Pregnant Mice Research Articles

9264 The interplay of FOXO1 and NR3C1 in the development and function of pituitary somatotropes

Abstract Disclosure: P. Das: None. D.A. Jabal: None. D.A. Sunny: None. B.S. Ellsworth: None. Our research focuses on the role of glucocorticoid (GC) in regulating the maturation of pituitary somatotropes. We previously demonstrated that deletion of the forkhead transcription factor, FOXO1, affects the development of somatotropes both in vivo and in vitro. Our studies reveal that treating pregnant mice with the synthetic glucocorticoid, dexamethasone leads to premature somatotrope maturation. Interestingly, we have observed that the ability of GC to promote Gh1 expression is compromised in the absence of FOXO1 in a somatotrope-like cell line. This finding leads to further investigation into the GC receptor, NR3C1, and its developmental role in the pituitary gland. In mouse embryos, we detect NR3C1-positive cells localized primarily in the nucleus, initially in small numbers at embryonic day (e)12.5 and becoming more abundant by e14.5. At e14.5 there is a subset of cells where NR3C1 co-localizes with POU1F1, a marker of pre-somatotropes, suggesting the importance of NR3C1 in the formation of the somatotrope lineage. In dexamethasone-treated animals, we observe an increase in NR3C1-positive cells. However, no significant change was noted in POU1F1 expression. Significantly, the premature somatotropes identified are NR3C1 and POU1F1-positive, suggesting the pituitary cells expressing both POU1F1 and NR3C1 at e14.5 are likely differentiating into somatotropes when exposed to GC. Normally, by e16.5, GH-positive cells begin to appear in mice. Double immunostaining reveals that some of these cells also express NR3C1. Further supporting this finding, the deletion of Nr3c1 results in a decreased number of GH-positive cells at e16.5. Altogether these findings demonstrate that NR3C1 and FOXO1 are key factors regulating somatotrope maturation. Presentation: 6/2/2024

5152 The interplay of FOXO1 and NR3C1 in the development and function of pituitary somatotropes

Abstract Disclosure: P. Das: None. D.A. Jabal: None. D.A. Sunny: None. B.S. Ellsworth: None. Our research focuses on the role of glucocorticoid (GC) in regulating the maturation of pituitary somatotropes. We previously demonstrated that deletion of the forkhead transcription factor, FOXO1, affects the development of somatotropes both in vivo and in vitro. Our studies reveal that treating pregnant mice with the synthetic glucocorticoid, dexamethasone leads to premature somatotrope maturation. Interestingly, we have observed that the ability of GC to promote Gh1 expression is compromised in the absence of FOXO1 in a somatotrope-like cell line. This finding leads to further investigation into the GC receptor, NR3C1, and its developmental role in the pituitary gland. In mouse embryos, we detect NR3C1-positive cells localized primarily in the nucleus, initially in small numbers at embryonic day (e)12.5 and becoming more abundant by e14.5. At e14.5 there is a subset of cells where NR3C1 co-localizes with POU1F1, a marker of pre-somatotropes, suggesting the importance of NR3C1 in the formation of the somatotrope lineage. In dexamethasone-treated animals, we observe an increase in NR3C1-positive cells. However, no significant change was noted in POU1F1 expression. Significantly, the premature somatotropes identified are NR3C1 and POU1F1-positive, suggesting the pituitary cells expressing both POU1F1 and NR3C1 at e14.5 are likely differentiating into somatotropes when exposed to GC. Normally, by e16.5, GH-positive cells begin to appear in mice. Double immunostaining reveals that some of these cells also express NR3C1. Further supporting this finding, the deletion of Nr3c1 results in a decreased number of GH-positive cells at e16.5. Altogether these findings demonstrate that NR3C1 and FOXO1 are key factors regulating somatotrope maturation. Presentation: 6/2/2024

Fetal hypoxia exposure induced Hif1a activation and autophagy in adult ovary granulosa cells.

Environmental hypoxia adversely impacts the reproduction of humans and animals. Previously, we showed that fetal hypoxia exposure led to granulosa cell (GC) autophagic cell death via the Foxo1/Pi3k/Akt pathway. However, the upstream regulatory mechanisms underlying GC dysfunction remain largely unexplored. Here, we tested the hypothesis that fetal hypoxia exposure altered gene expression programs in adult GCs and impaired ovarian function. We established a fetal hypoxia model in which pregnant mice were maintained in a high-plateau hypoxic environment from gestation day (E) 0--16.5 to study the impact of hypoxia exposure on the ovarian development and subsequent fertility of offspring. Compared with the unexposed control, fetal hypoxia impaired fertility by disordering ovarian function. Specifically, fetal hypoxia caused mitochondrial dysfunction, oxidant stress and autophagy in GCs in the adult ovary. RNA-seq analysis revealed that 437 genes were differentially expressed in the adult GCs of exposed animals. Western blotting results also revealed that fetal exposure induced high levels of hypoxia-inducible factor 1-alpha (Hif1a) expression in adult GCs. We then treated GCs isolated from exposed mice with PX-478, a specific pharmacological inhibitor of Hif-1a, and found that autophagy and apoptosis were effectively alleviated. Finally, by using a human ovarian granulosa-like tumor cell line (KGN) to simulate hypoxia in vitro, we showed that Hif1a regulated autophagic cell death in GCs through the Pi3k/Akt pathway. Together, these findings suggest that fetal hypoxia exposure induced persistent Hif1a expression, which impaired mitochondrial function and led to autophagic cell death in the GCs of the adult ovary.

Metformin reverses infertility in a mouse model of endometriosis: unveiling disease pathways and implications for future clinical approaches

Research QuestionDoes metformin reverse endometriosis-associated infertility? DesignEndometriosis was induced by transplanting endometrial tissue fragments from B6CBAF1 mice into the same strain female recipients. Mice were divided into groups: Endometriosis-End (n=24), Sham-operated (n=12), Endometriosis with orally administrated metformin during 3 months (0,5mg/ml)-EndMet (n=21), and Sham-operated metformin-treated-ShamMet (n=16). Half of mice per group was used for fertility studies. Implant growth was monitored by ultrasound and serum estradiol, glucose, and cholesterol (total, LDL, HDL) levels were assessed. Fibrosis was quantified in Masson's trichrome-stained sections of eutopic-Eu and ectopic-Ec endometrial tissue by computer-assisted analysis. PCNA, CYP17a1, F4/80 and galectin-3 were analyzed by immunofluorescence and Western blotting; NFkB, GPX-1 and HO-1 only by Western blotting. Statistical significance was set at p<0.05. ResultsThe endometriosis model was successfully established. End animals showed lower fertility rates than sham-operated mice, whereas metformin treatment increased the number of fetuses per pregnant mouse, restoring fertility to control levels, besides reducing implant growth and vascularization. Ectopic endometrial tissue resembled eutopic counterpart but showed increased PCNA levels and fibrosis that decreased after metformin treatment. PCNA expression decreased in pregnant mice. Metformin diminished CYP17a1 expression in EuEnd and on the contrary upregulated F4/80, galectin-3, NFkB and antioxidant enzymes, HO-1 and GPX-1, in non-mated mice. ConclusionsThese results emphasize metformin's application, even in a subtherapeutic dose, to alleviate oxidative stress and to mitigate endometriosis lesions fibrosis in a murine model of endometriosis. The study highlights metformin's potential as a pharmacological intervention for improving infertility in endometriosis, reinforcing its promising contribution to reproductive health.

MiR-224-5p alleviates preeclampsia-like mouse symptoms by targeting PANX1 to inhibit ferroptosis in trophoblast cells

Preeclampsia (PE) is a high morbidity and lethality disease specific to pregnancy, and insufficient placental trophoblast invasion acts as a crucial factor contributing to PE development. The present study investigated the function and potential mechanism of microRNA (miR)-224-5p within PE. In the study, miR-224-5p expression was reduced within placental tissue samples of the PE mouse model and PE cell model. Restoration of miR-224-5p expression markedly inhibited ROS levels and ferroptosis, lowered blood pressure in pregnant mice, increased the live birth rate, and enhanced trophoblast cell proliferation and invasion as well as suppressed their apoptosis. miR-224-5p could target and suppress PANX1, and overexpression of PANX1 could significantly advance ferroptosis and cause trophoblast dysfunction, a process that might be relieved via restoring miR-224-5p expression. In conclusion, miR-224-5p/PANX1 ameliorates trophoblast dysfunction by inhibiting ferroptosis, which provides a potential new option for clinical treatment of PE.

Effect of acetaminophen use on GABA, NMDA, and synaptic plasticity-related genes in the immature mouse brain: A preliminary study

Abstract Background/aim: Acetaminophen is frequently used as an analgesic during pregnancy. The purpose of the present study was to evaluate the effects of acetaminophen administered to pregnant mice on the fetal brain, attention, memory, and learning functions in the postnatal period, and genetic mechanisms in these mice. Materials and methods: The study was designed with two different groups. The first group consisted of pregnant mice that were injected with acetaminophen, while the second group was comprised of pregnant mice that were injected with saline. 1st, 2nd, and 3rd days of pregnancy, one of the mice was injected subcutaneously with 100 mg/kg acetaminophen, and the other mouse was injected subcutaneously with 0.9% saline. On the 21st day after birth, five female and five male mice were randomly selected for the experimental and control groups. Behavioral tests were performed on mice at 2 months of age. In addition, changes in the transcript levels of 93 genes were evaluated by Real-Time PCR in the hippocampus. Results: The control group showed more interest in the new object than the acetaminophen group (p=0.002). In the marble burying test, greater burying activity was observed in the control group than in the acetaminophen group (p=0.0345). No significant difference was observed between the control and acetaminophen groups in the social interaction and tail suspension tests. GABRG3, GRM3, PICK1, CEBPB, and EGR4 mRNA expression levels increased in the acetaminophen group (0.0317, 0.0159, 0.0069, 0.0457, 0.015, p value respectively). Conclusions: Prenatal acetaminophen exposure affected both behavioral tests and transcript levels. Therefore, the potential effects of prenatal acetaminophen exposure should be carefully investigated.

Direct Effects of Inflammatory Cytokines on Mouse Uterine Contraction.

Uterine contractions signal labor onset, with elevated pro-inflammatory cytokines playing a pivotal role. Prior studies have explored their effects on prostaglandins, oxytocin, and signaling pathways, but have overlooked their direct effects on uterine contractions. Here, we aim to investigate the direct effects of interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) on contractions to ascertain if they have immediate observable effects like those reported for lipopolysaccharide (LPS) and other effects. Tension recordings were used to assess the direct effects of cytokines and/or LPS on mouse uterine contractions. Calcium imaging was employed to observe calcium oscillations in cytokine-pretreated myometrial smooth muscle cells (MSMCs) in response to oxytocin. The release of inflammatory cytokines and chemokines from uterine explants after LPS and/or cytokines application was investigated using Luminex. IL-1β, IL-6, and TNF-α rapidly enhanced contractions of term pregnant mouse uterus. LPS combined with TNF-α intensified contractions compared to LPS alone, although this effect was not statistically significant in our results (p > 0.050). Pretreatment of MSMCs with IL-1β, IL-6, or TNF-α increased calcium oscillations in response to oxytocin. LPS and/or cytokine significantly stimulated the release of IL-1β, IL-6, TNF-α, Chemokine (C-X-C motif) ligand 1 (CXCL1), and monocyte chemoattractant protein-1 (MCP1) from uterine explants in vitro. Inflammatory cytokines have short-term and long-term effects on mouse uterine contractions, which together contribute to progressively stronger contractions during labor.

Benzo(a)pyrene promotes autophagy to impair endometrial decidualization via inhibiting CXCL12/CXCR4 axis

Benzo(a)pyrene (BaP), a pervasive environmental pollutant with endocrine-disrupting properties, has been associated with detrimental effects on pregnancy. During early pregnancy, the endometrial decidualization process is critical for embryo implantation. Abnormal decidualization can lead to implantation failure, aberrant placental formation, and pregnancy loss. We previously revealed that BaP exposure impaired decidualization and implantation in mice, yet the underlying mechanisms remained elusive. Autophagy, a cellular mechanism pivotal for energy and material recycling, contributes to the decidualization process. The chemokine C-X-C motif chemokine ligand 12 (CXCL12), secreted by endometrium stromal cells (ESCs), is involved in regulating endometrial decidualization and autophagy. Therefore, this study aimed to explore the hypothesis that BaP disrupts the decidualization process by interfering with autophagic pathways via the CXCL12/CXCR4 axis during early pregnancy. We found that BaP inhibited CXCL12/CXCR4 expression, and induced autophagy by promoting autophagosome formation, which in turn impaired the decidualization in early pregnant mice uterus and decidual stromal cells (DSCs). Using autophagy inhibitors 3-methyladenine and chloroquine in combination with BaP to treat DSCs, successfully weakened BaP-induced autophagy, and relieved decidual injury. Additionally, activation of CXCL12/CXCR4 by recombinant protein CXCL12 attenuated BaP-induced autophagy, inhibited the PI3K/AKT signal activation caused by BaP, and partly rescued the expression of decidualization-related genes. In summary, this study demonstrates that BaP induces autophagy in DSCs by inhibiting the CXCL12/CXCR4 axis, leading to damage in endometrial decidualization during early pregnancy. The findings provide a critical chemokine-mediated regulatory mechanism involved in embryo implantation and contribute valuable knowledge to the reproductive toxicology of BaP.

The P300-ARRDC3 axis participates in maternal subclinical hypothyroidism and is involved in abnormal hepatic insulin sensitivity in adult offspring

Numerous studies have suggested potential associations between maternal subclinical hypothyroidism (SCH) and adverse metabolic outcomes in offspring, however, the underlying mechanism remains unclear. In this study, we generated a maternal SCH mouse model by administering 50 ppm 6-propyl-2-thiouracil (PTU) in the drinking water of pregnant mice until delivery. This model was used to investigate the mechanisms influencing glucose metabolism in offspring. RNA sequencing (RNA-seq) revealed a substantial increase in ARRDC3 expression in the livers of the offspring of the SCH model mice, which may contribute to insulin resistance. Additionally, the phosphorylation levels of key proteins in the insulin signalling pathway, such as protein kinase B (Akt), glycogen synthase kinase 3 beta (GSK-3β), and Forkhead box protein O1 (FoxO1), were correspondingly reduced in the SCH offspring. Moreover, overexpression of ARRDC3 in Hepa1‒6 cells suppressed the Akt/GSK-3β/FoxO1 signalling pathway and increased the expression of glucose-6-phosphatase (G6Pase) and phosphoenolpyruvate carboxykinase (PEPCK), which was consistent with the molecular changes observed in SCH offspring. Our results also indicated that the upregulation of ARRDC3 in SCH offspring may result from increased H3K27 acetylation of the ARRDC3 promoter region, driven by elevated expression of P300. Importantly, adequate L-T4 supplementation during pregnancy improved insulin sensitivity and reversed the molecular alterations in the insulin signalling pathway observed in SCH offspring. In conclusion, exposure to intrauterine SCH resulted in altering the P300-ARRDC3 axis in offspring and impaired insulin sensitivity by disrupting the Akt/GSK-3β/FoxO1 signalling pathway. Timely L-T4 supplementation during pregnancy is an effective strategy to prevent insulin resistance in offspring of SCH mothers. This study elucidates potential molecular mechanisms behind insulin resistance in SCH offspring and suggests novel therapeutic targets for treating metabolic disorders related to maternal SCH.

Moringa oleifera, Cyclea barbata, Centella asiatica Leaves Extract Intervention Ability to Improve Fetus Development and Blood Protein Levels in Malnutrition Pregnant Model Mice

Background: Pregnant women experiencing chronic energy deficiency are at risk of giving birth to low birth weight and premature (stunted) babies. Objectives: In an effort to prevent stunting, the study investigates the effects of a 1:1:1 ratio of Moringa oleifera, Cyclea barbata, and Centella asiatica leaf extract on fetal growth and blood protein levels. Methods: This research used a laboratory experimental approach with 25 adult female Mus musculus Balb/C mice as a model of malnourished pregnancy, was divided into 5 groups: pre-test, positive control, negative control, placebo and test group. Moringa oleifera, Cyclea barbata, and Centella asiatica leaf extracts are administered to the test group and positive control in 1:1:1 ratio. Results: The study results indicated that in pregnant mice without malnutrition receiving a mixture of Moringa oleifera, Cyclea barbata, and Centella asiatica leaf extracts, the average fetal body length was 9.7% higher and their weight was 7.4% heavier than pregnant mice with experiencing chronic energy deficiency. Conclusions: The administration of Moringa oleifera, Cyclea barbata, and Centella asiatica leaf extract can contribute to improving fetal development and blood protein levels. However, its effectiveness is more pronounced in normal pregnancies than in pregnancies with chronic energy deficiency as it can prevent stunting.

Extract from Falcaria vulgaris loaded with exosomes for the treatment of hypertension in pregnant mice: In vitro and In vivo investigations.

Hypertensive disorders during pregnancy pose significant risks to both maternal and fetal health, necessitating safe and effective therapeutic interventions. This study aimed to investigate the potential of an extract derived from Falcaria vulgaris (FV), loaded with exosomes to form the Exo/FV complex, as a novel therapeutic agent for the management of hypertension in pregnant mice: antioxidants, antimicrobials, and phenolic compounds present in FV lower blood pressure. The isolation of exosomes was done by ultracentrifugation methods and the FV was loaded into the exosomes by electroporation method. The Exo/FV was found to be spherical with diameter ranges from 20 to 30nm and they were tested for biocompatibility in NHI 3T3 cell lines and found to be effective. This research investigated invivo hypertension in mice induced by L-NAME and treated with FV and Exo/FV and found that AChE and MAO determine mice's redox state tends to reduce blood pressure. Increased non-protein thiol (NP-SH) and decreased lipid peroxidation were also found, and PDE-5, ACE, Arginase, and MDA activity has also been tested. This analysis showed that Exo/FV effectively treated hypertension during pregnancy.

Enhanced clindamycin delivery using chitosan-coated niosomes to prevent Toxoplasma gondii strain VEG in pregnant mice: an experimental study

BackgroundCongenital toxoplasmosis occurs when a pregnant woman becomes infected with Toxoplasma gondii (T. gondii) for the first time. Treatment typically involves antimicrobial medications, with spiramycin commonly used to prevent transmission. However, spiramycin's effectiveness is limited due to poor placental penetration. Clindamycin, another antibiotic, can cross the placenta but reaches the fetus at only half the maternal concentration. Encapsulating the drug in chitosan-coated niosomes (Cs-Nio) could enhance its effectiveness by targeting specific organs and ensuring sustained release. To address the challenges of using clindamycin, a niosome-coated chitosan system was investigated for treating congenital toxoplasmosis caused by the VEG strain of T. gondii in an animal model.MethodsPregnant mice were infected with VEG strain of T. gondii on the 12th day of pregnancy, followed by treatment with various drugs across six groups. The treatments included chitosan-coated niosomes loaded clindamycin (Cs-Nio-Cli) and other controls. Parasitological evaluations (microscopic examination and real-time PCR), along with histopathological and immunological assessments were conducted to assess treatment efficacy. Finally, statistical analysis was conducted using GraphPad Prism 8.0 and SPSS 26, comparing test and control groups with T test and Mann–Whitney test. A p ≤ 0.05 was considered statistically significant.ResultsThe study found that treatment with Cs-Nio-Cli significantly reduced the number of T. gondii cysts in the brain and eyes (97.59% and 92.68%, respectively) compared to the negative control group. It also mitigated inflammatory changes, prevented cell death, and reduced vascular cuffs in the brain. In addition, Cs-Nio-Cli treatment decreased bleeding, placental thrombosis, and inflammatory cell infiltration in the placenta while improving eye tissue health by reducing retinal folds and bleeds. Immunologically, nanoclindamycin treatment resulted in lower TNF-α cytokine levels and higher IL-10 levels, indicating an enhanced anti-inflammatory response.ConclusionsAlthough Cs-Nio-Cli demonstrates promise in reducing the transmission of congenital toxoplasmosis and mitigating the effects of congenital toxoplasmosis, additional research is necessary to determine the optimal treatment regimens for the complete eradication of the parasite in the fetus.

Cadmium-induced fetal erythropoiesis disturbances in mice

Maternal anemia has been identified as a contributing factor to adverse reproductive outcomes associated with cadmium (Cd) exposure, a common heavy metal. Our recent findings suggest that inhibited erythroid differentiation and enucleation also play significant roles in the direct embryonic toxicity resulting from maternal Cd exposure. However, the effects of Cd exposure on lipid metabolism remodeling, which is essential for physiological erythropoiesis, remain poorly understood. In the present study, pregnant mice were administered low doses of CdCl2 via oral exposure from early to late gestation to mitigate Cd-induced maternal anemia. Compared to vehicle-treated controls, embryos from Cd-treated mice exhibited a slight decrease in weight, though without signs of atrophy. Consistent with our previous observations, fetal livers from Cd-exposed embryos demonstrated a dose-dependent inhibition of erythroid differentiation, as confirmed by ex vivo analysis. Notably, an intrinsic decrease in lipid peroxidation during erythroid differentiation was observed in the bone marrow and fetal livers of vehicle-treated mice, attributed to diminished lipid content. In contrast, this decrease in lipid peroxidation was absent in fetal liver erythroblasts from Cd-treated mice, where an increase in lipid peroxidation was instead noted. These findings elucidate a potential mechanism, lipid peroxidation, underlying Cd-induced embryonic toxicity.

Prenatal exposure to low doses of benzophenone-3 elicits disruption of cortical vasculature in fetuses through perturbations in Wnt/β-catenin signaling correlating with depression-like behavior in offspring mice

Benzophenone-3 (BP-3), commonly used in personal care products, is routinely detected in environmental and human matrices. Evidence delineates a correlation between gestational BP-3 exposure and emotional and social disorders in children and adolescents. However, sensitive target cells and the mode of action underlying the early responses to environmentally relevant level of BP-3 exposure remain unclear. In this study, 0.3 and 3 mg/kg of BP-3 were administered to pregnant mice. Compared with the control group, the cortical blood vessel development process manifested the highest susceptibility to BP-3 exposure using transcriptomic sequencing at embryonic day 14 (E14). Notably, the diminution in vascular density and tight junction proteins presence was observed in the fetal cortex at E14, concomitant with the suppressed transcriptional activity of genes essential to angiogenesis and barrier formation. Strikingly, the investigation revealed that BP-3 exposure impeded vascular sprouting in aortic ring explants and neuroendothelial migration, implicating the Wnt/β-catenin signaling pathway. Moreover, BP-3 exposure compromised perivascular neural stem cell differentiation. Cortical vascular injury correlated with the exhibition of depression-like behavior in four-week postnatal progeny. These insights underscore the cerebrovasculature as an early sensitive target for low doses of BP-3 exposure, fostering the development of biomarkers and the establishment of the adverse outcome pathway framework for BP-3 hazard evaluation.

Pregnancy enhances antiviral immunity independent of type I IFN but dependent on IL-17-producing γδ+ T cells in the nasal mucosa.

Pregnancy is associated with profound changes in immunity. However, pregnancy-related respiratory immune adaptations in response to influenza infection and their impact on disease severity remain unclear. Here, we describe, in a preclinical model of mid-gestation pregnancy, a mechanism of enhanced host defense against influenza A virus (IAV) localized to the nasal cavity that limits viral replication and reduces the magnitude of intrapulmonary immune responses. Consequently, the pregnant mice show reduced pulmonary pathology and preserved airway function after IAV infection. The early restriction of viral replication is independent of type I interferon (IFN) but dependent on increased antimicrobial peptides (AMPs) driven by interleukin-17+ (IL-17+) γδ+ T cells within the nasal passages. This pathway of host defense against IAV infection in the upper airways during pregnancy restricts early viral infection and prevents virus dissemination into the lung supporting maternal fitness.

Postnatal hypoxic preconditioning attenuates lung damage from hyperoxia in newborn mice.

Preterm infants frequently require oxygen supplementation at birth. However, preterm lung is especially sensible to structural and functional damage caused by oxygen free radicals. The adaptive mechanisms implied in the fetal-neonatal transition from a lower to a higher oxygen environment were evaluated in a murine model using a custom-designed oxy-chamber. Pregnant mice were randomly assigned to deliver in 14% (hypoxic preconditioning group) or 21% (normoxic group) oxygen environment. Eight hours after birth FiO2 was increased to 100% for 60 min and then switched to 21% in both groups. A control group remained in 21% oxygen throughout the study. Mice in the normoxic group exhibited thinning of the alveolar septa, increased cell death, increased vascular damage, and decreased synthesis of pulmonary surfactant. However, lung histology, lamellar bodies microstructure, and surfactant integrity were preserved in the hypoxic preconditioning group after the hyperoxic insult. Postnatal hyperoxia has detrimental effects on lung structure and function when preceded by normoxia compared to controls. However, postnatal hypoxic preconditioning mitigates lung damage caused by a hyperoxic insult. Hypoxic preconditioning, implemented shortly after birth mitigates lung damage caused by postnatal supplemental oxygenation. The study introduces an experimental mice model to investigate the effects of hypoxic preconditioning and its effects on lung development. This model enables researchers to delve into the intricate processes involved in postnatal lung maturation. Our findings suggest that hypoxic preconditioning may reduce lung parenchymal damage and increase pulmonary surfactant synthesis in reoxygenation strategies during postnatal care.

Gestational Interrelationships among Gut-Metabolism-Transcriptome in Regulating Early Embryo Implantation and Placental Development in Mice.

Decidualization of the uterine endometrium is a critical process for embryo implantation in mammals, primarily occurring on gestational day 8 in pregnant mice. However, the interplay between the maternal gut microbiome, metabolism, and the uterus at this specific time point remains poorly understood. This study employed a multi-omics approach to investigate the metabolic, gut microbiome, and transcriptomic changes associated with early pregnancy (gestational day 8 (E8)) in mice. Serum metabolomics revealed a distinct metabolic profile at E8 compared to controls, with the differential metabolites primarily enriched in amino acid metabolism pathways. The gut microbial composition showed that E8 mice exhibited higher alpha-diversity and a significant shift in beta-diversity. Specifically, the E8 group displayed a decrease in pathogenic Proteobacteria and an increase in beneficial Bacteroidetes and S24-7 taxa. Transcriptomics identified myriads of distinct genes between the E8 and control mice. The differentially expressed genes were enriched in pathways involved in alanine, aspartate, and glutamate metabolism, PI3K-Akt signaling, and the PPAR signaling pathway. Integrative analysis of the multi-omics data uncovered potential mechanistic relationships among the differential metabolites, gut microbiota, and uterine gene expression changes. Notably, the gene Asns showed strong correlations with specific gut S24-7 and metabolite L-Aspartatic acid, suggesting its potential role in mediating the crosstalk between the maternal environment and embryo development during early pregnancy. These findings provide valuable insights into the complex interplay between the maternal metabolome, the gut microbiome, and the uterine transcriptome in the context of early pregnancy, which may contribute to our understanding of the underlying mechanisms of embryo implantation and development.

Suppression of certain intestinal microbiota metabolites may lead to gestational diabetes in mice fed a high-fat diet.

We aim to establish a gestational diabetes mellitus (GDM) mouse model with mice fed with a high-fat diet (HFD) in comparison with pregnant mice with normal blood glucose levels to investigate the role of intestinal microbiota in the development of HFD-induced GDM. We divided healthy 6-week-old female C57BL mice into an HFD-induced GDM group and a normal diet group. Their bacterial flora and metabolites in intestinal fecal exosomes were co-analyzed using 16 s multi-region sequencing and compared. Alpha (α) diversity was lower within the model group compared to the control group. Beta (β) diversity was significantly different between the two groups. The relative abundances of Lactobacillus, Actinomyces, Rothia, and Bacteroidetes were significantly different between the two groups. Fermentation and nitrate consumption were significantly higher in the GDM group. Multiple bacteria were associated with glycerophosphocholine, S-methyl-5'-thioadenosine, quinolinate, galactinol, deoxyadenosine, DL-arginine, and 2-oxoadenic acid. Imbalances in the production of Lactobacillus, Bacteroidetes, Actinomyces, and Rothia and their related metabolites may lead to metabolic disturbances in GDM. These indicators may be used to assess changes affecting the intestinal microbiota during pregnancy and thus help modulate diet and alter blood glucose.

Multifaceted therapeutic approach via thiazolidinedione-infused magnolol in chitosan nanoparticles targeting hyperlipidemia and oxidative stress in gestational diabetes mellitus in experimental mice.

Recent advancements in nanotechnology have sparked interest in the synthesis of chitosan nanoparticles and their potential applications in medicine. This study investigates the synthesis of chitosan nanoparticles infused with thiazolidinedione and magnolol (TZ/ML-ChNPs) and their therapeutic effects on gestational diabetes mellitus (GDM) in experimental mice. Using streptozotocin-induced diabetic pregnant mice as a model, the study examines the anti-diabetic effects of TZ/ML-ChNPs in vitro and explores possible mechanisms of action. Results show a notable decrease in α-amylase and α-glucosidase activities in TZ/ML-ChNPs-treated samples. Cytocompatibility and flow cytometry analysis in streptozotocin-induced diabetic pregnant mice conducted on RIN-5F cell line demonstrate the safety profile of TZ/ML-ChNPs. The primary objective of this research is to assess whether TZ/ML-ChNPs can mitigate hyperlipidemia and oxidative stress in diabetic pregnant mice. Chitosan nanoparticles with thiazolidinedione and magnolol have therapeutic effects that may be used in clinical and pharmaceutical applications.

Microplastics caused embryonic growth retardation and placental dysfunction in pregnant mice by activating GRP78/IRE1α/JNK axis induced apoptosis and endoplasmic reticulum stress

Microplastics (MPs), a brand-new class of worldwide environmental pollutant, have received a lot of attention. MPs are consumed by both humans and animals through water, food chain and other ways, which may cause potential health risks. However, the effects of MPs on embryonic development, especially placental function, and its related mechanisms still need to be further studied. We investigated the impact on fetal development and placental physiological function of pregnant mice by consecutive gavages of MPs at 0, 25, 50, 100 mg/kg body weight during gestational days (GDs 0–14). The results showed that continuous exposure to high concentrations of MP significantly reduced daily weight gain and impaired reproductive performance of pregnant mice. In addition, MPs could significantly induce oxidative stress and placental dysfunction in pregnant mice. On the other hand, MPs exposure significantly decreased placental barrier function and induced placental inflammation. Specifically, MPs treatment significantly reduced the expression of tight junction proteins in placentas, accompanied by inflammatory cell infiltration and increased mRNA levels of pro-inflammatory cytokines and chemokines in placentas. Finally, we found that MPs induced placental apoptosis and endoplasmic reticulum (ER) stress through the GRP78/IRE1α/JNK axis, leading to placental dysfunction and decreased reproductive performance in pregnant mice. We revealed for the first time that the effects of MPs on placental dysfunction in pregnant animals. Blocking the targets of MPs mediated ER stress will provide potential therapeutic ideas for the toxic effects of MPs on maternal pregnancy.