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Defining the mechanisms underlying the programming of early life growth is fundamental for improving adult health and wellbeing. While the association between maternal diet, offspring growth and adult disease risk is well-established, the effect of father's diet on offspring development is largely unknown. Therefore, we fed male mice an imbalanced low protein diet (LPD) to determine the impact on post-fertilisation development and fetal growth. We observed that in preimplantation embryos derived from LPD fed males, expression of multiple genes within the central metabolic AMPK pathway was reduced. In late gestation, paternal LPD programmed increased fetal weight, however, placental weight was reduced, resulting in an elevated fetal:placental weight ratio. Analysis of gene expression patterns revealed increased levels of transporters for calcium, amino acids and glucose within LPD placentas. Furthermore, placental expression of the epigenetic regulators Dnmt1 and Dnmt3L were increased also, coinciding with altered patterns of maternal and paternal imprinted genes. More strikingly, we observed fetal skeletal development was perturbed in response to paternal LPD. Here, while offspring of LPD fed males possessed larger skeletons, their bones comprised lower volumes of high mineral density in combination with reduced maturity of bone apatite. These data offer new insight in the underlying programming mechanisms linking poor paternal diet at the time of conception with the development and growth of his offspring., (Copyright © 2017 Elsevier B.V. All rights reserved.)

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.

The use of cannabis during pregnancy has emerged as a mounting cause for concern due to its potential adverse consequences on both the mother and her offspring. This review will focus on the dangers associated with prenatal exposure to cannabis, particularly those related to neurodevelopment. It will also discuss the features of maternal and placental functioning that are likely to have long-term effects on the offspring's development. The most pertinent and up-to-date materials can be found through a literature search. The literature emphasizes the substantial hazards associated with prenatal exposure to cannabis. These include impairments in cognitive function and difficulties in behavior in this particular instance. Structural and functional alterations in the brain can be noticed in offspring. The use of cannabis has been associated with an increased likelihood of experiencing pregnancy-related complications, such as giving birth prematurely and having a baby with a low birth weight. Additionally, it has been connected to potential negative effects on mental and emotional well-being. Studies have shown that when a pregnant woman is exposed to cannabis, it can negatively impact the functioning of the placenta and the growth of the fetus. This might potentially contribute to the development of placental insufficiency and restricted growth in the womb. Longitudinal studies reveal that children who were exposed to cannabis in the womb experience additional long-term developmental challenges, such as decreased cognitive abilities, reduced academic performance, and behavioral issues. In order to address the problem of cannabis usage during pregnancy, it is essential to adopt a comprehensive and coordinated strategy. This method should integrate and synchronize public health policy, education, and research initiatives. By implementing these targeted strategies, it is possible to mitigate potential health and welfare concerns for both present and future generations. [ABSTRACT FROM AUTHOR]

Trophoblast cell syncytialization is essential for placental and fetal development. Abnormal trophoblast cell fusion leads to pregnancy pathologies, such as preeclampsia (PE), intrauterine growth restriction (IUGR), and miscarriage. 27-hydroxycholesterol (27-OHC) is the most abundant oxysterol in human peripheral blood synthesized by sterol 27-hydroxylase (CYP27A1) and is considered a critical mediator between hypercholesterolemia and a variety of related disorders. Gestational hypercholesterolemia was associated with spontaneous preterm delivery and low birth weight (LBW) in term infants, yet the mechanism is unclear. In this study, two trophoblast cell models and CD-1 mice were used to evaluate the effects of 27-OHC on trophoblast fusion during placenta development. Two different kinds of trophoblast cells received a dosage of 2.5, 5, or 10 uM 27-OHC. Three groups of pregnant mice were randomly assigned: control, full treatment (E0.5-E17.5), or late treatment (E13.5-E17.5). All mice received daily intraperitoneal injections of saline (control group) and 27-OHC (treatment group; 5.5 mg/kg). In vitro experiments, we found that 27-OHC inhibited trophoblast cell fusion in primary human trophoblasts (PHT) and forskolin (FSK)-induced BeWo cells. 27-OHC up-regulated the expression of the PI3K/AKT/mTOR signaling pathway-related proteins. Moreover, the PI3K inhibitor LY294002 rescued the inhibitory effect of 27-OHC. Inhibition of trophoblast cell fusion by 27-OHC was also observed in CD-1 mice. Furthermore, fetal weight and placental efficiency decreased and fetal blood vessel development was inhibited in pregnant mice treated with 27-OHC. This study was the first to prove that 27-OHC inhibits trophoblast cell fusion by Activating PI3K/AKT/mTOR signaling pathway. This study reveals a novel mechanism by which dyslipidemia during pregnancy results in adverse pregnancy outcomes. [ABSTRACT FROM AUTHOR]

Objective: Birth weight, fetal growth and placental function influence cognitive development. The gradient of these associations is understudied, especially among those with a birth weight considered appropriate‐for‐gestational age. The aim of this study was to evaluate the associations between birth‐weight centile and intellectual development in term/near‐term infants across the entire birth‐weight spectrum, in order to provide a basis for better understanding of the long‐term implications of fetal growth restriction and reduced placental function. Methods: This was a population‐based cohort study of 266 440 liveborn singletons from uncomplicated pregnancies, delivered between 36 and 42 weeks of gestation. Perinatal data were obtained from the Dutch Perinatal Registry over the period 2003–2008 and educational data for children aged approximately 12 years were obtained from Statistics Netherlands over the period 2016–2019. Regression analyses were conducted to assess the association of birth‐weight centile with school performance. The primary outcomes were mean school performance score, on a scale of 501–550, and proportion of children who reached higher secondary school level. Results: Mean school performance score increased gradually with increasing birth‐weight centile, from 533.6 in the 1st–5th birth‐weight‐centile group to 536.8 in the 81st–85th birth‐weight‐centile group. Likewise, the proportion of children at higher secondary school level increased with birth‐weight centile, from 43% to 57%. Compared with the 81st–85th birth‐weight‐centile group, mean school performance score and proportion of children at higher secondary school level were significantly lower in all birth‐weight‐centile groups below the 80th centile, after adjusting for confounding factors. Conclusions: Birth‐weight centile is associated positively with school performance at 12 years of age across the entire birth‐weight spectrum, well beyond the conventional and arbitrary cut‐offs for suspected fetal growth restriction. This underlines the importance of developing better tools to diagnose fetal growth restriction and reduced placental function, and to identify those at risk for associated short‐ and long‐term consequences. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology. [ABSTRACT FROM AUTHOR]

Simple Summary: Despite the relevance of biometrical and blood flow assessments for studying fetoplacental physiology during pregnancy, there is no detailed description of any animal model, which is needed to extrapolate results to human pregnancy. Here, we examined biometry and intrauterine blood flow in pregnant guinea pigs from the second trimester until term. We show that fetal and placental biometry, as well as changes in the main vascular beds across pregnancy, compared qualitatively to data from humans. These findings emphasize that the guinea pig is a reliable model to study fetal development and placental function with translational significance for human pregnancy. Background: Biometrical and blood flow examinations are fundamental for assessing fetoplacental development during pregnancy. Guinea pigs have been proposed as a good model to study fetal development and related gestational complications; however, longitudinal growth and blood flow changes in utero have not been properly described. This study aimed to describe fetal and placental growth and blood flow of the main intrauterine vascular beds across normal guinea pig pregnancy and to discuss the relevance of this data for human pregnancy. Methods: Pregnant guinea pigs were studied from day 25 of pregnancy until term (day ~70) by ultrasound and Doppler assessment. The results were compared to human data from the literature. Results: Measurements of biparietal diameter (BPD), cranial circumference (CC), abdominal circumference, and placental biometry, as well as pulsatility index determination of umbilical artery, middle cerebral artery (MCA), and cerebroplacental ratio (CPR), were feasible to determine across pregnancy, and they could be adjusted to linear or nonlinear functions. In addition, several of these parameters showed a high correlation coefficient and could be used to assess gestational age in guinea pigs. We further compared these data to ultrasound variables from human pregnancy with high similarities. Conclusions: BPD and CC are the most reliable measurements to assess fetal growth in guinea pigs. Furthermore, this is the first report in which the MCA pulsatility index and CPR are described across guinea pig gestation. The guinea pig is a valuable model to assess fetal growth and blood flow distribution, variables that are comparable with human pregnancy. [ABSTRACT FROM AUTHOR]

SARS-CoV-2 has infected more than 16 million people worldwide. Related complications and death from COVID-19 disease and their underlying pathophysiology are intensely investigated. Pregnant women are among the affected. Although the severity of disease in pregnancy does not appear to be increased, the effects of infection on pregnancy should not escape careful examination. The currently known receptor for the virus, ACE2, regulates the renin-angiotensin system and is increased during pregnancy. Virus-receptor interactions may have significant effects on placental function, fetal development, and maternal immunity. The manifestation of cardiovascular complications of infection produces the hypothesis that a significant effect of the virus may be its influence on the maternal vascular system. Interference with the vascular adaptations to pregnancy and the post-partum may have implications for concurrent and future pregnancies as well as for long-term cardiovascular health. We should not miss the opportunity to learn from this virus about the physiology of pregnancy. [ABSTRACT FROM AUTHOR]

Background/Aim. The placenta is essential in pregnancy, facilitating nutrient and gas exchange between mother and fetus. However, the regulatory proteins involved in this process are not fully understood across gestation. This study aimed to identify the top 20 differentially expressed genes (DEGs) in the placenta across different pregnancy stages to elucidate the molecular mechanisms at play. Methods. Differential gene expression analysis was performed on the placental samples from the first, second, and third trimesters using microarray data from Gene Expression Omnibus and Array Express. Analysis was conducted in RStudio using the R programming language. DEGs were identified using a significance score (π-value) based on the method developed by Xiao Y et al. (2014), which combines fold change and p-value. Volcano plots were created to visualize DEGs, and the top 20 were analyzed for functional enrichment using STRING and EnrichR databases, including Gene Ontology and KEGG pathways. Results. In the transition from the first to the second trimester, significant DEGs included genes involved in steroid metabolism such as HSD11B1, HSD3B2, and HSD17B2. These genes are critical in the biosynthesis and metabolism of steroid hormones, essential for sustaining pregnancy and supporting fetal development. Enrichment analysis showed these genes were significantly associated with steroid biosynthesis and steroidogenesis pathways. For the transition from the second to the third trimester, different sets of genes were highlighted, particularly those related to endocrine regulation and pregnancy-specific functions. Key genes included CRH, INHBA, REN, and members of the pregnancy-specific glycoprotein (PSG) family. These genes are involved in hormone regulation, reproductive processes, and maintaining maternal-fetal homeostasis, with significant associations with pathways related to endocrine processes, reproductive health, and vascular function. For example, the involvement of CRH and REN in endocrine regulation suggests their role in modulating maternal and fetal physiology during the later stages of pregnancy. Also, the genes associated with vascular and hemostatic functions were identified, indicating the importance of maintaining proper blood flow and preventing bleeding complications as pregnancy progresses. Notable genes included SDC1 and HBE1, which are crucial for vascular integrity and oxygen transport. Volcano plots illustrated these shifts in gene expression, with the top 20 genes identified by π-value prominently displayed. Conclusions. This study provides an analysis of gene expression changes in the placenta throughout pregnancy, identifying key genes and pathways that regulate placental function and impact fetal development. These findings enhance the understanding of placental biology and may highlight potential targets for ensuring optimal fetal development. [ABSTRACT FROM AUTHOR]

Objectives: To investigate whether a near infrared spectroscopy (NIRS) system is useful for evaluation of the placental function in cases of fetal growth restriction (FGR). Methods: Subjects included 282 delivered neonates of appropriate for gestational age (AGA) and 44 small for gestational age (SGA) babies. The measurement of the concentration of oxyhemoglobin (HbO2) and deoxyhemoglobin (HHb) was conducted using transabdominal NIRS targeting the placenta at around 20 weeks, 30 weeks and after 36 weeks of gestation and calculated tissue oxygen indexes (TOI=HbO2/total Hb). We correlated between TOIs and causes of FGR. Results: TOIs measured immediately before delivery in the SGA group with severe pre-eclampsia (79.2±3.8 (%±standard deviation (SD); P=0.002)) and placental abnormalities (78.2±3.6; P=0.043) were higher than in the AGA group (74.0±4.5). TOIs in the SGA group with umbilical cord abnormalities were lower (69.7±7.7; P=0.024) than in the AGA group. Conclusion: NIRS might provide information about blood oxygen level of the intervillous space and thus explain the cause of FGR. [ABSTRACT FROM AUTHOR]

The aim of the paper is to realize an update concerning the published data on the correlation between maternal obesity, placental dysfunction and fetal development. The association between gestational obesity and maternal-fetal health remains incompletely known, themechanisms linking the maternal obesogenic environment and the short and long term fetal consequences being complex and partly unknown. We analyzed the online data published in Pub Med and Cochrane databases over the past 5 years on the impact of obesity on pregnancy and fetal and neonatal outcome. Reproduction is controlled by the maternal energy balance, adipokines playing a significant role in providing a favorable environment for implantation and placentation. During pregnancy, the placenta secretes cytokines with significant role in the fetal allograft fate. The production of TNFα, IL-6 and IL-1β contributes to the increase of proinflammatorystate creating a low-level inflammation called meta-inflammation. This state generates intolerance to maternal glucose and insulin resistance conducting to cardiovascular and neuroendocrinemodulation. The levels of maternal adipokines and hormones with metabolic effects and their ways of interaction with placental function and fetal growth were examined. Maternal obesity generates a vicious circle: newborns have a two times higher risk of infant obesity, metabolic, cardiovascular, neuropsychiatric and cognitive complication and a depressed and anxious phenotype, with socializing and hyperactivity disorders. Programming hypothalamic development affected by leptin resistance controls organ growth, including brain, appetite and cognition. There is a close link between the maternal nutritional status, body fat metabolism, placental function and nutrient transfer to the fetus, controlling fetal growth. Maternal obesity is correlated with an adipokine-induced inflammatory process that interferes with maternal glucose intolerance, insulin resistance, neuroendocrine and cardiovascular modeling associated with changes in BMI. In obese pregnancies, pro-inflammatory cytokines include high maternal circulating levels of TNFα, IL- 6 andleptin, while adiponectin levels are reduced, increasing the transplacental nutrient transport leading to the development of macrosomes. Overexpression of placental TLR4 in obese pregnancies correlates with increased IL-6 expression, hyperglycemia and maternal insulin resistance, thus associating increased risk of premature birth, preeclampsia and placental endothelial dysfunction. This is manifested by the reduction of both the PIGF and the VEGF / Flt1 ratio, limiting angiogenesis and generating a reduction in nutrient transport to the fetus and, consequently SGA or IUGR. Maternal obesity can cause the birth of a very wide range of birth-weight newborns, which has a major impact on the child's later neurobehavioral development. Restoring maternal adiponectin levels in obese pregnant women could be considered a method of preventing obesity and metabolic diseases in the descendants. [ABSTRACT FROM AUTHOR]