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Uterine atony is a major contributor to postpartum hemorrhage. We previously proposed the novel histological concept of postpartum acute myometritis (PAM) to elucidate the pathophysiology of uterine atony. This concept involves the infiltration of macrophages and neutrophils, as well as mast cell and complement activation in the myometrium. However, the pathological mechanism underlying uterine atony in the context of PAM remains unclear. Herein, we focused on uterine contraction-associated proteins (CAPs) including connexin 43 (Cx43), oxytocin receptors (OXR), prostaglandin receptors EP1, EP3, FP, and protease-activated receptor (PAR)-1. This follow-up study aimed to compare CAP expression between PAM and control groups. We selected 38 PAM subjects from the cases enrolled in our amniotic fluid embolism registry between 2011 and 2018. Control tissues from 10 parturients were collected during cesarean section. We stained the myometrial tissues with the following CAP markers, inflammatory cell markers, and other markers: Cx43, OXR, EP1, EP3, FP, PAR-1, C5a receptor, tryptase, neutrophil elastase, CD68, β-actin, and Na + /K + -ATPase. The immunostaining-positive areas of Cx43, OXR, EP1, EP3, and FP standardized by β-actin in the PAM tissue were significantly smaller than in the control group, whereas those of PAR-1 and Na + /K + -ATPase increased significantly in the PAM group. The Cx43- and OXR-positive areas correlated negatively with the immunostaining-positive cell numbers of CD68 and tryptase with halo, respectively. PAM may impair individual and synchronized myocyte contraction, leading to uterine atony refractory to uterotonics. Further cell-based studies are needed to elucidate the molecular mechanism by which inflammatory cells suppress CAP expression., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Tomoaki Oda, Naoaki Tamura, Naomi Furuta-Isomura, Naohiro Kanayama, and Hiroaki Itoh report financial support was provided by Japan Society for the Promotion of Science. Hiroaki Itoh reports financial support was provided by Japan Agency for Medical Research and Development. If there are other authors, they 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 © 2024 Elsevier B.V. All rights reserved.)

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.

Amniotic fluid embolism (AFE) and placental abruption (PA) are typical obstetric diseases associated with disseminated intravascular coagulation (DIC). AFE is more likely to be complicated with enhanced fibrinolysis than PA. AFE may have an additional mechanism activating fibrinolytic cascade. We aimed to compare the coagulation/fibrinolysis factors among AFE, PA, and peripartum controls. We assessed AFE cases registered in the Japanese AFE Registry, and PA cases complicated with DIC (severe PA) and peripartum controls recruited at our hospital. The following factors in plasma were compared: prothrombin fragment 1 + 2 (PF1 + 2), plasmin α2-plasmin inhibitor complex (PIC), tissue factor (TF), tissue plasminogen activator (tPA), annexin A2 (AnnA2), total thrombin activatable fibrinolysis inhibitor (TAFI) including its activated form (TAFIa), and plasminogen activator inhibitor-type 1 (PAI-1). PF1 + 2 and PIC were markedly increased in both AFE (n = 27) and severe PA (n = 12) compared to controls (n = 23), without significant difference between those disease groups; however, PIC in AFE showed a tendency to elevate relative to PF1 + 2, compared with severe PA. AFE had significantly increased tPA and decreased total TAFI levels compared with severe PA and controls, which might be associated with further plasmin production in AFE and underlie its specific fibrinolytic activation pathway., (© 2024. The Author(s).)

Rapid infantile growth (RG) markedly increases the risk of obesity and metabolic disorders in adulthood, particularly among neonates born small. To elucidate the molecular mechanisms by which RG following undernourishment in utero (UN) contributes to the deterioration of adult fat deposition, we developed a UN mouse model using maternal energy restriction, followed by RG achieved by adjustments to 4 pups per litter soon after birth. A high-fat diet (HFD) was fed to weaned pups treated or not (Veh) with tauroursodeoxycholic acid (TU). UN-RG pups showed the deterioration of diet-induced obesity and fat deposition, which was ameliorated by TU. We performed a microarray analysis of epididymal adipose tissue and two gene enrichment analyses (NN-Veh vs UN-RD-Veh and UN-RG-Veh vs UN-RG-TU). The results obtained identified 4 common gene ontologies (GO) terms of inflammatory pathways. In addition to the inflammatory characteristics of 4 GO terms, the results of heatmap and principal component analyses of the representative genes from 4 GO terms, genes of interest (GOI; Saa3, Ubd, S100a8, Hpx, Casp1, Agt, Ptgs2 ) selected from the 4 GO terms, and immunohistochemistry of macrophages collectively suggested the critical involvement of inflammation in the regulation of fat deposition in the responses to UN and TU. Therefore, the present results support the 'Developmental Origins of Metaflammation', the last word of which was recently proposed by the concept of metabolic disorders induced by low-grade systemic inflammation., 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 © 2022 Suzuki, Kohmura-Kobayashi, Ueda, Furuta-Isomura, Matsumoto, Oda, Kawai, Itoh, Matsuya, Narumi, Tamura, Uchida, Mochizuki and Itoh.)

The aim of present study was to investigate the association of placental pathological findings with infantile neurodevelopment during the early 40 months of life. 258 singleton infants were enrolled in the Hamamatsu Birth Cohort for Mothers and Children (HBC Study) whose placentas were saved in our pathological division. To assess the infantile neurodevelopment, we used Mullen Scales of Early Learning (gross motor, visual reception, fine motor, receptive language, expressive language) at 10, 14, 18, 24, 32, and 40 months. For obtaining placental blocks, we carried out random sampling and assessed eleven pathological findings using mixed modeling identified 'Accelerated villous maturation', 'Maternal vascular malperfusion', and 'Delayed villous maturation' as significant predictors of the relatively lower MSEL composite scores in the neurodevelopmental milestones by Mullen Scales of Early Learning. On the other hand, 'Avascular villi', 'Thrombosis or Intramural fibrin deposition', 'Fetal vascular malperfusion', and 'Fetal inflammatory response' were significant predictors of the relatively higher MSEL composite scores in the neurodevelopmental milestones by Mullen Scales of Early Learning. In conclusion, the present study is the first to report that some placental pathological findings are bidirectionally associated with the progression of infantile neurodevelopment during 10-40 months of age., (© 2022. The Author(s).)

Metabolic syndrome refers to obesity-associated metabolic disorders that increase the risk of type 2 diabetes, coronary diseases, stroke, and other disabilities. Environmental imbalance during the early developmental period affects health and increases susceptibility to non-communicable diseases, including metabolic syndrome, in later life; therefore, the Developmental Origins of Health and Disease (DOHaD) theory was established. According to the DOHaD theory, the hypothesis of the energy-saving 'Thrifty Phenotype' in undernourished fetuses is one of the well-accepted schemes as a risk of developing metabolic syndrome. This phenotype is evolutionarily advantageous for survival of the fittest in a hangry environment after birth, a strong selection pressure, but increases the risk of developing metabolic syndrome under an obesogenic diet according to the 'Mismatch' hypothesis. Increasing evidences support that chronic inflammation pathophysiologically connects obesity to metabolic disorders in metabolic syndrome, leading to the concept of 'Metaflammation'. 'Metaflammation' in humans is proposed to originate from the evolutionary conservation of crosstalk between immune and metabolic pathways; however, few studies have investigated the contribution of evolutionary maladaptation to the pathophysiology of 'Metaflammation'. Therefore, it is promising to investigate 'Metaflammation' from the viewpoint of selective advantages and its 'Mismatch' to an unexpected environment in contemporary lifestyles, in consideration of the principal concept of evolutionarily conserved nutrient sensing and immune signaling systems., 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 © 2022 Itoh, Ueda, Suzuki and Kohmura-Kobayashi.)

Pulmonary thromboembolism (PTE) is one of the leading causes of maternal mortality. We previously reported that possible contamination of amniotic fluid (AF) into maternal circulation accelerated thrombin production and activated platelet function in maternal blood through the extrinsic pathway, which may be associated with the high incidence of PTE in early puerperium. However, it remains unclear whether the maternal anticoagulation system, e.g., the activated protein C (APC) pathway, contributes to the hypercoagulable condition induced by AF. Our previous study using an endogenous thrombin potential (ETP)-based assay revealed that sensitivity to APC was reduced during the postpartum first day, i.e., immediately after delivery, when parturients were supposed to be exposed to AF. Our aim is to investigate the susceptibility of maternal plasma to APC when mixed with AF. We collected plasma from 51 pregnant females and mixed with AF as well as APC. APC-sensitivity ratio (APC-sr) was calculated using the ETP-based assay. Addition of AF to maternal plasma showed a significant increase of ETP in the presence of APC. APC-sr was significantly increased, indicating decreased sensitivity to APC, after AF mixture to maternal plasma. The present APC-sr difference with AF contamination was smaller than that we reported previously in venous thromboembolism cases. The inhibitory effects of AF on the APC anticoagulation pathway may contribute, at least partly, to further promotion of thrombin production induced by AF. Combined with other classical thrombophilic risk factors, the present findings support possible involvements of AF exposure in the high incidence of PTE in early puerperium., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Neonatal respiratory disorders, such as transient tachypnea of the newborn and respiratory distress syndrome, occur frequently after an elective cesarean delivery. Although conventional pulse oximetry is recommended for neonatal resuscitation, it often requires several minutes after birth to obtain a reliable signal. In a previous study, we used novel tissue oximetry equipment to detect fetal and neonatal early tissue oxygen saturation (StO 2 ) before and immediately after vaginal delivery. Therefore, we hypothesized that low neonatal StO 2 levels measured by tissue oximetry may lead to neonatal respiratory disorder after a scheduled cesarean delivery. Hence, this study aimed to evaluate the StO 2 levels measured by tissue oximetry in neonates with or without a respiratory disorder subsequently diagnosed after an elective cesarean delivery. Materials and methods: We enrolled 78 pregnant Japanese women who underwent an elective cesarean section at ≥36 weeks' gestation. After combined spinal and epidural anesthesia were administered to the mother, fetal StO 2 levels were measured by tissue oximetry using an examiner's finger-mounted sensor during a pelvic examination immediately before the cesarean section. We measured the neonatal StO 2 levels at 1, 3, and 5 minutes after birth and retrospectively compared the fetal and neonatal StO 2 levels with the incidence of subsequent diagnoses of neonatal respiratory disorders. Results: The data of StO 2 levels in 35 neonates were collected. Seven neonates (respiratory disorder (RD) group) were subsequently diagnosed with respiratory disorders by neonatal medicine specialists, whereas the 28 remaining neonates (NR group) were not. The median fetal StO 2 (interquartile range) of the RD and NR groups was 52.0% (41.8%-60.8%) and 42.5% (39.0%-52.5%), respectively ( P = 0.12). The median neonatal StO 2 (interquartile range) of the RD and NR groups at 1 minute after birth was 42.0% (39.0%-44.0%) and 46.0% (42.0%-49.0%), respectively ( P = 0.091). At 3 minutes after birth, the median neonatal StO 2 (interquartile range) of the RD and NR groups was 41.0% (39.0%-46.0%) and 47.0% (44.3%-53.5%), respectively ( P = 0.004). Finally, at 5 minutes after birth, the median neonatal StO 2 (interquartile range) of the RD and NR groups was 45.0% (44.0%-52.0%) and 54.0% (49.3%-57.0%), respectively ( P = 0.007). Conclusions: The StO 2 values in the RD group were lower than those in the NR group at 3 and 5 minutes after birth, suggesting that neonates with low StO 2 levels soon after birth may be predisposed to clinically diagnosed neonatal respiratory disorders., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Objectives: Amniotic fluid embolism is a rare disease that induces fatal coagulopathy; however, due to its rarity, it has not yet been examined in detail. The strict diagnostic criteria by Clark for amniotic fluid embolism include severe coagulopathy complicated by cardiopulmonary insufficiency, whereas the Japanese criteria also include postpartum hemorrhage or Disseminated Intravascular Coagulation in clinical practice. Amniotic fluid embolism cases with preceding consumptive coagulopathy may exist and are potential clinical targets for earlier assessments and interventions among amniotic fluid embolism cases fulfilling the Japanese, but not Clark criteria. The present study was performed to compare coagulopathy in the earlier stage between the amniotic fluid embolism patients diagnosed by Clark criteria (Clark group, n = 6), those by the Japanese criteria (Non-Clark group, n = 10), and peripartum controls and identify optimal clinical markers for earlier assessments of amniotic fluid embolism-related consumptive coagulopathy., Design: Retrospective case-control study., Setting: A single university-based center. Our amniotic fluid embolism registry program has accumulated clinical information and blood samples since 2003., Patients: Amniotic fluid embolism patients in the Clark and Non-Clark groups between 2009 and 2017 and peripartum controls., Interventions: None., Measurements and Main Results: Clinical information was collected on hemoglobin levels, platelet counts, and coagulation- and fibrinolysis-related variables. Fibrinolytic parameters were also measured and compared among the three groups before blood transfusion. Fibrinogen levels in all patients in the Clark group and most in the Non-Clark group decreased earlier than hemoglobin levels, which was consistent with the high hemoglobin/fibrinogen ratio and, thus, is a promising clinical marker for the earlier assessment of amniotic fluid embolism-related consumptive coagulopathy., Conclusions: Earlier evaluations of consumptive coagulopathy and hyperfibrinolysis using the hemoglobin/fibrinogen ratio following preemptive treatment may reduce the occurrence or prevent the aggravation of severe coagulopathy in amniotic fluid embolism patients.

An opaque fetal membrane based on gross appearance is traditionally indicative of histological chorioamnionitis; however, to the best of our knowledge, there is currently no supportive evidence, and its diagnostic efficiency has not yet been scientifically demonstrated. The present study aimed to provide scientific insights into the traditional concept of an opaque fetal membrane based on gross appearance being an indicator of histological chorioamnionitis. We examined the placental pathology after screening of the placental gross appearance and perinatal complications and did not examine uncomplicated deliveries. We investigated the relationship between the presence of an opaque fetal membrane and histological chorioamnionitis (Cohort 1, 571 placentas) or the outcomes of neonates delivered at term (Cohort 2, 409 placentas) at Hamamatsu University School of Medicine between 2010 and 2017. The judgment of a positive opaque fetal membrane based on gross appearance correlated with histological chorioamnionitis (Cohort 1). Its sensitivity and specificity were 66.7 and 89.9%, respectively, while positive and negative predictive values were 86.8 and 73.0%, respectively. The judgment of a positive opaque fetal membrane based on gross appearance significantly correlated with chorioamnionitis-related complications in term newborns after adjustments for confounding factors (OR;1.82 [1.07-3.11], P<0.05) (Cohort 2). A correlation was observed even after adjustments for confounding factors. The present study is the first to demonstrate that the judgment of a positive opaque fetal membrane based on gross appearance correlated with histological chorioamnionitis as well as chorioamnionitis-related complications in newborns delivered at term. The present results provide support for the traditionally-described importance of gross inspections for an opaque fetal membrane soon after birth., Competing Interests: No authors have competing interests.

In Japan, pregnant women are diagnosed as obese if the prepregnancy body mass index (BMI) is ≥25 kg/m 2 . However, this is different from other countries. The Institute of Medicine (IOM) classifies prepregnancy BMI as underweight (BMI <18.5 kg/m 2 ), normal weight (BMI 18.5-24.9 kg/m 2 ), overweight (BMI 25.0-29.9 kg/m 2 ), and obese (BMI ≥30 kg/m 2 ). In addition to these four categories, the American College of Obstetricians and Gynecologists (ACOG) classifies prepregnancy BMI as obesity class I (BMI 30.0-34.9 kg/m 2 ), obesity class II (BMI 35.0-39.9 kg/m 2 ), and obesity class III (BMI ≥40 kg/m 2 ). We conducted a retrospective cohort study to compare obstetric outcomes by the three different categorizations in 6,066 pregnant women who gave birth between 2010 and 2019. According to Japanese classification, 668 (11%) pregnant women were classified as obese, and significant odds ratios (OR) were observed for hypertensive disorders of pregnancy (HDP; 3.32), gestational diabetes mellitus (GDM; 3.39), large for gestational age (LGA; 2.91), and macrosomia (4.01). According to the classification of IOM, 474 (7.8%) and 194 (3.1%) were classified as overweight and obese pregnant women, respectively. Specifically, a high OR was observed in obese pregnant women for HDP (5.85) and GDM (5.0). ACOG classification categorized 474 (7.8%) pregnant women as overweight, 141 (2.3%) as obesity class I, 41 (0.6%) as obesity class II, and 12 (0.2%) as obesity class III. In obesity class III, a significantly high OR was observed for HDP (12.89), GDM (8.37), and LGA (5.74). The Japanese classification may be useful for low-risk pregnancies, whereas IOM classification may be applicable to identify high-risk pregnancies. ACOG criteria may be useful for step-wise assessments of HDP and GDM risks in Japanese pregnant women; however, the number of class II and III obese pregnant women was small., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Uterine atony is a major cause of postpartum hemorrhage. We recently proposed the new histological concept of postpartum acute myometritis (PAM) for the pathophysiology of refractory uterine atony of unknown etiology, which is characterized by the diffuse activation of mast cells and the complement system as well as the massive infiltration of macrophages and neutrophils into the uterine body. We herein focused on the uterine isthmus just adjacent to the body. The isthmus becomes significantly elongated throughout pregnancy. It is composed of myocytes and fibroblasts with an extracellular matrix that forms a passive lower segment during labor. The aim of this study was to histologically examine the uterine isthmus in cases of PAM in the uterine body. Under the amniotic fluid embolism-registry program in Japan, we selected PAM cases from uterine samples obtained by cesarean hysterectomy and delivered to us for analyses between 2011 and 2017. Control tissues were collected during elective cesarean section. We investigated the isthmus tissues of these cases and performed immunohistochemistry for inflammatory cell markers, i.e. neutrophil elastase, mast cell tryptase, CD68, CD3, and C5a receptor (C5aR). The numbers of tryptase-positive degranulating mast cells, elastase-positive neutrophils, CD68-positive macrophages, and C5aR-positive cells in the isthmus were significantly higher in uteri with PAM in the body than in controls without PAM. CD3 was negative in both groups. In conclusion, inflammation and an anaphylactoid reaction were histologically detected not only in the uterine body, but in the isthmus among cases of refractory PPH of unknown etiology after cesarean section., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: Among atopic diseases, atopic dermatitis is the most common allergic disease in children and influences both infantile and parental quality of life., Objective: The present study investigated the sex-specific relationship between the fetal/placental weight ratio and The incidence of atopic dermatitis in infants during the first 14 months of life., Methods: Study participants were 922 infants (462 female and 460 male) from singleton pregnancies enrolled in the Hamamatsu Birth Cohort for Mothers and Children (HBC Study) after the exclusion of 298 with missing data on atopic dermatitis. The enrollment of infants with atopic dermatitis was based on a positive response from parents regarding whether a physician had ever diagnosed their child with atopic dermatitis by 14 months of age. The two-sample Wilcoxon rank-sum test or χ 2 test was adopted for descriptive analyses where appropriate. Unadjusted odds ratios and 95% confidence intervals for the infantile incidence of atopic dermatitis were compared using logistic regression analyses., Results: Maternal and perinatal factors did not correlate with the incidence of infantile atopic dermatitis. Fetal/placental weight ratio, but not birth or placental weight, correlated with the incidence of atopic dermatitis in female, but not male, infants. A correlation was still observed after adjustments for maternal allergies, gestational age at birth, maternal smoking during pregnancy, and household income at birth (odds ratio: 1.57; 95% confidence interval, 1.05-2.33)., Conclusion: We speculated that the intrauterine fetal environment, represented by a relatively small placenta, programs a predisposition in only female infants to atopic dermatitis during the first 14 months of life., (© 2020 The Authors. Published by Elsevier Inc. on behalf of Women's Dermatologic Society.)

We recently reported that a treatment with tauroursodeoxycholic acid (TUDCA), a secondary bile acid, improved developmentally-deteriorated hepatic steatosis in an undernourishment (UN, 40% caloric restriction) in utero mouse model after a postnatal high-fat diet (HFD). We performed a microarray analysis and focused on two genes (Cidea and Cidec) because they are enhancers of lipid droplet (LD) sizes in hepatocytes and showed the greatest up-regulation in expression by UN that were completely recovered by TUDCA, concomitant with parallel changes in LD sizes. TUDCA remodeled developmentally-induced histone modifications (dimethylation of H3K4, H3K27, or H3K36), but not DNA methylation, around the Cidea and Cidec genes in UN pups only. Changes in these histone modifications may contribute to the markedly down-regulated expression of Cidea and Cidec genes in UN pups, which was observed in the alleviation of hepatic fat deposition, even under HFD. These results provide an insight into the future of precision medicine for developmentally-programmed hepatic steatosis by targeting histone modifications.

Aim: Uterine atony is a major cause of postpartum hemorrhage. We recently proposed a new concept for the histopathophysiology of refractory uterine atony, postpartum acute myometritis (PAM), characterized by acute inflammatory changes with massive stromal edema, increased numbers of complement C5a receptors and diffuse mast cell activation in the myometrium. We herein focused on the possible involvement of the kinin-kallikrein system in the rapid development of interstitial edema in PAM, particularly bradykinin receptor type 1 (B1R), which is up-regulated under inflammatory conditions. The present study investigated B1R expression with uterine interstitial edema in PAM., Methods: Our institution plays an important role in a Japanese amniotic fluid embolism registry project. We selected PAM cases from uterine samples delivered to us for further analyses between 2012 and 2017. Control tissues were collected during cesarean section and planned hysterectomy. B1R expression was semi-quantitatively measured by immunohistochemistry, while uterine interstitial edema was estimated by semi-quantitative measurements of the alpha smooth muscle actin-negative area using immunohistochemistry., Results: There were 36 and 8 cases in the PAM and control groups, respectively. The alpha smooth muscle actin-negative area was increased in the PAM group, concomitant with the significant up-regulation of B1R expression in uterine smooth muscle cells, vascular endothelial cells, and neutrophils. A positive correlation was observed between these two factors., Conclusion: We demonstrated the up-regulated expression of B1R in the myometrium and its positive correlation with histologically estimated interstitial edema, suggesting the contribution of the kinin-kallikrein-B1R system to the development of interstitial edema in PAM cases., (© 2019 Japan Society of Obstetrics and Gynecology.)

Introduction: Pulmonary thromboembolism (PTE) is a leading cause of maternal death and frequently occurs during early puerperium. Amniotic fluid components are frequently observed in the maternal circulation in parturition; however, it currently remains unclear whether amniotic fluid contamination in maternal blood is related to the high incidence of PTE in early postpartum., Objectives: To examine the influence of amniotic fluid on blood coagulation and fibrinolysis systems with thromboelastometry., Materials and Methods: Twenty-one pregnant women were recruited. We used whole citrated blood in ROTEM® (Tem Innovations GmbH, Munich, Germany), including the non-activated assay (NATEM), assessments for extrinsic (EXTEM) and intrinsic pathways (INTEM), fibrin polymerization (FIBTEM), and hyperfibrinolysis (APTEM), with amniotic fluid contamination, and measured the clotting time (CT), clot formation time (CFT), alpha, amplitude at 10 min (A10), maximum clot firmness (MCF), and lysis indices at 30 min (LI30) and 60 min (LI60)., Results: Short CT in all assays as well as short CFT, high alpha, and increased A10 and MCF in NATEM were observed with amniotic fluid contamination. A10 and MCF as well as LI30 and LI60 decreased in EXTEM. Decreased LI60 with the mixture of amniotic fluid was not improved by tranexamic acid in APTEM., Conclusions: Amniotic fluid accelerated thrombin production and activated platelet aggregation without inducing hyperfibrinolysis in whole blood. The activated tissue factor pathway with amniotic fluid produced soft and fragile clots due to its influence on platelets, which may be associated with, at least partly, the high incidence of PTE in early puerperium, particularly after cesarean section., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Nonalcoholic fatty liver disease (NAFLD) is a hepatic manifestation of metabolic syndrome. The prevalence of NAFLD in Japan has nearly doubled in the last 10-15 years. Increasing evidence supports undernourishment in utero being causatively connected with the risk of NAFLD in later life. Low body mass index (BMI) has been common among Japanese women of childbearing age for several decades due to their strong desire to be thin. It is plausible that insufficient maternal energy intake by pregnant Japanese women may underlie the rapid increase in the prevalence of NAFLD in Japan. In order to clarify the mechanisms by which undernourishment in utero primes adult hepatic steatosis, we developed a mouse model of fetal undernourishment with a hepatic fat deposit-prone phenotype on an obesogenic high fat diet in later life. We found that endoplasmic reticulum (ER) stress response parameters were activated concomitantly with the deterioration of hepatic steatosis and also that the alleviation of ER stress with the chemical chaperone, tauroursodeoxycholic acid (TUDCA), significantly improved hepatic steatosis. Therefore, undernourishment in utero may program the future integration of ER stress in the liver on an obesogenic diet in later life and also induce the deterioration of hepatic steatosis. These results also provide an insight into interventions for the potential high-risk population of NAFLD, such as those born small or exposed to maternal undernourishment during the fetal period, with the alleviation of ER stress by dietary supplements and/or specific food including chaperones., (© 2016 Japanese Teratology Society.)

In order to investigate the possible involvement of endoplasmic reticulum (ER) stress in the developmental origins of hepatic steatosis associated with undernourishment in utero, we herein employed a fetal undernourishment mouse model by maternal caloric restriction in three cohorts; cohort 1) assessment of hepatic steatosis and the ER stress response at 9 weeks of age (wks) before a high fat diet (HFD), cohort 2) assessment of hepatic steatosis and the ER stress response on a HFD at 17 wks, cohort 3) assessment of hepatic steatosis and the ER stress response at 22 wks on a HFD after the alleviation of ER stress with a chemical chaperone, tauroursodeoxycholic acid (TUDCA), from 17 wks to 22 wks. Undernourishment in utero significantly deteriorated hepatic steatosis and led to the significant integration of the ER stress response on a HFD at 17 wks. The alleviation of ER stress by the TUDCA treatment significantly improved the parameters of hepatic steatosis in pups with undernourishment in utero, but not in those with normal nourishment in utero at 22 wks. These results suggest the pivotal involvement of the integration of ER stress in the developmental origins of hepatic steatosis in association with undernourishment in utero.

Placental villi play pivotal roles in feto-maternal transportation and phospholipids constitute a major part of the villous membrane. We have been developing and optimizing an imaging system based on a matrix-assisted laser desorption/ionization (MALDI)-based mass spectrometer, which provides clear two-dimensional molecular distribution patterns using highly sensitive mass spectrometry from mixtures of ions generated on tissue surfaces. We recently applied this technology to normal human uncomplicated term placentas and detected the specific distribution of sphingomyelin (SM) (d18:1/16:0) in stem villi and phosphatidylcholine (PC) (16:0/20:4) in terminal villi. In the present study, we applied this technology to nine placentas with maternal or fetal complications, and determined whether a relationship existed between these specific distribution patterns of phospholipid molecules and the six representative pathological findings of placentas, i.e., villitis of unknown etiology (VUE), thrombus, atherosis, chorioamnionitis (CAM), immature terminal villi, and multiple branched terminal villi. In two placentas with the first and second largest total number of positive pathological findings, i.e., five and three positive findings, the specific distribution of SM (d18:1/16:0) in stem villi and PC (16:0/20:4) in terminal villi disappeared. The common pathological findings in these two placentas were atherosis, immature terminal villi, and multiple branched terminal villi, suggesting the possible involvement of the underperfusion of maternal blood into the intervillous space. On the other hand, the number of pathological findings were two or less in the seven other placentas, in which no specific relationships were observed between the differential expression patterns of these two phospholipids in stem and terminal villi and the pathological findings of the placentas; however, the specific distribution pattern of SM (d18:1/16:0) in stem villi disappeared in four placentas, while that of PC (16:0/20:4) in terminal villi was preserved. These results suggested that the absence of the specific distribution of PC (16:0/20:4) in terminal villi, possibly in combination with the absence of SM (d18:1/16:0) in stem villi, was linked to placental morphological changes in response to maternal underperfusion of the placenta.