An exploration into the transplacental transfer of microplastics through placental transporters.

ABSTRACT Background Cancer during pregnancy is a fragile scenario where the maternal body undergoes significant molecular changes, including at proteomic and metabolomic levels, with damage to placenta and fetal development. Proteomic and metabolomic interaction analyses can clarify the complex dynamics in cancer associated with pregnancy. Leucine is involved in protein synthesis and metabolic regulation and may attenuate tumor-induced damage. Objective We investigated placental proteomic and metabolomic profiles in the complex relationships among pregnancy, cancer, and leucine supplementation. Materials Exploratory, non-targeted proteomic (mass spectrometry) and metabolomic (NMR spectrometry) analyses were performed on the placenta tissue of four pregnant groups: control (PC), Walker-256 tumor-bearing (PW), leucine (PL), and tumor-bearing fed a leucine-rich diet (PWL). Statistical comparisons were performed on technical replicate data within each group. Results Tumor affected maternal weight, but leucine attenuated the decrease in placental weight and fetal resorption. Leucine supplementation restored the placental proteins involved in the nuclear structure, cytoskeleton, and immune response. Tumor evolution impaired pathways related to protein folding and chromosome localization, whereas leucine modulated interferon-gamma and hydrogen peroxide responses. PW placentas exhibited decreased adenosine, glucose, glutamate, and succinate, with enhanced lactate, creatine, and histamine levels, whereas leucine supplementation restored adenosine and pyridoxine and reduced lactate levels. The affected alanine/aspartate/glutamate and purine metabolism, beta-alanine metabolism, and the citrate cycle were minimized in leucine treatment (PWL), which mainly modulates purine and alanine/aspartate/glutamate pathways and pyruvate metabolism. Conclusion A leucine-rich diet partially restored placental protein and metabolite levels, leading affected pathways to shift towards amino acid biosynthesis and pyruvate metabolism and minimizing effects on fetal development.

SARS-CoV-2 infection disrupts iron homeostasis in organs such as the lung. Emerging evidence suggests similar dysregulation in the placenta may impair function and fetal growth. Ferroptosis, an iron-dependent form of cell death, is driven by the accumulation of labile ferrous iron, catalyzing the peroxidation of polyunsaturated fatty acids in the absence of sufficient iron storage or antioxidant defenses. This pathway has been implicated in SARS-CoV-2-related tissue damage in other organs and may contribute to placental dysfunction during pregnancy. However, the influence of infection timing, symptom severity, and fetal sex on placental iron regulation remains unexamined. We analyzed placental samples from a cohort of SARS-CoV-2-exposed pregnancies in the first (n=6), second (n=14), or third trimester (n=30), classified by symptom severity (asymptomatic n=23, symptomatic n=27) and fetal sex, alongside unexposed controls (n=47). We assessed placental iron deposition, lipid peroxidation, and mRNA and protein expression of ferroptosis markers. Publicly available RNA-sequencing datasets from human placenta tissue, exposed or not to SARS-CoV-2, were analyzed to assess ferroptosis-related gene expression. SARS-CoV-2 infection, particularly in symptomatic cases, was associated with reduced placental weight and birth weight. Asymptomatic cases showed increased placental iron deposition, which correlated with lower birthweight and was accompanied by elevated expression of nuclear receptor coactivator 4, a cytosolic adaptor protein that mediates the selective autophagic degradation of ferritin (ferritinophagy) and iron release. Placentas from symptomatic patients exhibited evidence of altered iron transport and sex-specific down-regulation of antioxidant defenses. Transcriptomic analyses further suggested widespread disruption of ferroptosis pathways in placentas from infected patients. Our findings reveal that SARS-CoV-2 infection alters placental iron homeostasis and is associated with ferroptosis-related changes, with distinct molecular responses based on timing of infection, symptom severity, and fetal sex.

Liquid crystal monomers (LCMs), essential components of electronic displays, have been found in environmental and human samples due to their noncovalent integration and extensive use. Global liquid crystal display (LCD) panel production rose from 192 million m2 in 2017 to 450 million m2 by 2025, driving a greater environmental release of LCMs. Although LCMs exhibit endocrine-disrupting potential, information regarding their transplacental transfer and impacts on the reproduction and development remains largely unknown. Here, we compile the measured LCM concentrations in various maternal and fetal/offspring samples and examine their potential for transplacental transfer. Transfer may occur via passive diffusion, active transport, or placental sequestration, influenced by their chemical properties, tissue lipid profiles, and interactions with placental transporters. Available molecular docking studies on prevalent LCMs with key placental proteins are discussed to illustrate possible transporter-specific interactions, acknowledging the preliminary nature of these findings. We also compile human biomonitoring data and limited epidemiological studies alongside preclinical toxicology evidence from animal and in vitro models to assess their potential reproductive and developmental effects. Current evidence suggests that LCM exposure during pregnancy may pose risks to maternal-offspring health through mechanisms such as endocrine disruption, oxidative stress, altered intracellular signaling, and immune-inflammatory crosstalk. These findings underscore the need for mechanistic studies and regulatory attention to LCM exposure risks during pregnancy, offering insights into human exposure, transplacental transfer, and related toxicities.

Placental signaling pathways regulate nutrient transport and fetal growth, with potential long-term consequences for offspring metabolic health. Most prior human studies have focused on individual placental markers, limiting insight into the role of coordinated activity across multiple pathways in relation to offspring outcomes. Our objective was to identify patterns across placental nutrient signaling pathways and assess whether the latent placental signaling patterns were associated with early childhood adiposity, and secondarily, explore associations of adiposity-associated patterns with metabolic biomarkers. Among 108 mother-child pairs from the Healthy Start cohort, we quantified 33 placental signaling proteins and their phosphorylated-to-total protein ratios involved in nutrient sensing, insulin/growth factor signaling, stress/inflammation, and mitochondrial biogenesis using Simple Western assays of term placental villus tissue. We applied unsupervised methods to identify latent patterns and LASSO regression was used to select patterns associated with %fat mass at age 4. Multivariable linear regression was used to estimate associations adjusting for offspring age, sex, and maternal pre-pregnancy BMI. These same models were used in exploratory analysis of fasting levels of adiponectin, leptin, insulin, glucose, and lipids at age 4. We identified two placental signaling patterns associated with %fat mass. The insulin-mTOR-energy sensing pattern was associated with lower childhood %fat mass (β = -2.46, 95% CI - 4.84, - 0.09) and adiponectin, and the stress-inflammatory MAPK pattern was associated with higher %fat mass (β = 1.28, 95% CI 0.05, 2.51), leptin, and triglycerides; however, the FDR p-values ranged from 0.06 to 0.13. Two placental signaling patterns were associated with childhood %fat mass and metabolic markers. These findings indicate that capturing placental activity across several signaling pathways may yield insights into early origins of adiposity and metabolic health.

ABSTRACTIntroductionSpecies differences exist in Fc domain‐containing molecule transfer/biodistribution to the embryo‐fetus during pregnancy. Placentation was reviewed and placental neonatal Fc receptor (FcRn) quantitation in the chorioallantoic placenta (CAP) and/or inverted yolk sac placenta (InvYSP) was investigated across species throughout gestation to further understand and inform developmental toxicity testing of Fc domain‐containing molecules.MethodsQuantitative mass spectrometry was used to quantify FcRn protein in CAP and/or InvYSP throughout gestation in mouse, rat, guinea pig, rabbit, and nonhuman primate (NHP). In human placental tissues, immunohistochemistry was used to localize FcRn distribution during each trimester.ResultsFcRn protein was detected and concentration increased throughout gestation in mouse, rat, guinea pig, and rabbit; with InvYSP concentration markedly higher compared with CAP at all gestational ages. In contrast, NHP FcRn protein concentration in the CAP remained constant throughout gestation. In humans, during 1st trimester, FcRn occurred in decidua, maternal endothelium, and maternal and fetal macrophages. During 2nd trimester, fetal FcRn increased in syncytiotrophoblasts and fetal chorionic vessels. FcRn expression decreased in maternal endothelium near term.ConclusionsFcRn protein was detected throughout gestation (including organogenesis) in placental tissue of all animal species. Regardless of FcRn location, these data support that Fc domain‐containing molecules can access the embryo‐fetus throughout gestation in all species, with the extent of transfer likely depending on FcRn concentration and size of the placenta. This information on placental FcRn ontogeny will help improve study design and translation of nonclinical developmental toxicity data to human safety assessment of Fc domain‐containing molecules.

Longitudinal patterns of urinary biomarkers of placental and renal function in pregnancy and associations with early pregnancy exposure to phthalates and replacements.

Gestational diabetes mellitus (GDM) is a prevalent pregnancy complication associated with adverse maternal and neonatal outcomes. This study aims to investigate the expression of key inflammatory markers - tumor necrosis factor-α (TNF-α), interleukin-10 (IL-10), interleukin-6 (IL-6), and nuclear-factor kappa-light chain of B (NFκB) in the placental tissue of GDM and non-GDM women. Additionally, the study explores associations between these markers and neonatal characteristics, placental dimensions, and resolvins levels.This cross-sectional study included 416 singleton pregnant women, comprising 209 with GDM and 207 non-GDM. Placental protein and mRNA expression levels of TNF-α, IL-10, IL-6, and NFκB were measured using ELISA and RT-qPCR. Associations between resolvins and inflammatory markers were also assessed.Placental protein levels of TNF-α, IL-10, and NFκB, as well as gene expression levels of IL-6, were elevated in the GDM group. Furthermore, TNF-α was negatively associated with major axis, thickness and center and cord insertion. Inflammatory markers were negatively associated with head circumference at birth. A negative association was found between placental resolvin E1 (RvE1) levels and the inflammatory markers IL-10, NFκB, and TNF-α.The study highlights the association between pro-inflammatory and pro-resolving mediators in the placenta, providing insights into GDM and its adverse outcomes.

This study investigates the relationship between maternal apical periodontitis (AP) and neonatal health. Twenty-four Wistar rats were assigned to three groups: control (CN), one induced apical periodontitis (AP1), and four induced apical periodontitis (AP4). Apical periodontitis was induced for all experimental groups. After 30 days, the rats were mated and sacrificed on the 21st day of gestation. Placental weight, maternal glycemia, insulinemia, insulin resistance, and placental protein levels were analysed. Neonates were evaluated for their number, weight, capillary glycemia, and liver tumour necrosis factor-α (TNF-α) content. The results showed that no significant differences were observed in maternal glycemia. However, insulinemia and homeostatic model assessment for insulin resistance were higher in the AP groups compared with CN and were more pronounced in AP4 than AP1. Placental weight and placental labyrinth area were reduced exclusively in the AP4 group, while the number of fetuses per rat did not differ among groups. The AP4 group exhibited increased placental TNF-α gene expression and protein content compared with CN and AP1. In addition, placental caspase-3 expression was increased in the AP4 group, with no significant differences in nuclear factor-kappaB (p50 and p65) phosphorylation status among groups. Foetal analyses demonstrated a reduction in naso-anal length in fetuses from the AP4 group, lower capillary glycemia in fetuses from AP rats compared with CN, and increased TNF-α content in foetal liver tissue from AP groups. Overall, most alterations were more pronounced with an increasing number of maternal teeth affected by AP, emphasizing the importance of maternal oral health in preventing placental dysfunction and adverse fetal developmental outcomes.

First-episode psychosis during pregnancy (FEP-PW) is a rare but serious condition that intersects maternal mental health and placental-fetal biology. While psychosis is characterized by disruptions in perception and cognition, its impact on placental neuroendocrine signaling and fetal development remains poorly understood. The placenta, as a key mediator of intrauterine environment, expresses receptors involved in neurotransmission and stress response, potentially linking maternal psychopathology to fetal neurodevelopmental risk. This study investigates the expression of five critical neuroendocrine and stress-related molecules-dopamine receptor D2 (DRD2), serotonin receptor 1B (HTR1B), glucocorticoid receptor (NR3C1), 11β-hydroxysteroid dehydrogenase type 2 (HSD11B2), and melatonin receptor 1B (MTNR1B)-in placental tissue from women with FEP-PW compared to healthy pregnant controls (HC-PW). Using a prospective case-control design, placental samples from 22 FEP-PW and 20 HC-PW women were analyzed. Gene expression was quantified by real-time quantitative polymerase chain reaction (RT-qPCR), and protein localization and abundance assessed via immunohistochemistry (IHC). Significant alterations in placental gene and protein expression were observed in FEP-PW placentas: DRD2, NR3C1, and HSD11B2 were markedly upregulated (all p < 0.001 at gene and protein levels), whereas HTR1B and MTNR1B were significantly downregulated compared to controls (p < 0.05, p < 0.01 respectively at gene level and p < 0.01, p < 0.001 at protein level). These findings indicate dysregulated dopaminergic, serotonergic, glucocorticoid, and melatonin signaling pathways in the placenta associated with maternal psychosis. Our results provide novel evidence of distinct placental molecular adaptations in FEP-PW, reflecting heightened maternal stress and disrupted neurohormonal environments. These alterations may contribute to adverse placental function and influence fetal neurodevelopmental trajectories, underscoring the placenta's role as a critical mediator in the maternal-placental-fetal axis in psychiatric disorders. Further research is needed to clarify the functional consequences and explore these molecules as potential biomarkers or therapeutic targets in perinatal psychiatry.

Maternal-fetal transfer of emerging bisphenols: Exposure profile and potential link to latrogenic preterm birth.

Zearalenone (ZEA) contaminates various food crops and water systems worldwide. We investigate whether gestational ZEA exposure disrupts the placental barrier and elucidates its underlying mechanisms. This study employed a mouse model and human trophoblast cells. We found that ZEA accumulated in mouse placental tissue. Compared with the well-defined tight junctions observed in controls, ZEA disrupted placental barrier integrity. Consistent with the morphological disruption, ZEA significantly downregulated the expression of placental barrier proteins. Furthermore, ZEA elevated fetal glucocorticoid levels by suppressing placental 11β-HSD2 protein expression and enzymatic activity. Mechanistically, ZEA inhibited placental protein synthesis via integrated stress response (ISR) activation. ISR inhibition attenuated ZEA-induced disruption of the placental barrier and downregulation of barrier proteins, and ameliorated adverse pregnancy outcomes. Our results suggest that ZEA causes placental barrier disruption and adverse pregnancy outcomes through triggering ISR. These mechanistic insights into ZEA's developmental toxicity may guide protective strategies for human and animal health.

Genetic associations with placental and pregnancy proteins in maternal serum identify biomarkers for hypertension in pregnancy.

The immunotoxicological evaluation of collagen-based medical devices typically relies on wild-type rodent models, but interspecies differences may cause biases in immune response. To address this, we developed a human Type III collagen transgenic mouse model. In accordance with ISO/TS 10993-20 guidelines, we assessed the immunotoxicity of human collagen and recombinant/cell-engineered collagens (CCs) using this model, alongside wild-type controls. The full-length human COL3A1 gene was integrated into C57BL/6J mice, with expression confirmed through mRNA and peptide analysis. Mice were injected with human placental stromal protein (positive control), two recombinant humanized collagens (RC-1, RC-2), and CC. The experimental design adhered to GB/T 16886.20 (ISO 10993-20) and YY/T 1465 standards, with assessments including serum antibody detection at multiple timepoints (0-90 days) and terminal analyses at 30 and 90 days, focusing on splenic lymphocyte subsets and local tissue reactions. Results showed that transgenic mice had lower antibody levels compared to wild-type controls, with wild-type mice displaying significantly higher antibody responses at 60 days. These findings suggest altered immune recognition patterns in transgenic mice. The study also indicated that recombinant/CCs triggered only transient immune responses, with no sustained activation. This model provides new insights for refining immunoevaluation strategies for collagen-based materials.

Fetal growth restriction (FGR) affects ∼10% of pregnancies worldwide and is often associated with placental insufficiency. Iron is essential for maternal haematopoietic adaptations and placental processes such as mitochondrial iron-sulphur (Fe-S) cluster assembly, haem synthesis and erythropoiesis. This study aimed to characterise iron transport and downstream utilisation in FGR. Placental tissues from term uncomplicated (n=19) and FGR (n=18) pregnancies were analysed. Maternal iron status was retrospectively assessed from clinical records. Placental mRNA and protein expression of iron-dependent pathways were analysed via RT-qPCR, LC-MS and western blotting. Placental iron content was assessed histologically, and haem levels were measured by an activity assay. FGR pregnancies showed significantly elevated maternal serum ferritin and lower red cell distribution width, although these remained within normal clinical values. Placental iron uptake transporters TFRC and DMT1 were significantly upregulated, while the iron exporter to the fetus, ferroportin, was reduced, indicating increased iron retention in the FGR placenta. Despite altered transporter expression, Fe3 + iron levels were unchanged, suggesting iron utilisation over storage. Subsequent investigations identified reduced mitochondrial Fe-S synthesis components (FDXR, FDX2, NDUFAB1, HSPA9), and a prioritisation of mitochondrial and cytosolic haem synthesis enzymes in FGR. Protein levels of haemoglobin subunits (HBG1, HBG2, HBB, HBA1) and erythrocyte membrane markers (EPB41, EPB42, SPTA1, SPTB, ANK1) were decreased. These findings reveal a compensatory response in FGR placentae, with increased iron uptake and utilisation favouring haem synthesis over Fe-S cluster formation, possibly to support oxygen handling under poor placental vascularisation and reduced fetal oxygenation, with potential consequences for mitochondrial energy metabolism. KEY POINTS: Iron plays a critical role in placental function, and while iron-dependent pathway components are well-characterised, their integrated response and adaptive reprogramming in fetal growth restriction (FGR) remain poorly understood. In FGR, maternal iron status was unchanged, however, placental iron uptake proteins were increased and ferroportin reduced, suggesting that the placenta retains iron. FGR placentae showed altered de novo mitochondrial iron-sulphur cluster (Fe-S) formation and a bottleneck in late-stage Fe-S cluster assembly. This shift in Fe-S synthesis prioritises mitochondrial and cytosolic haem synthesis pathways, consistent with increased haem utilisation and breakdown. Globin subunits were lower in protein abundance and impaired placental erythrocyte structure in FGR. Dysregulation of erythrocyte membrane proteins in FGR placentae suggests altered erythrocyte structure, potentially representing an adaptive response to inadequate vascularisation, attempting to optimise oxygen delivery to the fetus.

Organic anion transporter (OAT) 4 is a kidney and placental membrane protein implicated in the transport of xenobiotics, including pollutants. The present study was designed to determine whether environmental bisphenol (BP) analogues, including emerging bisphenol A substitutes, can interact with OAT4. 6-carboxyfluorescein-related OAT4 activity displayed by OAT4-overexpressing HEK-293cells was inhibited by 7/23 BP analogues used at 10μM, especially by the thermal paper-contained color developer Pergafast® 201 (PF201) and the flame retardants tetrabromobisphenol A (TBBPA) and tetrachlorobisphenol A (TCBPA), acting in a concentration-dependent manner (with IC50 values in the 0.95-1.48μM range). Most of these BP analogues moreover decreased membrane transport of estrone-3-sulfate, a hormonal endogenous substrate for OAT4. Some of them, especially PF201, additionally blocked activity of the renal transporters OAT1 and OAT3. Interaction of BP analogues with OAT4 was further supported by docking simulation studies, indicating that PF201 binds to the Arg473-containing electropositive pocket of OAT4, presumed to play a key role in inhibition of OAT4-mediated transport. BP analogues however failed to trans-stimulate OAT4 activity and OAT4-overexpressing cells exhibited no or marginally increased sensitivity to PF201, TBBPA and TCBPA, thus suggesting that these BP analogues are not or poorly transported by OAT4. In vitro to in vivo extrapolation finally demonstrated that occupational exposure to PF201 is predicted to result in human OAT4 inhibition. Overall, OAT4 was demonstrated to be a target for BP analogues, including BPA substitutes, with possible deleterious consequences in terms of OAT4-mediated transport of endogenous compounds or drugs, notably for workers exposed to PF201.

ABSTRACTTo better understand the crosstalk between the placenta and the fetus, we aimed to identify proteins released by the placenta into the fetal circulation, as well as proteins taken up by the placenta. This study included 75 healthy term pregnancies, analyzing proteins from plasma samples collected from the umbilical artery and vein using the Somalogic 5000‐plex platform. Placental protein release and uptake were determined by comparing protein abundances in the umbilical artery and vein. Additionally, transcriptomic data mapping and gene ontology enrichment analysis were conducted to assign cellular and tissue origin and functions to the proteins. After controlling for the false discovery rate, we identified 766 proteins released by the placenta into the fetal circulation and 926 proteins taken up by the placenta (q < 0.05). Among the released proteins, 70% were previously recognized as expressed in the placenta, affirming their placental origin. Conversely, the proteins taken up from the fetal circulation showed an overrepresentation of proteins specific to bone marrow, tongue, and skeletal muscle, while proteins specific to salivary glands, liver, and placenta were underrepresented. Enrichment analysis revealed molecular functions and biological processes that promote tissue growth and differentiation. Our findings demonstrate a considerable interaction between the placenta and fetus in healthy term pregnancies, with a high number of proteins being exchanged. This research enhances our understanding of the fetal‐placental interactions, paving the way for new insights into pathophysiological processes and potential therapeutic strategies in utero.

Abnormal placental angiogenesis contributes significantly to fetal growth restriction (FGR) and related complications. Methionine adenosyl-transferase 2A (MAT2A) can regulate the process of embryonic development; however, the role of MAT2A in placental angiogenesis during fetal development remains poorly understood. In this study, placentas from paired normal birth weight (NBW) and FGR piglets were used to quantify placental vascular density and biochemical indexes, while porcine trophoblast cells (pTrs) and porcinevascular endothelial cells (PVECs) were used to investigate the regulatory mechanism of MAT2A on placental angiogenesis. Here, we found that FGR placentas exhibited reduced vascular density and increased glycogen levels. Moreover, FGR placentas showed reduced S-adenosylmethionine (SAM) levels and downregulated protein expression of MAT2A and CD31. Placental SAM levels were positively correlated with vascular density, while MAT2A expression was positively correlated with CD31 expression. Further study showed that MAT2A knockdown disrupted the metabolism of methionine, glycolysis, the tricarboxylic acid cycle and oxidative phosphorylation, and hindered protein synthesis, thereby impairing cell proliferation and migration in pTrs and/or PVECs, and inhibited angiogenesis in a co-culture system. In contrast, SAM supplementation promoted phosphorylation of ribosomal protein S6 kinase 1 (S6K1), downstream of the mammalian target of rapamycin complex 1 signalling pathway, and upregulated vascular endothelial growth factor-A protein expression, thereby increasing endothelial cell tube formation. In conclusion, our study demonstrates the potential of MAT2A in interventional therapy for placental development of FGR. KEY POINTS: Placental vascular density is correlated with decreased S-adenosylmethionine (SAM) levels caused by downregulated adenosyl-transferase 2A (MAT2A) expression. MAT2A regulates the placental mTORC1 signalling pathway and protein synthesis. MAT2A knockdown disrupts methionine metabolism, glycolysis, the tricarboxylic acid cycle and oxidative phosphorylation. MAT2A regulates the proliferation and migration capacity of placental trophoblast and endothelial cells. MAT2A regulates placental angiogenesis via the SAM-mTORC1-S6K1-VEGF-A signalling pathway.

ABSTRACTAddressing sarcopenia and frailty in aging populations is crucial for improving quality of life and reducing healthcare dependence among these patients. Although no specific drugs have been approved for treating sarcopenia, protein supplements rich in branched‐chain amino acid (BCAA) have been reported to increase muscle mass and function in elderly individuals. Fermentation of salmon placenta protein is an effective approach to improve BCAA content compared to previous sarcopenia‐related protein supplements. Therefore, this study aimed to evaluate BCAA content through salmon placenta protein (Sal) fermented with Saccharomyces cerevisiae (F‐Sal), analyze the expression of muscle‐forming genes in C2C12 myoblasts in vitro, measure the weight gain of quadriceps femoris and gastrocnemius muscle, measure the volume and thickness of gastrocnemius muscle, and measure the expression of biomarkers related to sarcopenia in quadriceps femoris and gastrocnemius muscle in a mouse model of sarcopenia. Here, we report for the first time that salmon placental extracts (Sal) fermented with S. cerevisiae (F‐Sal) exhibit drastically elevated levels of BCAA, including leucine, isoleucine, and valine, and ameliorated the conditions of sarcopenia in both in vitro and in vivo sarcopenia models. When the addition of Sal or F‐Sal to cultured C2C12 myoblasts with dexamethasone‐induced sarcopenia, the expression level of the muscle‐forming gene MyoD was significantly increased in F‐Sal compared to Sal (p < 0.01), and the expression level of the muscle‐degrading gene MuRF1 was significantly decreased in F‐Sal compared to Sal (p < 0.01). In a mouse model of sarcopenia, oral administration of F‐Sal for 14 days following dexamethasone treatment increased muscle weight and the expression of muscle‐forming genes while mitigating muscle loss and reducing the expression of muscle‐degrading genes in both the quadriceps femoris and gastrocnemius muscles. These findings provide a therapeutic basis for treating muscle weakness in patients with end‐stage disease as well as sarcopenia‐related muscle conditions in elderly by improving BCCA content with S. cerevisiae ‐fermented salmon placental protein (F‐Sal).

Several microRNAs play vital roles in placental development. miR-155 has been implicated in placental development and can directly interact with a variety of targets, including angiotensin type II receptor 1 (AT1R) (Agtr1) mRNA. The AT1R is pro-proliferative and promotes early placental development. We therefore tested the hypothesis that miR-155 downregulates Agtr1 mRNA expression and impairs placental development. Placentae and fetuses from wild-type C57Bl/6 mice (miR-155+/+, control) and C57Bl/6 mice with a null mutation in miR-155 (miR155-/-) were mated with males of the same genotype and analyzed on gestational day 18.5, when placental morphology and miR-155 and AGTR1 expression were assessed. Additionally, HTR8/SVneo cells were cultured with a miR-155 mimic to determine the effects on trophoblast proliferation, migration and invasion. miR-155-/- dams produced significantly heavier pups with unchanged placental weights and fetal-to-placental weight ratios. Placentae from miR-155-/- dams had significantly larger labyrinth zones and labyrinth-to-placental area ratios than controls, with altered stereological parameters. Placental Agtr1 mRNA and AGTR1 protein levels were significantly increased in miR-155-/- dams. Finally, in vitro treatment in human HTR-8/SVneo cells with the miR-155 mimic increased miR-155 expression, decreased AGTR1 mRNA levels and decreased the rates of trophoblast cell proliferation, migration and invasion. Thus, miR-155 is demonstrated to attenuate placental development in mice. We propose that this is at least partly due to its effects on the AT1R.