 × 10-12), and PP (ρ^g = -0.152, P = 6.04 × 10-8), and detected 143, 137 and 135 pleiotropic genes shared between fetal-specific birthweight and PP, SBP and DBP, respectively. These genes often exhibited opposite genetic effects, and were more likely to be differentially expressed in pancreas, liver, heart, brain, whole blood and muscle skeletal tissues. A causal negative association of maternal-specific birthweight was identified with SBP (P = 2.20 × 10-2) and PP (P = 7.67 × 10-3) but not DBP (P = 0.396) in mother-offspring pairs, after accounting for the influence of fetal-specific GRS; and the two significant relations were robust against the horizontal pleiotropy of instruments and the confounding influence of gestational duration and preterm birth. However, these causal associations could not be detected in father-offspring pairs. CONCLUSIONS: This study revealed common genetic components underlying birthweight and blood pressure, and provided important insight into aetiology and early prevention of high blood pressure.

Association between history of miscarriage and autism spectrum disorder.

This case-control study was designed to examine the association between different types of miscarriage history and autism spectrum disorder (ASD), and determine whether the number of miscarriage history affects the risk of ASD. All of 2274 children with ASD and 1086 healthy controls were recruited. Sociodemographic and prenatal, perinatal, and neonatal characteristics were compared between the two groups. Multivariable logistic regression analyses were applied to investigate association between miscarriage history and ASD. Stratified analyses based on sex and types of miscarriages were similarly performed. History of miscarriage was potential risk factors for ASD ([aOR] = 2.919; 95% [CI] = 2.327-3.517). Stratified analyses revealed that induced ([aOR] = 2.763, 95% [CI] = 2.259-3.379) and spontaneous miscarriage history ([aOR] = 3.341, 95% [CI] = 1.939-4.820) were associated with high risk of ASD, respectively. A sex-biased ratio in the risk of ASD was observed between females ([aOR] = 3.049, 95% [CI] = 2.153-4.137) and males ([aOR] = 2.538, 95% [CI] = 1.978-3.251). Stratified analysis of induced miscarriage history revealed that only iatrogenic miscarriage history was associated with an increased risk ASD ([aOR] = 2.843, 95% [CI] = 1.534-4.268). Also, multiple spontaneous miscarriage histories ([aOR] = 1.836, 95% [CI] = 1.252-2.693) were associated with higher autism risk than one spontaneous miscarriages history ([aOR] = 3.016, 95% [CI] = 1.894-4.174). In conclusion, miscarriage history is related to an increased risk for ASD in offspring, which is affected by the types of miscarriage and sex of the fetus.

Effects of excessive weight gain during pregnancy on offspring health: a review / 预防医学

@#Excessive gestational weight gain has already become a global clinical and public health problem that seriously affects maternal health. Excessive gestational weight gain not only increases the cesarean section rate and induces adverse pregnant outcomes, but also affects offspring development and health. This article reviews the effects of excessive weight gain during pregnancy on offspring health and its underlying mechanisms. Excessive gestational weight gain may increase the risk of obesity, cardiovascular diseases, infectious diseases of the respiratory tract, diabetes, polycystic ovary syndrome, mental or psychological illness among offspring, and the pathophysiological mechanisms include inflammatory response, intestinal flora dysbiosis and epigenetics theory. However, further studies are required to validate these hypotheses and to evaluate the effect of excessive weight gain at different gestational stages on offspring health, so as to provide insights into reasonable management of weight gain during pregnancy and improvements of offspring health.

Maternal Fructose Intake, Programmed Mitochondrial Function and Predisposition to Adult Disease.

Fructose consumption is now recognised as a major risk factor in the development of metabolic diseases, such as hyperlipidaemia, diabetes, non-alcoholic fatty liver disease and obesity. In addition to environmental, social, and genetic factors, an unfavourable intrauterine environment is now also recognised as an important factor in the progression of, or susceptibility to, metabolic disease during adulthood. Developmental trajectory in the short term, in response to nutrient restriction or excessive nutrient availability, may promote adaptation that serves to maintain organ functionality necessary for immediate survival and foetal development. Consequently, this may lead to decreased function of organ systems when presented with an unfavourable neonatal, adolescent and/or adult nutritional environment. These early events may exacerbate susceptibility to later-life disease since sub-optimal maternal nutrition increases the risk of non-communicable diseases (NCDs) in future generations. Earlier dietary interventions, implemented in pregnant mothers or those considering pregnancy, may have added benefit. Although, the mechanisms by which maternal diets high in fructose and the vertical transmission of maternal metabolic phenotype may lead to the predisposition to adult disease are poorly understood. In this review, we will discuss the potential contribution of excessive fructose intake during pregnancy and how this may lead to developmental reprogramming of mitochondrial function and predisposition to metabolic disease in offspring.

Assessing whether genetic scores explain extra variation in birthweight, when added to clinical and anthropometric measures.

BACKGROUND: Human birthweight is a complex, multifactorial trait. Maternal characteristics contribute to birthweight variation by influencing the intrauterine environment. Variation explained by genetic effects is also important, but their contributions have not been assessed alongside other key determinants. We aimed to investigate variance in birthweight explained by genetic scores in addition to easily-measurable clinical and anthropometric variables. METHODS: We analysed 549 European-ancestry parent-offspring trios from a UK community-based birth cohort. We investigated variance explained in birthweight (adjusted for sex and gestational age) in multivariable linear regression models including genetic scores, routinely-measured maternal characteristics, and parental anthropometric variables. We used R-Squared (R2) to estimate variance explained, adjusted R-squared (Adj-R2) to assess improvement in model fit from added predictors, and F-tests to compare nested models. RESULTS: Maternal and fetal genetic scores together explained 6.0% variance in birthweight. A model containing maternal age, weight, smoking, parity and 28-week fasting glucose explained 21.7% variance. Maternal genetic score explained additional variance when added to maternal characteristics (Adj-R2 = 0.233 vs Adj-R2 = 0.210, p < 0.001). Fetal genetic score improved variance explained (Adj-R2 = 0.264 vs 0.248, p < 0.001) when added to maternal characteristics and parental heights. CONCLUSIONS: Genetic scores account for variance explained in birthweight in addition to easily measurable clinical variables. Parental heights partially capture fetal genotype and its contribution to birthweight, but genetic scores explain additional variance. While the genetic contribution is modest, it is comparable to that of individual clinical characteristics such as parity, which suggests that genetics could be included in tools aiming to predict risk of high or low birthweights.

Development of pups born to rats established as a model of underweight Japanese women and the onset of impaired glucose tolerance.

An increasing number of Japanese women of childbearing age are underweight (BMI <18.5), but the association between this and the increased number of low-birth-weight babies born remains unclear. Here, a rat model was established to mimic the undernutrition (85% of the energy required for those with normal activity levels) experienced by such women and to evaluate the associated impaired glucose tolerance. The undernourished Wistar rat group showed increased serum corticosterone level reflecting stress, and greater adrenal weight and size. It also showed greater insulin resistance, higher expression of FOXO-1, a transcription factor related to muscle atrophy, and lower expression of p-Akt, an insulin-dependent signaling factor. Overall, this work shows the key role of undernutrition during pregnancy as a cause of impaired glucose tolerance and increased diabetes risk in offspring. The findings of this study may inform preemptive measures to prevent the development of metabolic syndrome in offspring of undernourished mothers.

Is birthweight influenced equally by maternal and paternal anthropometry?

OBJECTIVES: To elucidate the influence of parental biometric factors on fetal birthweight (BW). STUDY DESIGN: This prospective study was conducted between 2015 and 2017 in Hadassah University Hospital. Inclusion criteria included singletons that were born to healthy mothers at 37-41 weeks' gestation and had no growth abnormality or congenital malformation. Maternal and paternal head circumference, weight, and height were measured. Other data including neonatal head circumference and neonatal birthweight were also collected. Neonatal head circumference and birthweight percentiles were converted to sex-specific ranks according to the neonatal Intergrowth 21 charts (rank = 1 for percentile <3, rank = 2 for percentile 3-10, etc.). RESULTS: One hundred and ninety-nine trios (mother, father, and neonate) were included in the final analysis. In univariate analysis, maternal head circumference (p = .006), maternal height (p = .001), maternal weight before pregnancy (p < .001), maternal weight at term (p < .001), gestational weight gain (p = .009), paternal height (p = .018), neonatal head circumference (p < .001), and neonatal head circumference percentile rank (p < .001) were significant predictors of neonatal birthweight percentile rank. In multivariate regression, the three factors that were significant independent predictors of neonatal birthweight percentile rank were maternal weight before pregnancy (p = .047), maternal weight at term (p = .01), and neonatal head circumference percentile rank (p < .001). No interaction was found between neonatal sex and any of the tested variables. Neonatal sex-specific multivariate analysis showed that maternal height (p = .013), gestational weight gain (p = .005), and neonatal head circumference percentile rank (p < .001) were predictors of birthweight percentile rank in males. Maternal weight at term (p < .001) and neonatal head circumference percentile rank (p < .001) were predictors of birthweight percentile rank in females. CONCLUSIONS: Maternal height and weight parameters as well as neonatal head circumference percentile rank were found to be independent predictors of birthweight percentile rank. Paternal parameters did not show any significant association in multivariable analysis. The biological regulation of fetal size is assumed to be the result of strong evolutionary selection. As the fetus must pass through the mother's birth canal, there should be a natural match between maternal and fetal size to ensure the successful birth and survival of mother and offspring.

Cerebral palsy and the placenta: A review of the maternal-placental-fetal origins of cerebral palsy.

Accumulating evidence from clinical and neuropathological study has identified a number of seemingly disparate associations carrying a predisposition for cerebral palsy (CP). We narratively reviewed clinical studies reporting associations between prenatal and perinatal environmental factors and the risk of developing CP. As expected, some processes with direct central nervous system involvement (e.g. perinatal hypoxic-ischemic encephalopathy or infectious encephalomalacia) carry >10% absolute risk of CP. Other acute perinatal processes including placental abruption, uterine rupture, and neonatal sepsis are also associated with increased risk of CP but carry <3% absolute risk of CP. Indirect markers of chronic placental insufficiency such as fetal and placental growth patterns are associated with increased risk of CP, and risk of CP in infants with growth abnormalities born extremely preterm exceeds 10%. We synthesize these findings within a framework of risk accumulating across several defined pre- and perinatal developmental windows. Causal links remain incompletely understood, but genetic background, the intrauterine environment, general fetal health, and fetal neurologic health all appear to contribute.

Maternal and early life exposures and their potential to influence development of the microbiome.

At the dawn of the twentieth century, the medical care of mothers and children was largely relegated to family members and informally trained birth attendants. As the industrial era progressed, early and key public health observations among women and children linked the persistence of adverse health outcomes to poverty and poor nutrition. In the time hence, numerous studies connecting genetics ("nature") to public health and epidemiologic data on the role of the environment ("nurture") have yielded insights into the importance of early life exposures in relation to the occurrence of common diseases, such as diabetes, allergic and atopic disease, cardiovascular disease, and obesity. As a result of these parallel efforts in science, medicine, and public health, the developing brain, immune system, and metabolic physiology are now recognized as being particularly vulnerable to poor nutrition and stressful environments from the start of pregnancy to 3 years of age. In particular, compelling evidence arising from a diverse array of studies across mammalian lineages suggest that modifications to our metagenome and/or microbiome occur following certain environmental exposures during pregnancy and lactation, which in turn render risk of childhood and adult diseases. In this review, we will consider the evidence suggesting that development of the offspring microbiome may be vulnerable to maternal exposures, including an analysis of the data regarding the presence or absence of a low-biomass intrauterine microbiome.

In utero exposure to endocrine disruptors and developmental neurotoxicity: Implications for behavioural and neurological disorders in adult life.

Endocrine disrupting chemicals (EDCs) are a class of environmental toxicants that interfere with the endocrine system, resulting in developmental malformations, reproductive disorders, and alterations to immune and nervous system function. The emergence of screening studies identifying these chemicals in fetal developmental matrices such as maternal blood, placenta and amniotic fluid has steered research focus towards elucidation of in utero effects of exposure to these chemicals, as their capacity to cross the placenta and reach the fetus was established. The presence of EDCs, a majority of which are estrogen mimics, in the fetal environment during early development could potentially affect neurodevelopment, with implications for behavioural and neurological disorders in adult life. This review summarizes studies in animal models and human cohorts that aim to elucidate mechanisms of action of EDCs in the context of neurodevelopment and disease risk in adult life. This is a significant area of study as early brain development is heavily mediated by estrogen and could be particularly sensitive to EDC exposure. A network analysis presented using genes summarized in this review, further show a significant association with disorders such as major depressive disorder, alcoholic disorder, psychotic disorders and autism spectrum disorder. Functional outcomes such as alterations in memory, behaviour, cognition, learning memory, feeding behaviour and regulation of ion transport are also highlighted. Interactions between genes, receptors and signaling pathways like NMDA glutamate receptor activity, 5-hydroxytryptamine receptor activity, Ras-activated Ca2+ influx and Grin2A interactions, provide further potential mechanisms of action of EDCs in mediating brain function. Taken together with the growing pool of human and animal studies, this review summarizes current status of EDC neurotoxicity research, limitations and future directions of study for researchers.

The jury is still out on the existence of a placental microbiome.

The human microbiome is crucial for regulating normal development, but the exact point when it is established remains unknown. A sterile placenta was traditionally considered a prerequisite for a healthy pregnancy, but studies have revealed that the placenta harbours microbial communities, even under normal conditions. However, reports have failed to provide evidence for the consistent presence of bacteria in the normal human placenta, challenging the in utero colonisation hypothesis. This mini review examines our understanding of the potential placental microbial colonisation in normal healthy pregnancies. This may impact the metabolic and immune functions of the growing foetus and have long-term consequences.

Fetal Growth Restriction and Subsequent Low Grade Fetal Inflammatory Response Are Associated with Early-Onset Neonatal Sepsis in the Context of Early Preterm Sterile Intrauterine Environment.

There is no information about whether fetal growth restriction (FGR) is an independent risk factor for low-grade fetal inflammatory response (FIR), and which is more valuable for the prediction of early-onset neonatal sepsis (EONS) between low-grade FIR or fetal inflammatory response syndrome (FIRS) in the context of human early preterm sterile intrauterine environment. We examined FIR (umbilical cord plasma (UCP) CRP concentration at birth) according to the presence or absence of FGR (birth weight < 5th percentile for gestational age (GA)) and EONS in 81 singleton preterm births (GA at delivery: 24.5~33.5 weeks) within 72 h after amniocentesis and with sterile intrauterine environment. A sterile intrauterine environment was defined by the presence of both a sterile amniotic fluid (AF) (AF with both negative culture and MMP-8 < 23 ng/mL) and inflammation-free placenta. Median UCP CRP (ng/mL) was higher in cases with FGR than in those without FGR (63.2 vs. 34.5; p = 0.018), and FGR was an independent risk factor for low-grade FIR (UCP CRP ≥ 52.8 ng/mL) (OR 3.003, 95% CI 1.024-8.812, p = 0.045) after correction for confounders. Notably, low-grade FIR (positive likelihood-ratio (LR) and 95% CI, 2.3969 (1.4141-4.0625); negative-LR and 95% CI, 0.4802 (0.2591-0.8902)), but not FIRS (positive-LR and 95% CI, 2.1071 (0.7526-5.8993); negative-LR and 95% CI, 0.8510 (0.6497-1.1145)), was useful for the identification of EONS. In conclusion, FGR is an independent risk factor for low-grade FIR, and low-grade FIR, but not FIRS, has a value for the identification of EONS in the context of the early preterm sterile intrauterine environment.

Increasing mTORC1 Pathway Activity or Methionine Supplementation during Pregnancy Reverses the Negative Effect of Maternal Malnutrition on the Developing Kidney.

BACKGROUND: Low nephron number at birth is associated with a high risk of CKD in adulthood because nephrogenesis is completed in utero. Poor intrauterine environment impairs nephron endowment via an undefined molecular mechanism. A calorie-restricted diet (CRD) mouse model examined the effect of malnutrition during pregnancy on nephron progenitor cells (NPCs). METHODS: Daily caloric intake was reduced by 30% during pregnancy. mRNA expression, the cell cycle, and metabolic activity were evaluated in sorted Six2 NPCs. The results were validated using transgenic mice, oral nutrient supplementation, and organ cultures. RESULTS: Maternal CRD is associated with low nephron number in offspring, compromising kidney function at an older age. RNA-seq identified cell cycle regulators and the mTORC1 pathway, among other pathways, that maternal malnutrition in NPCs modifies. Metabolomics analysis of NPCs singled out the methionine pathway as crucial for NPC proliferation and maintenance. Methionine deprivation reduced NPC proliferation and lowered NPC number per tip in embryonic kidney cultures, with rescue from methionine metabolite supplementation. Importantly, in vivo, the negative effect of caloric restriction on nephrogenesis was prevented by adding methionine to the otherwise restricted diet during pregnancy or by removing one Tsc1 allele in NPCs. CONCLUSIONS: These findings show that mTORC1 signaling and methionine metabolism are central to the cellular and metabolic effects of malnutrition during pregnancy on NPCs, contributing to nephrogenesis and later, to kidney health in adulthood.

Significance and effects of prenatal and postnatal microbiome in the period of early individual development and options for interventional treatment / A praenatalis és postnatalis mikrobiom jelentosége és hatásai a korai egyedfejlodés idoszakában és az intervenciós kezelés lehetoségei.

Összefoglaló. A humán mikrobiom az emberi szervezetben és az emberi testfelszínen élo mikrobaközösségek összessége, amelyek többsége a gyomor-bél rendszerben él. Ezek a mikrobaközösségek számos és sokféle baktériumot tartalmaznak, gombákat, vírusokat, archeákat és protozoonokat. Ez a mikrobiális közösség, vagy mikrobiota, a gazdaszervezetben nagyrészt egymással kölcsönösségi viszonyban tenyészik, és gondoskodik a bélben a tápanyagok anyagcseréjérol, kalibrálja az anyagcsere-muködést, tanítja az immunrendszert, fenntartja a közösség integritását, és véd a kórokozók ellen. A majdan megszületendo magzat a megfelelo tápanyagellátását az anyai véráramból kapja, és így az anyai szervezetben a mikrobiota indukálta baktériumkomponensek vagy metabolitok hatékonyan átvihetok a magzatba. Az anyai mikrobiális közösségek - ideértve a praenatalis bélrendszeri, hüvelyi, száj- és bormikrobiomot - a terhesség alatt valójában kifejezett változásokon mennek keresztül, amelyek befolyásolhatják az egészség megorzését, és hozzájárulhatnak a közismert betegségek kialakulásához. A magzat nem steril, és immunológiai szempontból sem naiv, hanem az anya révén környezeti ingerek hatásaitól befolyásolva kölcsönhatásba lép az anyai immunrendszerrel. Számos anyai tényezo - beleértve a hormonokat, a citokineket és a mikrobiomot - módosíthatja az intrauterin környezetet, ezáltal befolyásolva a magzati immunrendszer fejlodését. A fokozott stresszben élo anyák csecsemoinél nagyobb az allergia és a gyomor-bél rendszeri rendellenességek aránya. A várandós étrendje is befolyásolja a magzati mikrobiomot a méh közvetítésével. A bélflóránk, vagyis a mikrobiom, a belünkben élo mikrobák összessége és szimbiózisa, amelynek kényes egyensúlya már csecsemokorban kialakul, és döntoen meghatározza az intestinalis barrier és a bélasszociált immunrendszer muködését. A probiotikumok szaporodásához szükséges prebiotikummal is befolyásolható a bélflóra. A pre- és a probiotikum kombinációja a szimbiotikum. Az anyatej a patogénekkel szemben protektív hatású, részben azáltal, hogy emeli a Bifidobacterium-számot az újszülött bélflórájában. A dysbiosis a kommenzális, egészséges bélflóra megváltozása. Ennek szerepét feltételezik funkcionális gastrointestinalis kórképekben, egyre több pszichiátriai és neurológiai kórképben is, mint az autizmus-spektrumzavar. Orv Hetil. 2021; 162(19): 731-740. Summary. The human microbiome is the totality of microbe communities living in the human body and on the human body surface, most of which live in the gastrointestinal tract. These microbe communities contain many and varied bacteria, fungi, viruses, archaea and protozoa. This microbial community or microbiota in the host is largely reciprocal and takes care of nutrient metabolism in the gut, calibrates metabolism, teaches the immune system, maintains community integrity, and protects against pathogens. The fetus to be born is adequately supplied with nutrients from the maternal bloodstream, and thus microbial-induced bacterial components or metabolites can be efficiently transferred to the fetus in the maternal body. Maternal microbial communities, including prenatal intestinal, vaginal, oral, and dermal microbiomes, actually undergo pronounced changes during pregnancy that can affect health maintenance and contribute to the development of well-known diseases. The fetus is not sterile or immunologically naïve, but interacts with the maternal immune system through the effects of environmental stimuli through the mother. Many maternal factors, including hormones, cytokines, and the microbiome, can modify the intrauterine environment, thereby affecting the development of the fetal immune system. Infants of mothers under increased stress have higher rates of allergies and gastrointestinal disorders. The diet of the gravida also affects the fetal microbiome through the uterus. Our intestinal flora, or microbiome, is the totality and symbiosis of the microbes living in them, the delicate balance of which is established in infancy and decisively determines the functioning of the intestinal barrier and the intestinal associated immune system. The prebiotic required for the proliferation of probiotics can also affect the intestinal flora. The combination of pre- and probiotic is symbiotic. Breast milk has a protective effect against pathogens, in part by raising the number of Bifidobacteria in the intestinal flora of the newborn. Dysbiosis is a change in the commensal, healthy gut flora. Its role is hypothesized in functional gastrointestinal disorders, as well as in more and more psychiatric and neurological disorders such as the autism spectrum disorder. Orv Hetil. 2021; 162(19): 731-740.