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Introduction: The distribution of myeloperoxidase (MPO) and dendritic cells (DCs) in sponge trophoblast cells may contribute to the syncytialisation of trophoblast cells and the establishment of uterine placental circulation. Our previous series of studies have shown that MPO plays an important role in angiogenesis and repair, and placental vascular dysfunction can lead to serious pregnancy complications and even miscarriage., Methods: Mouse model of MPO knockout was constructed, and the crosstalk between MPO and dendritic cells (DC) cells was investigated to determine whether MPO is involved in the pregnancy process. Abnormal decidual vasculogenesis in MPO -/- pregnant mice was also suggested by RNA-seq analysis of uterine tissues from pregnant mice. In addition, we extracted mouse BMDC, analyzed the relationship between Mpo and BMDC, and established a co-culture system between BMCD and endothelial cells., Results: It was found that angiogenesis in the decidual tissue of MPO -/- mice was impaired in early pregnancy, while in WT mice of the same pregnancy period, MPO and DC were observed to co-localize at the site of vascular development, it was found that immature BMDC can significantly promote the tube formation ability of endothelial cells in vitro, while MPO it is the key for BMDC to maintain immature phenotype., Discussion: In conclusion, our study reveals a new role of immature DCs induced by MPO in promoting vascular remodeling of decidual tissue and functional placental formation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025. Published by Elsevier Ltd.)

The placenta plays a pivotal role in fetal development and the dam's subsequent lactation performance, because it facilitates nutrient transfer, heat dissipation, and gas exchange with the growing fetus, and regulates key hormones essential for mammary gland development. Heat stress experienced during gestation and lactation can significantly reduce the placenta's capacity to perform these critical functions. To investigate the impact of heat stress, trials were conducted over the summer months of 2020, 2022, and 2023 in Florida. Multiparous pregnant Holstein cows were dried off 54 ± 5 d before their expected calving date and randomly assigned to 1 of 2 treatments for the entire dry period: active cooling (CL; access to barn shade, natural ventilation plus forced air circulation via fans, and water soakers; n = 20) or heat stress (HT; access to barn shade and natural ventilation; n = 20). Gestation length and calf birth weights were recorded. Placentas were collected from a subset of cows shortly after calving (4.00 ± 1.54 h; n = 10/treatment) and analyzed for total placental weight, as well as cotyledon weight, number, and surface area within 1 h after expulsion. A representative cotyledon sample was isolated for histological analysis. Tissues were also processed for RNA sequencing and DNA methylation analysis. DNA methylation was analyzed by double restriction enzyme reduced representation bisulfate sequencing. Differentially methylated cytosines between HT and CL were identified via logistic regression with a cut-off value of 15% methylation difference and a q-value <0.2. Morphological and histological data were analyzed using generalized linear mixed models. Results indicate that gestation length was shorter in HT cows compared with CL cows (274.2 vs. 277.2 ± 1.46 d), and heifers born to HT dams were lighter at birth (31.4 vs. 34.8 ± 1.59 kg). Placentas from HT dams tended to have lower total weight (3.54 vs. 4.54 ± 0.38 kg) and fewer cotyledons (66.2 vs. 103.3 ± 8.65). However, placental efficiency was higher in the HT versus CL group (11.5 vs. 8.52 ± 0.91%). Cotyledons from HT cows had greater vascular area (43.1% vs. 31.8% ± 10.4% of total area) and a tendency for less connective tissue (52.7% vs. 65.8% ± 5.39% of total area). A total of 289 differentially expressed genes were identified between HT and CL placentas, with 179 upregulated and 110 downregulated in the HT group. Key genes affected included NPSR1, SPATC1L, PGF, HSPB8, IL6, HBA/HBB, MMP12, PAPPA2, PAG14, and SLC7A10. Dysregulated pathways in HT placentas involved gas and oxygen transport, nutrient transport, inflammatory response, and cortisol biosynthesis. Heat stress induced hypermethylation of regulatory pathways, including collagen biosynthesis and degradation, extracellular matrix structural components, and placental tissue organization. Our findings demonstrate that late-gestation HT causes significant transcript alterations in the placenta, leading to adaptations for thermoregulation and morphological changes. These alterations negatively affect birth weight, health, and dam lactation performance, underscoring the need to address HT during late gestation to ensure optimal fetal development and postnatal outcomes. Addressing these issues can help improve dairy cow resilience to climate change, enhancing animal welfare and productivity., (The Authors. Published by Elsevier Inc. on behalf of the American Dairy Science Association®. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).)

Introduction: Maternal hyperthermia (i.e. heat stress) can adversely affect placental development and function, with severity varying based on pregnancy stage. During the last half of pregnancy, cow uterine blood flow increases 4.5-fold, and decreased maternal blood circulation can reduce placental diffusion capacity, impacting fetal growth., Material and Methods: Milk removal was discontinued (i.e. dried off) in multiparous pregnant Holstein cows 54 ± 5 days before expected calving and assigned to cooling (CLD) or heat stress (HT) treatments. Oxygen measurements were taken within ±3 h after birth (n = 7 per group) using the Rad-G Pulse Oximeter. RNA sequencing of cotyledonary tissue examined pathways and genes related to gas and oxygen transport., Results: Heifers exposed to late gestation in utero hypoxia (HT) had significantly lower oxygen saturation at birth compared with those from dams with normal (CLD) oxygen levels (83.4 % vs. 90.7 %, p = 0.03). The peripheral index of oxygen diffusion was also lower in HT-exposed heifers (2.04 % vs. 4.84 %, p = 0.01). Gene enrichment analysis of cotyledonary tissue revealed affected pathways, including response to hypoxia, oxygen transport, and VEGF signaling. Late gestation HT potentially influenced blood circulation and nitric oxide biosynthesis pathways, with various genes showing upregulation and downregulation., Discussion: The placenta is vital for fetal development, and late gestation hyperthermia can significantly affect its function, reducing fetal oxygen delivery and altering genes regulating placental gas and oxygen transport. These disruptions may result in fetal hypoxemia and growth restriction., Competing Interests: Declaration of competing interest None of the authors have any conflict of interest for the manuscript., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Objectives: T2*-weighted magnetic resonance imaging (MRI) sequences have been identified as non-invasive tools with which to study placental oxygenation in vivo. This study aimed to use these to investigate both static and dynamic responses to hyperoxia of the normal placenta across gestation., Methods: We conducted a single-center prospective study including 52 uncomplicated pregnancies. Two T2*-weighted sequences (T2* relaxometry) were performed, one before and one after maternal hyperoxia. The distribution of placental T2* values was modeled by fitting a gamma probability density function (T2* ~ Γ α β ), describing the structure of the histogram using the mean T2* value, the shape parameter (α) and the rate (β). A dynamic acquisition (blood-oxygen-level-dependent (BOLD) MRI) was also performed before and during maternal oxygen supply, until placental oxygen saturation had been achieved. The signal change over time was modeled using a sigmoid function, to determine the intensity of enhancement (ΔBOLD (% with respect to baseline)), a temporal variation coefficient (λ (min -1 ), controlling the slope of the curve) and the maximum steepness (Vmax (% of placental enhancement/min))., Results: The histogram analysis of the T2* values in normoxia showed a whole-placenta variation, with a decreasing linear trend in the mean T2* value (Pearson's correlation coefficient (R) = -0.83 (95% CI, -0.9 to -0.71), P < 0.001), along with an increasingly peaked and narrower distribution of T2* values with advancing gestation. After maternal hyperoxia, the mean T2* ratios (mean T2* hyperoxia /mean T2* baseline ) were positively correlated with gestational age, while the other histogram parameters remained stable, suggesting a translation of the histogram towards higher values with a similar appearance after maternal hyperoxia. ΔBOLD showed a non-linear increase across gestation. Conversely, λ showed an inverted trend across gestation, with a weaker correlation (R = -0.33 (95% CI, -0.58 to -0.02), P = 0.04, R 2  = 0.1). As a combination of ΔBOLD and λ, the changes in Vmax throughout gestation were influenced mainly by the changes in ΔBOLD and showed a positive non-linear correlation with gestational age., Conclusions: Our results suggest that the decrease in the T2* placental signal as gestation progresses does not reflect placental dysfunction. The BOLD dynamic signal change is representative of a free-diffusion model of oxygenation and highlights the increasing differences in oxygen saturation between mother and fetus as gestation progresses (ΔBOLD) and in the placental permeability to oxygen (λ). © 2024 International Society of Ultrasound in Obstetrics and Gynecology., (© 2024 International Society of Ultrasound in Obstetrics and Gynecology.)

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., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Introduction: Duplicated genes or paralogs play important roles in the adaptive function of eukaryotic genomes. Animal studies have shown evidence for the functional role of paralogs in pregnancy, but our knowledge about the role of paralogs in the fetoplacental regulation remains limited. In particular, if fetoplacental metabolic regulation is modulated by differential expression of paralogs remains unexamined., Methods: In this study, gene expression profiles of day-15 placenta and fetal brain were compared to identify families or groups of paralogous genes expressed in the placenta and brain of male versus female fetuses in mice. A Bayesian modeling was applied to infer directional relationship of transcriptional variation of the paralogs relative to the phylogenetic variation of the genes in each family. Gas chromatography-mass spectrometry (GC-MS) was used to perform untargeted metabolomics analysis of day-15 placenta and fetal brain of both sexes., Results: We identified paralog groups that were expressed in a sex and/or tissue biased manner between the placenta and fetal brain. Bayesian modeling showed evidence for directional relationship between expression and phylogeny of specific paralogs. These relationships were sex specific. GC-MS analysis identified metabolites that were expressed in a sex-bias manner between the placenta and fetal brain. By performing integrative analysis of the metabolomics and gene expression data, we showed that specific groups of metabolites and paralogous genes were expressed in a coordinated manner between the placenta and fetal brain., Discussion: The findings of this study collectively suggest that paralogs play an influential role in the regulation of the brain-placental axis in mice., Competing Interests: Declaration of competing interest None., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Objectives: Evidence regarding placental function in pregnancies complicated by confined placental mosaicism (CPM) is conflicting. We aimed to compare placental function between CPM and non-CPM pregnancies prenatally and at birth. A secondary objective was to evaluate the relationship between placental function and chromosomal subtype of CPM., Methods: This was a retrospective study of pregnancies with CPM and control pregnancies delivered at a tertiary hospital in Denmark between 2014 and 2017. Placental volume and placental transverse relaxation time (T2*) were estimated on magnetic resonance imaging (MRI), fetal weight and uterine artery pulsatility index (UtA-PI) were estimated on ultrasound and fetoplacental ratio was assessed on MRI and at birth. These estimates of placental function were adjusted for gestational age and compared between groups using the Wilcoxon rank-sum test. Within the group of CPM pregnancies, measures of placental function were compared between those at high risk (chromosome numbers 2, 3, 7, 13 and 16) and those at low risk (chromosome numbers 5, 18 and 45X)., Results: A total of 90 pregnancies were included, of which 12 had CPM and 78 were controls. MRI and ultrasound examinations were performed at a median gestational age of 32.6 weeks (interquartile range, 24.7-35.3 weeks). On MRI assessment, CPM placentae were characterized by a lower placental T2* Z-score (P = 0.004), a lower fetoplacental ratio (P = 0.03) and a higher UtA-PI Z-score (P = 0.03), compared with non-CPM placentae. At birth, the fetoplacental ratio was significantly lower (P = 0.02) and placental weight Z-score was higher (P = 0.01) in CPM pregnancies compared with non-CPM pregnancies. High-risk CPM pregnancies showed a reduced placental T2* Z-score (P = 0.003), lower birth-weight Z-score (P = 0.041), earlier gestational age at delivery (P = 0.019) and higher UtA-PI Z-score (P = 0.028) compared with low-risk CPM pregnancies. Low-risk CPM pregnancies did not differ in any of these parameters from non-CPM pregnancies., Conclusions: CPM pregnancies are characterized by an enlarged and dysfunctional placenta. Placental function was highly related to the chromosomal type of CPM; placental dysfunction was seen predominantly in high-risk CPM pregnancies in which chromosomes 2, 3, 7, 13 or 16 were involved. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology., (© 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.)

Aim: Noninvasive blood oxygen level-dependent magnetic resonance imaging (BOLD-MRI) has recently been used to evaluate placental oxygenation. However, this method still has unresolved problems, such as long testing times and lack of normal values set. In the present study, we used a shorter protocol in BOLD-MRI and established normal values for placental oxygenation in late pregnancy., Methods: We recruited 18 healthy singleton pregnant women (>32 weeks of gestation) who had a normal body size before pregnancy and a normal course of pregnancy. They underwent BOLD-MRI with three consecutive 4-min periods of different oxygenation: normoxia (21% O 2 ), hyperoxia (10 L O 2 /min), and then normoxia. Placental time-activity curves were presented as signal intensity change relative to baseline (ΔR2*). The time from starting maternal oxygen administration to peak ΔR2*. To assess the relationship between peak ΔR2* values and placenta-related parameters and fetal development, the correlation between peak ΔR2*, placental weight, and neonatal birth weight was evaluated using Spearman's rank correlation test., Results: In all cases, the BOLD signal was elevated by maternal oxygen administration, with the peak resolving within 4 min after the end of oxygen administration. Peak ΔR2* and time to peak ΔR2* during oxygenation were 7.99 ± 2.58, and 458.1 ± 73.9 s, respectively. There was a significant correlation between peak ΔR2* and neonatal birth weight (percentile) ( r  = 0.537, p  = .022), and between placental weight and neonatal birth weight ( r  = 0.769, p  < .01)., Conclusions: In all cases, the BOLD signal increased with maternal hyperoxia using this protocol. So, 4 min observation following maternal oxygen administration is sufficient for peak ΔR2* evaluation. These reference values set in this study may be one of the indicators of BOLD signal changes in normal pregnancies after 32 weeks of gestation.

Introduction: Placental dysfunction is one of the most common causes of Intrauterine Fetal Demise (IUFD). Due to its characteristics, the placenta may be the target of molecular research aimed to investigate potential causes of IUFD. In the literature, there are no studies on human placentas that have investigated possible associations between somatic mutations and the occurrence of IUFD. The aim of this study was to identify the presence of gene mutations in placental tissues in a series of cases of IUFD and to evaluate potential correlations with placental microscopic findings., Materials and Methods: Thirty-seven samples of formalin-fixed and paraffin-embedded placental tissues were retrospectively selected from pregnancies ending in IUFD between 23rd to 40th week. Six control placentas of physiological pregnancies were included as controls. After sampling, made according to standardized protocol and conventional histopathological examination, placental tissues were subjected to DNA extraction and sequencing by means of Next Generation Sequencing with a 56-gene panel., Results: The most frequent mutation observed in 32/37 IUFD cases (86.5%) and absent in any of the 6 control placentas was in c-KIT gene, which is implicated in placental tissue differentiation. However, no significant correlation was found between the presence of individual gene mutations and placental histopatological findings., Discussion: As the present study found an elevated frequency of c-KIT mutation in IUFD, it further supports the hypothesis that c-KIT is involved in abnormal tissue differentiation leading to altered placental vascularization and function., Competing Interests: Declaration of competing interest The authors certify that they have no affiliations with or involvement in any organization or entity with any financial interest or non-financial interest in the subject matter or materials discussed in this manuscript., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

The prevalence of maternal obesity is increasing at an alarming rate, and is providing a major challenge for obstetric practice. Adverse effects on maternal and fetal health are mediated by complex interactions between metabolic, inflammatory, and oxidative stress signaling in the placenta. Endoplasmic reticulum (ER) stress and activation of the unfolded protein response (UPR) are common downstream pathways of cell stress, and there is evidence that this conserved homeostatic response may be a key mediator in the pathogenesis of placental dysfunction. We summarize the current literature on the placental cellular and molecular changes that occur in obese women. A special focus is cast onto placental ER stress in obese pregnancy, which may provide a novel link for future investigation., Competing Interests: Declaration of interests No interests are declared., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Fetal growth restriction (FGR) is commonly associated with placental insufficiency and inflammation. Nonetheless, the role played by inflammasomes in the pathogenesis of FGR is poorly understood. We hypothesised that placental inflammasomes are differentially expressed and contribute to the aberrant trophoblast function. Inflammasome gene expression profiles were characterised by real-time PCR on human placental tissues collected from third trimester FGR and gestation-matched control pregnancies (n = 25/group). The functional significance of a candidate inflammasome was then investigated using lipopolysaccharide (LPS)-induced models of inflammation in human trophoblast organoids, BeWo cells in vitro, and a murine model of FGR in vivo. Placental mRNA expression of NLRP3, caspases 1, 3, and 8, and interleukin 6 increased (>2-fold), while that of the anti-inflammatory cytokine, IL-10, decreased (<2-fold) in FGR compared with control pregnancies. LPS treatment increased NLRP3 and caspase-1 expression (>2-fold) in trophoblast organoids and BeWo cell cultures in vitro, and in the spongiotrophoblast and labyrinth in the murine model of FGR. However, the LPS-induced rise in NLRP3 was attenuated by its siRNA-induced down-regulation in BeWo cell cultures, which correlated with reduced activity of the apoptotic markers, caspase-3 and 8, compared to the control siRNA-treated cells. Our findings support the role of the NLRP3 inflammasome in the inflammation-induced aberrant trophoblast function, which may contribute to FGR.

Ultrasound imaging is a vital tool for exploring in vivo the placental function which is essential to understand pathological phenomena such as preeclampsia or intrauterine growth restriction. As technology advances including ready availability of three-dimensional (3D) probes and novel software, new markers of placental function become possible. The objective of this review was to provide an overview of the new ultrasound markers of placental function with a focus on the potential clinical application of three-dimensional power Doppler (3DPD). A broad-free text literature search was undertaken based on human placental studies and sixty full-text studies were included in this review. Three-dimensional power Doppler is a promising technique to predict preeclampsia in the first trimester. However, the influence of external factors such as body mass index, parameter standardisation and machine settings still need to be addressed. Contrast-enhanced ultrasound is currently reserved for research, because the required injected contrast mediums are not currently approved for use in pregnancy, although the safety data is reassuring., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Obesity is a chronic condition associated with dyslipidemia and insulin resistance. Here, we show that the offspring of obese mothers are dyslipidemic and insulin resistant from the outset.Maternal and cord blood and placental tissues were collected following C-section at term. Patients were grouped as being normal weight (NW, BMI = 18-24.9) or obese (OB, BMI ≥ 30), and separated by fetal sex. We measured plasma lipids, insulin, and glucose in maternal and cord blood. Insulin resistance was quantified using the HOMA-IR. Placental markers of lipid and energy metabolism and relevant metabolites were measured by western blot and metabolomics, respectively.For OB women, total cholesterol was decreased in both maternal and cord blood, while HDL was decreased only in cord blood, independent of sex. In babies born to OB women, cord blood insulin and insulin resistance were increased. Placental protein expression of the energy and lipid metabolism regulators PGC1α, and SIRT3, ERRα, CPT1α, and CPT2 decreased with maternal obesity in a sex-dependent manner (P < 0.05). Metabolomics showed lower levels of acylcarnitines C16:0, C18:2, and C20:4 in OB women's placentas, suggesting a decrease in β-oxidation. Glutamine, glutamate, alpha-ketoglutarate (αKG), and 2-hydroxyglutarate (2-HG) were increased, and the glutamine-to-glutamate ratio decreased (P < 0.05), in OB placentas, suggesting induction of glutamate into αKG conversion to maintain a normal metabolic flux.Newly-born offspring of obese mothers begin their lives dyslipidemic and insulin resistant. If not inherited genetically, such major metabolic perturbations might be explained by abnormal placental metabolism with potential long-term adverse consequences for the offspring's health and wellbeing.

Introduction: Data on placental pathologic features associated with thyreoperoxidase antibodies (TPO Ab) and/or hypothyroidism are limited. The objective of the study was to analyze placental pathologic features of women with TPO Ab positivity., Methods: Prospective case-control observational study of pregnancy outcome among women screened for TPO Ab positivity and/or isolated hypothyroidism (TSH>4mU/L) during the first trimester of pregnancy. Placenta pathologic findings were recorded according to standard classification., Results: The overall rates of TPO Ab positivity and isolated hypothyroidism with negative TPO Ab were 9.6% (86/899) and 2.7% (24/899), respectively. Among TPO Ab positive cases, 77.9% (67/86) and 22.1% (19/86) had TSH ≥2.5mU/L or <2.5mU/L, respectively. Compared to controls, mean first and second trimester uterine artery Doppler pulsatility indices (PI) were higher, placental volume and area were lower among cases with TSH≥2.5mU/L. The rates of fetal growth restriction (FGR)/small for gestational age (SGA) (20/67 versus 8/110, Adjusted Odds Ratio (AdjOR) = 10.8,95%CI = 2.7-44), placental pathological features suggesting decidual vasculopathy (37/67 versus 27/110, AdjOR = 2.7,95%CI = 1.1-6.8) or severe maternal vascular malperfusion (MVM) (22/67 versus 9/110, AdjOR = 5.8,95%CI = 1.6-20.1) were higher among cases with TSH ≥2.5mU/L than in controls. Similar results were obtained comparing overall TPO Ab positive subjects to controls. The increased risk of defective placentation and FGR associated with TPO Ab was independent of simultaneous presence of antinuclear antibodies (ANA) and TSH concentration., Discussion: First trimester TPO Ab positivity was associated with increased rates of abnormal uterine artery Doppler PI and placental features of MVM. This association was independent of TSH concentration and presence of ANA., Competing Interests: Declaration of competing interest None., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Worldwide demand for petroleum products has resulted in increased oil and gas activities in many countries. Conventional and unconventional oil and gas extraction, production, and transport lead to increased levels of petroleum-derived polycyclic aromatic hydrocarbons (PAHs) in the environment. PAH exposure has profound effects on reproduction by affecting pathways involved in placental trophoblast cell function and impairing normal placental development and function-key contributors to reproductive success. However, other components found in petroleum and wastewaters from oil and gas extraction, including the sulfur-containing heterocyclic aromatic compounds such as dibenzothiophene (DBT) and its alkylated derivatives, may also impact reproductive success. The goal of this study was to examine the effect of exposure to DBT, a compound commonly detected in the environment, and one of its alkylated analogues, 2,4,7-trimethyldibenzothiophene (2,4,7-DBT), on steroidogenic and angiogenic pathways critical for mammalian development in placental trophoblast cells (HTR-8/SVneo cells). 2,4,7-DBT but not DBT increased estradiol output in association with increased tube-like formation (surrogate for angiogenesis). These changes in angiogenesis did not appear to be related to altered expression of the key placental angiogenic gene targets (ANGPTL4, VEGFA, and PGF). Neither compound showed a concentration related effect on progesterone synthesis or its receptor expression. Our results suggest that 2,4,7-DBT can disrupt key pathways important for placental trophoblast function and highlight the importance of determining the impact of exposure to both parent and alkylated compounds. Further, these data suggest that exposure to sulfur-containing heterocyclic aromatic compounds may lead to placental dysfunction and impact reproductive success at environmentally relevant levels., (© 2020 John Wiley & Sons, Ltd.)

Introduction: In this study, we aimed at quantifying placental concentrations of 22 chemical elements in small fetuses (SGA) as compared with normally grown fetuses (AGA), and to assess the relationship with Doppler markers of placental function., Methods: Prospective cohort study, including 71 SGA fetuses (estimated fetal weight < 10th percentile) and 96 AGA fetuses (estimated fetal weight > 10th percentile), recruited in the third trimester of gestation. The placental concentration of 22 chemical elements was determined by inductively coupled plasma optical emission spectrophotometer (ICP-OES, ICAP 6500 Duo Thermo): aluminum (Al), beryllium (Be), bismuth (Bi), calcium (Ca), cadmium (Cd), cobalt (Co), chrome (Cr), copper (Cu), magnesium (Mg), manganese (Mn), molybdenum (Mo), nickel (Ni), phosphorus (P), lead (Pb), rubidium (Rb), sulfur (S), strontium (Sr), titanium (Ti), thallium (Tl), antimony (Sb), selenium (Se), and zinc (Zn). Placental function was assessed by measuring the following fetal-maternal parameters: Uterine artery Pulsatility Index (UtA PI), Umbilical artery Pulsatility Index (UA PI) and Middle Cerebral artery Pulsatility Index (MCA PI). The association between the chemical elements concentration and study group and the association with Doppler measures were evaluated., Results: SGA was associated with significantly (p < 0.05) lower concentrations of Al (AGA 21.14 vs SGA 0.51 mg/kg), Cr (AGA 0.17 vs SGA 0.12 mg/kg), Cu (AGA 0.89 vs SGA 0.81 mg/kg), Mg (AGA 0.007 vs SGA 0.006 g/100g), Mn (AGA 0.60 vs SGA 0.47 mg/kg), Rb (AGA 1.68 vs SGA 1.47 mg/kg), Se (AGA 0.02 vs SGA 0.01 mg/kg), Ti (AGA 0.75 vs SGA 0.05 mg/kg) and Zn (AGA 9.04 vs SGA 8.22 mg/kg). Lower placental concentrations of Al, Cr, Mn, Se, Ti were associated with abnormal UtA, UA and MCA Doppler., Discussion: Lower placental concentrations of Al, Cr, Cu, Mn, Rb, Se, Ti and Zn are associated with SGA fetuses and abnormal fetal-maternal Doppler results. Additional studies are required to further understand how chemical elements affect fetal growth and potentially find strategies to prevent SGA., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

The dynamic cycling of N -acetylglucosamine, termed as O-GlcNAcylation, is a post-translational modification of proteins and is involved in the regulation of fundamental cellular processes. It is controlled by two essential enzymes, O-GlcNAc transferase and O-GlcNAcase. O-GlcNAcylation serves as a modulator in placental tissue; furthermore, increased levels of protein O-GlcNAcylation have been observed in women with hyperglycemia during pregnancy, which may affect the short-and long-term development of offspring. In this review, we focus on the impact of O-GlcNAcylation on placental functions in hyperglycemia-associated pregnancies. We discuss the following topics: effect of O-GlcNAcylation on placental development and its association with hyperglycemia; maternal-fetal nutrition transport, particularly glucose transport, via the mammalian target of rapamycin and AMP-activated protein kinase pathways; and the two-sided regulatory effect of O-GlcNAcylation on inflammation. As O-GlcNAcylation in the placental tissues of pregnant women with hyperglycemia influences near- and long-term development of offspring, research in this field has significant therapeutic relevance., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Ning and Yang.)

Placental-associated diseases account for most cases of adverse perinatal outcome in developing countries. Doppler evaluation has been incorporated as a predictive parameter at early pregnancy for high-risk placental disease, in the diagnosis and management of those fetuses with impaired intrauterine growth and for the evaluation of fetal wellbeing in those high-risk pregnancies. Uterine Doppler at second trimester predicts most instances of early-onset preeclampsia and intrauterine growth restriction. However, the growing evidence of an effective early propylactic strategy, has turned Uterine Doppler an essential parameter to be included in first trimester predictive algorithms. Umbilical artery Doppler helps in the identification of small-for-gestational-age fetuses at higher risk, and is one of the essential vessels in the assessment of fetal hypoxia impairment, especially in the early cases. It helps in the decision timing for ending the pregnancy improving thus perinatal outcomes. Moreover, in high-risk pregnancies, umbilical artery Doppler has demonstrated to reduce the risk of perinatal deaths and the risk of obstetric interventions. On the other hand, middle cerebral artery Doppler reflects fetal adaptation to hypoxia, and with the cerebroplacental ratio, they improve the detection of fetuses a high risk of adverse perinatal outcome, mostly of those late small fetuses, where most instances of adverse outcome occur in fetuses with normal umbilical artery. Ductus venosous Doppler waveform is a surrogate parameter of the fetal base-acid status. Its use has demonstrated to improve perinatal outcomes, mainly reducing the risk of fetal intrauterine death. Alone or in combination with computerized CTG, it helps tailoring the best moment to end the pregnancy among early cases., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

The study of placental lipid metabolism in uncomplicated pregnancies has not been developed in the literature to date. Its importance lies in expanding the knowledge of placental function to enable comparison with pathological pregnancies in future research. The aim of the present study was to compare the lipid metabolic activity and storage of the maternal and fetal sides of the placenta in healthy pregnancies. Moreover, we compare singleton vs. twin pregnancies to determine if placental metabolic needs differ. We analyzed placental explants from uncomplicated pregnancies, 20 from singleton and 8 from bichorial-biamniotic twin pregnancies (n = 28). Six cotyledon fragments were collected from each placenta at different distances from the umbilical cord, three close to the chorionic plate (hereinafter, we will refer to them as "fetal side") and another three close to the anchoring villi into the decidua basalis (referred to as "maternal side"). The samples were analyzed for quantitative assay placental fatty acid oxidation (FAO) and esterification (FAE) activities and triglyceride levels. The location of lipid storage in the chorionic villi was assessed by Oil red-O staining. Placental fatty acid oxidation did not show differences when comparing the maternal and fetal sides of the placenta or between single and twin pregnancies. When comparing placental sides, FAE was increased twofold in the maternal side compared to the fetal side of the placenta (P = 0.013). The tendency for lipogenesis in the placenta was exemplified by the FAE/FAO ratio, which was a 37.1% higher on the maternal side (P = 0.019). Despite this, triglyceride levels were five times higher in the fetal side than in the maternal one (P = 0.024). When analyzing singleton vs. twins, FAE was superior in the fetal side in multiple pregnancies (× 2.6, P = 0.007) and the FAE/FAO ratio was significantly higher in twins than in singleton pregnancies, on both sides of the placenta. Despite this finding, triglyceride levels were similar in twin and singleton pregnancies. Comparing the placentas of twins in the same pregnancy, there were no differences in lipid metabolism (FAO or FAE) or placental triglyceride levels between the two co-twins. Using Oil red-O staining, lipid storage in chorionic villi was found to be located on the syncytiotrophoblast cells and not in the connecting axis. The maternal side of the placenta is more active in the esterification of fatty acids, while the storage of neutral lipids concentrates on the fetal side. Moreover, multiple gestations have increased esterification without changes in the concentration of placental triglycerides, probably due to a higher transfer to the fetal circulation in response to the greater energy demand from twin fetuses.

Objective: To evaluate the association of antiretroviral therapy (ART) type and duration of exposure with early placental function using biomarkers of aneuploidy screening. Study design: Three hundred thirty-eight pregnant women living with HIV were enrolled in two Canadian centers. Multiple linear regressions were performed adjusting for confounding factors (race, age, gestational age, body mass index, parity, smoking, and fetal sex). Results: Women receiving ART had significantly increased second trimester alpha-fetoprotein (AFP) levels ( β  = 0.147, 95% CI = [0.067-0.227] for protease inhibitor-based ART and β  = 0.176, 95% CI = [0.080-0.272] for ART without protease inhibitor) compared to women who received no treatment. However, there was no significant association between ART type and the levels of free β-human chorionic gonadotrophin (β-hCG), pregnancy-associated plasma protein-A (first trimester), unconjugated estriol, total hCG, and inhibin A (second trimester). No significant association was shown between biomarker levels and duration of ART exposure. Conclusion: Early placental function does not appear to be significantly affected by ART, except for AFP.

Objective: To examine the associations of maternal age at the start of pregnancy across the full range with second and third trimester uterine and umbilical artery flow indices, and placental weight., Study Design: In a population-based prospective cohort study among 8271 pregnant women, we measured second and third trimester uterine artery resistance and umbilical artery pulsatility indices and the presence of third trimester uterine artery notching using Doppler ultrasound., Results: Compared to women aged 25-29.9 years, higher maternal age was associated with a higher third trimester uterine artery resistance index (difference for women 30-34.9 years was 0.10 SD (95% Confidence Interval (CI) 0.02 to 0.17), and for women aged ≥40 years 0.33 SD (95% CI 0.08 to 0.57), overall linear trend 0.02 SD (95% CI 0.01 to 0.03) per year). Compared to women aged 25-29.9 years, women younger than 20 years had an increased risk of third trimester uterine artery notching (Odds Ratio (OR) 1.97 (95% CI 1.30-3.00)). A linear trend was present with a decrease in risk of third trimester uterine artery notching per year increase in maternal age (OR 0.96 (95% CI 0.94 to 0.98)). Maternal age was not consistently associated with umbilical artery pulsatility indices or placental weight., Conclusions: Young maternal age is associated with higher risk of third trimester uterine artery notching, whereas advanced maternal age is associated with a higher third trimester uterine artery resistance index, which may predispose to an increased risk of pregnancy complications., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020 Elsevier B.V. All rights reserved.)

The mechanism underlying the potential risk associated with in vitro fertilization and embryo transfer (IVF‑ET) has been previously investigated but remains to be fully elucidated. As the placenta is a critical organ that sustains and protects the fetus, this is an important area of research. The aim of the present study was to determine the difference in trophoblast cell function in the first trimester between naturally conceived pregnancies and pregnancies achieved via IVF‑ET therapy. A total of 20 placental villi in first trimester samples were obtained through fetal bud aspiration from patients undergoing IVF‑ET due to oviductal factors between January 2016 and August 2018. In addition, a further 20 placental villi were obtained from those who naturally conceived and had normal pregnancies but were undergoing artificial abortion; these patients were recruited as the controls. Reverse transcription‑quantitative (RT‑q)PCR and semi‑quantitative immunohistochemical methods were used to detect the mRNA and protein expression of α‑fetoprotein (AFP), vascular endothelial growth factor (VEGF), transferrin (TF), tubulin β1 class VI (TUBB1), metallothionein 1G (MT1G), BCL2, glial cells missing transcription factor 1 (GCM1), epidermal growth factor (EGF) receptor (EGFR), PTEN and leukocyte associated immunoglobulin like receptor 2 (LAIR2) in villi from both groups. Differentially expressed genes were analyzed using Search Tool for the Retrieval of Interacting Genes, and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis was conducted. The RT‑qPCR data revealed that the mRNA expression levels of AFP, VEGF and TF were significantly higher in the IVF‑ET group than in the control group (P<0.05), and those of TUBB1, MT1G, BCL2, GCM1, EGFR, PTEN and LAIR2 were significantly lower (P<0.05). These gene products were expressed in the placental villus tissues, either in the cytoplasm, or in the membrane of syncytiotrophoblast and cytotrophoblast cells. The immunohistochemistry results were in line with those observed using RT‑qPCR. KEGG pathway analysis indicated that the trophoblast cell function of the IVF‑ET group in the first trimester was different from naturally conceived pregnancies with regard to proliferation, invasion, apoptosis and vascular development. The IVF‑ET process may trigger adaptive placental responses, and these compensatory mechanisms could be a risk for certain diseases later in life.

Background Half-Fourier acquisition single-shot turbo spin-echo (HASTE) imaging is now widely used for placental and fetal imaging because of its rapidity and low sensitivity to fetal movement. If placental dysfunction is also predicted by quantitative value obtained from HASTE image, then it might be beneficial for evaluating placental wellbeing. Purpose To ascertain the most suitable magnetic resonance (MR) signal indexes reflecting placental function using HASTE imaging. Material and Methods This retrospective study included 37 consequent patients who had given informed consent to MR imaging (MRI) examinations. All had undergone MRI examinations between February 2014 and June 2015. First, the correlation between T2-relaxation time of normal placenta and gestational age (GA) was examined. Second, correlation between signal intensity ratios (SIRs) using HASTE imaging and placental T2-relaxation time were assessed. The SIRs were calculated using placental signal intensity (SI) relative to the SI of the amniotic fluid, fetal ocular globes, gastric fluid, bladder, maternal psoas major muscles, and abdominal subcutaneous adipose tissue. Results Among the 37 patients, the correlation between T2-relaxation time of the 25 normal placentas and GA showed a moderately strong correlation (Spearman rho = -0.447, P = 0.0250). The most significant correlation with placental T2-relaxation time was observed with the placental SIR relative to the maternal psoas major muscles (SIR pl./psoas muscle ) (Spearman rho = -0.531, P = 0.0007). Conclusion This study revealed that SIR pl./psoas muscle showed the best correlation to placental T2-relaxation time. Results show that SIR pl./psoas muscle might be optimal as a clinically available quantitative index of placental function.

Aim: The aim of this research was to study and compare placental elasticity with acoustic radiation force impulse (ARFI) elastography in pre-eclamptic and normal pregnancies., Methods: A total of 107 singleton pregnancies in the third trimester (38 healthy control subjects, 34 patients with gestational hypertension, and 35 pre-eclampsia patients) were included in the study. ARFI elastography was used to determine the placental elasticity in the three predetermined regions of the placenta (the fetal edge, maternal edge, and central part of the placenta). The obstetrical data regarding grayscale and Doppler ultrasonography and perinatal outcomes were reviewed. A mean placental shear wave velocity cut-off value that predicts the presence of pre-eclampsia was determined., Results: The shear wave elasticity values in the pre-eclampsia group in all three regions were significantly higher than in the gestational hypertension and healthy control groups (P = 0.001). The most significant difference was found in the peripheral edge of the placenta from the fetal surface in the pre-eclampsia group (P = 0.001)., Conclusion: The stiffness of the placenta determined by the ARFI technique is significantly higher in pre-eclampsia patients. ARFI elastography of the placenta might be used as a non-invasive and easy method in the diagnosis and evaluation of pre-eclampsia as a supplement to the already existing methods., (© 2016 Japan Society of Obstetrics and Gynecology.)

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.

A possible mechanism for poor perinatal outcomes in singleton pregnancies conceived following assisted reproductive technologies (ART) and those conceived naturally following a period of infertility (>12 months) is thought to be placental dysfunction. This was investigated by measuring plasma concentrations of biochemical markers: (i) soluble fms-like tyrosine kinase1 (sFlt1); (ii) placental growth factor (PlGF); (iii) leptin; and (iv) plasminogen activator inhibitor 2 (PAI-2), serially at four antenatal time points. Baseline concentrations of each marker after delivery were also measured. The control group was naturally conceived singleton pregnancies with no history of infertility. Non-smoking, age-matched nulliparous women with no significant medical history were recruited to all groups. The ART group had significantly lower mean plasma concentrations of PlGF at all antenatal time points compared to the control group (p < 0.001). The subfertility (SF) group had significantly higher mean serum concentrations of leptin than the other groups at all time points (p < 0.001), even after correction for body mass index. There were no significant differences in sFlt1 and PAI-2 concentrations between the groups. Low plasma PlGF concentrations in the ART group might suggest abnormal placentation and/or abnormal function in ART pregnancies with relevance to pathogenesis of pregnancy complications in these women.

Introduction: The velocities of the lateral shear waves (Vs; m s⁻¹) generated by an acoustic radiation force impulse (ARFI) correlate with Young's modulus. Therefore, ARFI can be used as a new method to evaluate tissue elasticity. The aim of this study was to investigate the safety of ARFI imaging and the differences in placental elasticity in complicated cases., Methods: The study population included 115 patients between 26 and 41 weeks gestation, who were divided into three groups, namely normal, fetal growth restriction (FGR) and pregnancy-induced hypertension (PIH). After delivery, the Vs values of the placenta were measured ex vivo. After ARFI imaging, microscopic examination was performed, the Vs values were compared among the three groups and the relationship between the Vs values and neonatal birthweight Z-score was investigated., Results: No histological changes were noted even after ARFI imaging. The Vs values in the FGR group were significantly higher than those in the normal group (1.94 ± 0.74 and 1.31 ± 0.35 m s⁻¹, respectively; p < 0.05). The Vs values demonstrated a significant negative correlation with the Z-score. Moreover, as the Z-score became lower, the Vs values became higher in the range of Z-scores under -0.5 standard deviation (SD)., Discussion: We speculate that the increased Vs values in the FGR group may have been caused by histological changes, and that a more severe FGR might result in increased Vs values., Conclusion: ARFI imaging was observed to have no apparent histological damage to the placental tissue. Ex vivo placentas from the FGR group were significantly more firm. Moreover, Vs values and Z-scores of birthweight had a significant negative correlation. Additional investigations are needed about the utility of this method for the evaluation of placental function in vivo., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Synopsis: We introduce a new microflow imaging technique, which can show the blood perfusion and morphological structure of placental villi. [ABSTRACT FROM AUTHOR]

COVID-19 is an ongoing pandemic and has been extensively studied. However, the effects of COVID-19 during pregnancy, particularly on placental function, have not been verified. In this study, we used blood oxygen level-dependent magnetic resonance imaging (BOLD-MRI) to evaluate whether COVID-19 incidence during pregnancy has any lasting effects with respect to placental oxygenation. This is a case-control study, in which eight cases of singleton pregnancies before 30 weeks gestation with COVID-19 mothers were included. Placental oxygenation was evaluated using BOLD-MRI after 32 weeks of gestation. BOLD-MRI was consecutively performed under normoxia (21% O2), hyperoxia (100% O2), and normoxia for 4 min each. Individual placental time–activity curves were evaluated to calculate the peak score (peakΔR2*) and the time from the start of maternal oxygen administration to the time of peakΔR2* (time to peakΔR2*). Eighteen COVID-19-free normal pregnancies from a previous study were used as the control group. No significant differences were found between the two groups regarding maternal background, number of days of delivery, birth weight, and placental weight. The parameter peakΔR2* was significantly decreased in the COVID-19 group (8 ± 3 vs. 5 ± 1, p <.001); however, there was no significant difference in time to peakΔR2* (458 ± 74 s vs. 471 ± 33 s, p =.644). In this study, BOLD-MRI was used to evaluate placental oxygenation during pregnancy in COVID-19-affected patients. COVID-19 during pregnancy decreased placental oxygenation even post-illness, but had no effect on fetal growth; further investigation of the possible effects of COVID-19 on the fetus and mother is warranted. [ABSTRACT FROM AUTHOR]

Triadimefon is a fungicide that is broadly used to treat fungal diseases of plants. It causes developmental toxicity in the animal model. Whether triadimefon disrupts the placental function and the underlying mechanism remains unclear. Thirty-six female pregnant Sprague-Dawley rats were randomly assigned into four groups and were orally administered via gavage of triadimefon (0, 25, 50, and 100 mg/kg/day) for 10 days from gestational day (GD) 12–21. Triadimefon disrupted the structure of the placenta, leading to hypertrophy, abnormal hemodynamics, including fibrin exudation, edema, hemorrhage, infarction, and inflammation. RNA-seq analysis showed that triadimefon down-regulated the expression of developmental and metabolic genes, while up-regulating the immune/inflammatory genes. The qPCR showed that triadimefon markedly down-regulated the expression of Cpt1c , Scd2 , Ldlr , Dvl1 , Flt4 , and Vwf and their proteins, while up-regulating the expression of Cyp1a1 , Star , Ccl5, and Cx3cr1 and their proteins at 25–100 mg/kg. Western blot showed that triadimefon reduced the level of STAT3 at doses of 50 and 100 mg/kg and the phosphorylation of AMPK at 100 mg/kg. In conclusion, triadimefon severely damages the structure and function of the placenta, leading to placental hypertrophy, local blood circulation disorders, and inflammation and this may be associated with its down-regulation of genes related to metabolism and nutrient transport and the up-regulation of inflammatory genes via STAT3 and AMPK signals. [Display omitted] • Triadimefon reduces placental efficiency after gestational exposure. • Triadimefon increases placental thickness. • Triadimefon down-regulates the expression of nutrient transporter genes. • Triadimefon up-regulates the expression of inflammatory genes. • Triadimefon reduces AMPK phosphorylation and STAT3. [ABSTRACT FROM AUTHOR]

Placental function is essential for fetal development, but it may be susceptible to malnutrition and environmental stressors. To assess the impact of toxic and essential trace elements in placenta on placental function. Toxic metals (cadmium, lead, mercury, cobalt) and essential elements (copper, manganese, zinc, selenium) were measured in placenta of 406 pregnant women in northern Sweden using ICP-MS. Placental weight and birth weight were obtained from hospital records and fetoplacental weight ratio was used to estimate placental efficiency. Placental relative telomere length (TL) and mitochondrial DNA copy number (mtDNAcn) were determined by quantitative PCR (n = 285). Single exposure-outcome associations were evaluated using linear or spline regression, and joint associations and interactions with Bayesian kernel machine regression (BKMR), all adjusted for sex, maternal smoking, and age or BMI. Median cadmium, mercury, lead, cobalt, copper, manganese, zinc, and selenium concentrations in placenta were 3.2, 1.8, 4.3, 2.3, 1058, 66, 10626, and 166 μg/kg, respectively. In the adjusted regression, selenium (>147 μg/kg) was inversely associated with placental weight (B: −158; 95 % CI: −246, −71, per doubling), as was lead at low selenium (B: −23.6; 95 % CI: −43.2, −4.0, per doubling). Manganese was positively associated with placental weight (B: 41; 95 % CI: 5.9, 77, per doubling) and inversely associated with placental efficiency (B: −0.01; 95 % CI: −0.019, −0.004, per doubling). Cobalt was inversely associated with mtDNAcn (B: −11; 95 % CI: −20, −0.018, per doubling), whereas all essential elements were positively associated with mtDNAcn, individually and joint. Among the toxic metals, lead appeared to negatively impact placental weight and cobalt decreased placental mtDNAcn. Joint essential element concentrations increased placental mtDNAcn. Manganese also appeared to increase placental weight, but not birth weight. The inverse association of selenium with placental weight may reflect increased transport of selenium to the fetus in late gestation. • Manganese was positively, and selenium inversely, related to placental weight. • Placental lead was inversely related to placental weight at low selenium levels. • Cobalt was inversely associated with relative mtDNA copy number in placenta. • All micronutrients, individually and joint, were positively related to mtDNA. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

This study examined the effect of bisphenol A (BPA) on human placental gene expression using primary trophoblast cells as an in vitro model system. Trophoblast cells were isolated from human placentas at term, cultured and then exposed to environmentally relevant concentrations of BPA (0.1–2 μg/ml) for up to 24 h, after which levels of 11β-HSD2 mRNA, protein and activity were determined by standard radiometric conversion assay, western blotting, and qRT-PCR, respectively. The mRNA levels of several other prominent placental hormones/factors were also assessed by qRT-PCR. BPA dramatically increased levels of 11β-HSD2 activity, protein and mRNA in a time- and concentration-dependent manner (>4-fold). BPA also augmented aromatase, glucose transporter-1, CRH, and hCG mRNA levels while reducing the level of leptin mRNA. These findings demonstrate that BPA severely disrupts human placental gene expression in vitro , which suggests that exposure to BPA may contribute to altered placental function and consequent pregnancy complications. [ABSTRACT FROM AUTHOR]

Our previous work suggests that stressors that impact placental vascular growth result in a deformed chorionic surface shape, which reflects an abnormal placental three-dimensional shape. We propose to use variability of placental disk thickness as a reflector of deviations in placental vascular growth at the finer level of the fetal stems. We hypothesize that increased variability of thickness is associated with abnormal chorionic surface shape, but will be a predictor of reduced placental functional efficiency (smaller baby for a given placental weight) independent of shape. These measures may shed light on the mechanisms linking placental growth to risk of adult disease. The sample was drawn from the Pregnancy, Infection and Nutrition Study. In all, 94.6% of the cohort consented to placental examination. Of the 1023 delivered at term, those previously sectioned by the Pathology Department were excluded, leaving 587 (57%) cases with intact placentas that were sliced and photographed. The chorionic surface shape and the shape of a central randomly oriented placental slice were analyzed and measures were compared using correlation. Lower mean placental disk thickness and more variable disk thickness were each strongly and significantly correlated with deformed chorionic plate shapes. More variable disk thickness was strongly correlated with reduced placental efficiency independent of abnormal chorionic surface shape. Variability of placental disk thickness, simple to measure in a single randomly oriented central slice, may be an easily acquired measure that is an independent indicator of lowered placental efficiency, which may in turn program the infant and result in increased risk for development of adult diseases. [ABSTRACT FROM PUBLISHER]

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]

Iron deficiency and overload during pregnancy damage to maternal and fetal health. Placenta as an organ for the transport of nutrients between mother and fetus protects fetus from the harmful effects of iron deficiency and iron overload through regulation of placental iron homeostasis. To determine the effect of dietary iron supplementation during pregnancy on reproduction and the mechanism of placental iron regulation, we designed dietary high iron (HI: 344 mg/kg), medium iron (MI: 40 mg/kg), low iron (LI: 2 mg/kg) groups of pregnant female mice fed ferrous citrate 2 weeks before mating to 18.5 days of gestation. We find dietary iron supplementation during pregnancy effect maternal liver iron, placental iron, hemoglobin and fetal iron. Dietary iron significantly improves reproductive performance as litter weight and fetal weight. Correlation analysis suggest placental iron increased with liver iron, higher and lower liver iron is not conducive to the accumulation of fetal iron, placental iron deficiency and excess reduce litter weight. Placental transcriptome analysis revealed DEGs with the same trend in HI and LI groups compared with MI group, dietary iron may change biology process of ion transport and gland development in placenta. Granzyme may affect the placental trophoblast structure prior to delivery with iron overload uniquely. This research highlights the importance of moderate iron supplements in pregnancy due to damage of reproduction by affecting placental function under different dose of maternal iron supplementation. [ABSTRACT FROM AUTHOR]

Conceptus mortality is a significant factor limiting reproductive efficiency of livestock. In both singlet- (i.e., cattle) and litter- (i.e., pigs and sheep) bearing species, investigations of conceptus mortality have focused on the period immediately preceding and throughout the attachment phase, around the time of maternal recognition of pregnancy. Recently, data have emerged leading to the suggestion that conceptus loss later in gestation is also significant and that variation in placental size and function may play a very important part in determining whether a conceptus survives. In the pig, the number of conceptuses present after the initial period of loss that survive to term appears to be influenced by the total amount of placental mass present, such that litters containing individuals with relatively small placentae have a greater potential for a large litter size when compared with litters containing similar numbers of individuals with relatively large placentae. In ruminants, recent evidence supports the time of placental development and initial vascularization (between d 28 and 40) as a second period of significant loss, particularly in situations involving manipulation (ovulation synchronization for timed AI in cattle and out-of-season breeding in sheep). In the pig, not only does placental size vary, but efficiency (as measured by the ratio of fetal weight to placental weight) can also vary as much as threefold within a litter, leading to the suggestion that selection for small, very efficient placentae may provide a mechanism for increasing litter size. In ruminants, there are obvious cases where placental growth has been markedly altered (i.e., large offspring syndrome or heat stress) and a subsequent deviation from "normal" placental efficiency occurs. Less information is available on normal variation in placental size and efficiency; however, the timing of the secondary period of loss supports a role for events during placental development and vascularization being critical to survival and potentially contributing to the observed loss. [ABSTRACT FROM AUTHOR]