Risk factors of early adverse events associated with endoscopic ultrasound-guided hepaticogastrostomy using self-expandable metal stent.

Background and study aims This retrospective study aimed to investigate risk factors for early adverse events (AEs) associated with endoscopic ultrasonography-guided hepaticogastrostomy (EUS-HGS) using self-expandable metal stents (SEMS). Patients and methods The clinical success rate, technical success rate, and early AEs were assessed at two hospitals from 2010 to 2022. The analysis focused on risk factors associated with cholangitis, peritonitis, and SEMS migration. Results Technical success was achieved in all cases (94/94), and clinical success was 96.8% (91/94). Post-procedural acute cholangitis occurred in 12.8%of cases (12/94). However, no statistically significant risk factors were identified for cholangitis or biliary tract infection. Peritonitis occurred in only 2.1% of cases (2/94). Univariate analysis, using a 1.5 cm cut-off for the distance between the liver and gastrointestinal tract, revealed significant risk factors: braided-type SEMS, bile duct diameter (especially >4 mm), 6 mm diameter SEMS, and tract dilation ( P= 0.001, P= 0.020, P =0.023, and P =0.046, respectively). Adjusting the cut-offs to 2 cm underscored braided-type SEMS and tract dilation as risk factors ( P =0.002 and P =0.046, respectively). With 2.5-cm cut-offs, only braided-type SEMS remained significant ( P =0.018). Mortality within 14 and 30 days following EUS-HGS was 5.3% (5/94) and 16.0% (15/94), respectively. Conclusions EUS-HGS using SEMS demonstrated high technical and clinical success rates. Laser-cut SEMS may be superior in preventing early AEs.

Safety and Efficacy of Sedation During Emergency Endoscopy for Upper Gastrointestinal Bleeding: A Propensity Score Matching Analysis.

BACKGROUND AND AIM: This study aimed to compare patients with and without sedation during emergency endoscopy for upper gastrointestinal bleeding (UGIB) and to clarify the safety and efficacy of sedation in emergency endoscopy. METHODS: We retrospectively collected 389 patients who underwent emergency endoscopy for UGIB at Ureshino Medical Center from 2016 to 2021. Patients were divided into two groups: sedation group during emergency endoscopy and nonsedation group. Clinical characteristics, patient status on admission, and UGIB etiology were evaluated. Treatment outcomes and adverse events were evaluated using propensity score matching (PSM), and risk factors for mortality from UGIB were investigated using Cox multivariate analysis. RESULTS: The sedation group was significantly younger, composed of a higher proportion of males, and had chronic liver disease. Blood pressure and hemoglobin level on admission were significantly higher in the sedation group. The main cause of bleeding was peptic ulcer, which was significantly higher in the nonsedation group. PSM created 133 matched pairs. The success rate of endoscopic hemostasis was similar in both groups, and procedure time was significantly shorter in the sedation group than in the nonsedation group (17.6 ± 10.0 versus 20.2 ± 10.2 min, P = 0.04). There were no significant differences in adverse events between groups. Cox multivariate analyses revealed that red blood cell transfusion [hazard ratio (HR) 4.45, P < 0.02] and rebleeding (HR 3.30, P = 0.03) were associated with increased risk of 30-day mortality from UGIB. CONCLUSIONS: Sedation reduced the procedure time during emergency endoscopy for UGIB. Sedation during emergency endoscopy for UGIB is acceptable for safe endoscopic procedures.

Usefulness of discharge standards in outpatients undergoing sedative endoscopy: a propensity score-matched study of the modified post-anesthetic discharge scoring system and the modified Aldrete score.

BACKGROUND: This study aimed to evaluate the usefulness of discharge standards in outpatients undergoing sedative endoscopy by comparing the modified post-anesthetic discharge scoring system (MPADSS) and the modified Aldrete score. METHODS: We prospectively enrolled 376 outpatients who underwent gastrointestinal endoscopy under midazolam sedation; 181 outpatients were assessed regarding discharge after sedative endoscopy using the MPADSS (group M), and 195 patients were assessed by the modified Aldrete score (group A). The clinical characteristics, types of endoscopy, endoscopic outcomes, and anesthesia outcomes were evaluated between the two groups. We compared discharge score, recovery time, and adverse events using propensity-score matching. RESULTS: Propensity-score matching created 120 matched pairs. The proportion of patients who had a recovery time within 60 min after endoscopy was significantly higher in group A than that in group M (42.5% versus 25.0%, respectively; P < 0.01). The proportion of patients who required > 120 min of recovery time after endoscopy was significantly lower in group A than that in group M (0.0% versus 5.0%, respectively; P = 0.03). However, significantly more patients had drowsiness at discharge in group A compared with group M (19.1% versus 5.0%, respectively; P < 0.01). There was no significant difference in the adverse event rate within 24 h of discharge between the groups. CONCLUSIONS: Patients assessed by the modified Aldrete score were allowed to discharge earlier than those assessed by the MPADSS. However, a patient's level of consciousness should be assessed carefully, especially in patients who visit the hospital alone.

HSPA8 Single-Nucleotide Polymorphism Is Associated with Serum HSC70 Concentration and Carotid Artery Atherosclerosis in Nonalcoholic Fatty Liver Disease.

There is an association between nonalcoholic fatty liver disease (NAFLD) and atherosclerosis, but the genetic risk of atherosclerosis in NAFLD remains unclear. Here, a single-nucleotide polymorphism (SNP) of the heat shock 70 kDa protein 8 (HSPA8) gene was analyzed in 123 NAFLD patients who had been diagnosed using a liver biopsy, and the NAFLD phenotype including the maximum intima-media thickness (Max-IMT) of the carotid artery was investigated. Patients with the minor allele (A/G or G/G) of rs2236659 showed a lower serum heat shock cognate 71 kDa protein concentration than those with the major A/A allele. Compared with the patients with the major allele, those with the minor allele showed a higher prevalence of hypertension and higher Max-IMT in men. No significant associations between the HSPA8 genotype and hepatic pathological findings were identified. In decision-tree analysis, age, sex, liver fibrosis, and HSPA8 genotype were individually associated with severe carotid artery atherosclerosis (Max-IMT ≥ 1.5 mm). Noncirrhotic men aged ≥ 65 years were most significantly affected by the minor allele of HSPA8. To predict the risk of atherosclerosis and cardiovascular disease, HSPA8 SNP genotyping might be useful, particularly for older male NAFLD patients.

A case of pancreatic endocrine carcinoma with a different clinical diagnosis before chemotherapy and pathological autopsy.

We encountered a case of pancreatic neuroendocrine carcinoma (pNEC) diagnosed via pathological autopsy that was initially diagnosed clinically as G3 pancreatic neuroendocrine tumor (G3 pNET) and discussed the differences between these entities in the literature. A 76-year-old man was admitted to our department because of jaundice. Computed tomography revealed multiple round nodules in both lung fields, suggesting metastasis, and a mass lesion was detected in the head of the pancreas with poor contrast in the arterial phase and slight contrast enhancement in the equilibrium phase. Biopsy of the lungs and pancreas led to a diagnosis of multiple pulmonary metastases of G3 pNET. Because the lesions were unresectable, chemotherapy was administered. Treatment was started with everolimus for 5 weeks. However, the patient experienced severe loss of appetite and malaise, and the lung lesions progressed, prompting treatment discontinuation. Subsequently, the patient's disease progressed rapidly, and he died 99 days after the start of chemotherapy. We performed a pathological autopsy with the consent of the family because of the rapid tumor growth. A pathological autopsy revealed a final diagnosis of pNEC, which differed from the clinical diagnosis.

Successful endoscopic closure with an over-the-scope clip for sigmoid colon perforation due to bile duct stent migration.

An 86-year-old woman presented with a history of endoscopic papillary sphincterotomy for bile duct stones and diverticulitis. The patient was admitted as an emergency case of acute cholangitis due to choledocholithiasis, underwent endoscopic bile duct stenting, and was discharged with a plan for endoscopic lithotripsy. One month later, the patient was readmitted owing to abdominal pain. Abdominal computed tomography at admission showed that the bile duct stent had migrated to the sigmoid colon and the presence of a small amount of extraintestinal gas, suggesting a colonic perforation. Lower gastrointestinal endoscopy showed adhesions and intestinal stenosis in the sigmoid colon, probably after diverticulitis, and the bile duct stent that had perforated the same site. The stent was removed and endoscopic closure of the perforation was performed using an over-the-scope clip. Abdominal computed tomography 8 days after the closure showed no extraintestinal gas. The patient resumed eating and was discharged on the 14th day of admission. There was no recurrence of abdominal pain. Endoscopic closure of sigmoid colon perforation due to bile duct stent migration using an over-the-scope clip has not been reported thus far, and it may be a new treatment option in the future.

Effect of skin-capsular distance on controlled attenuation parameter for diagnosing liver steatosis in patients with nonalcoholic fatty liver disease.

The effect of the skin-capsular distance (SCD) on the controlled attenuation parameter (CAP) for diagnosis of liver steatosis in patients with nonalcoholic fatty liver disease (NAFLD) remains unclear. The SCD was measured using B-mode ultrasound, and the CAP was measured using the M probe of FibroScan®. According to the indications of the M probe, 113 patients with an SCD of ≤ 25 mm were included in the present study. The association between the SCD and CAP was investigated, and the diagnostic performance of the SCD-adjusted CAP was tested. The SCD showed the most significant positive correlation with the CAP (ρ = 0.329, p < 0.001). In the multiple regression analysis, the SCD and serum albumin concentration were associated with the CAP, independent of pathological liver steatosis. According to the multivariate analysis, two different formulas were developed to obtain the adjusted CAP using the SCD and serum albumin concentration as follows: adjusted CAP (dB/m) = CAP - (5.26 × SCD) and adjusted CAP (dB/m) = CAP - (5.35 × SCD) - (25.77 × serum albumin concentration). The area under the receiver operating characteristic curve for diagnosis of a steatosis score ≥ 2 of adjusted CAP was 0.678 and 0.684 respectively, which were significantly greater than the original CAP (0.621: p = 0.030 and p = 0.024). The SCD is associated with the CAP independent of liver steatosis. Adjustment of the CAP using the SCD improves the diagnostic performance of the CAP in NAFLD.

Successful retrograde transvenous embolization under balloon occlusion for rectal arteriovenous malformation.

A 57-year-old man was admitted to our hospital because of frequent hematochezia. Colonoscopy exhibited a submucosal tumor-like lesion in the lower rectum. Abdominal contrast-enhanced computed tomography showed a rectal arteriovenous malformation (AVM) on the right side wall of the lower rectum. The feeder was the superior rectal artery, with early venous return. Embolization of the draining vein and feeding artery of the AVM with N-butyl-2-cyanoacrylate under balloon occlusion was planned. Angiography of the superior rectal artery showed the nidus in the rectum with early venous return of contrast material. The portal vein was punctured percutaneously under ultrasound guidance, and a balloon catheter advanced to the distal part of the superior rectal vein. Venography under balloon occlusion showed the outflow vein and nidus. Transvenous and transarterial nidus embolization with N-butyl-2-cyanoacrylate under balloon occlusion was then performed. Since the embolization, there have been no further episodes of bleeding. There is no established treatment for AVMs. Successful treatment requires targeting and eradication of the nidus. We successfully performed embolization therapy for a rectal AVM via a retrograde transvenous approach. This technique may be suitable for completely eradicating the nidus without the risk of embolism.

Prediction of Nonalcoholic Fatty Liver Disease Using Noninvasive and Non-Imaging Procedures in Japanese Health Checkup Examinees.

Access to imaging is limited for diagnosing nonalcoholic fatty liver disease (NAFLD) in general populations. This study evaluated the diagnostic performance of noninvasive and nonimaging indexes to predict NAFLD in the general Japanese population. Health checkup examinees without hepatitis virus infection or habitual alcohol drinking were included. Fatty liver was diagnosed by ultrasonography. The hepatic steatosis index (HSI), Zhejiang University (ZJU) index, and fatty liver index (FLI) were determined, and risk of advanced liver fibrosis was evaluated by the fibrosis-4 index. NAFLD was diagnosed in 1935 (28.0%) of the 6927 subjects. The area under the receiver operating characteristic (AUROC) curve of the HSI, ZJU index, and FLI was 0.874, 0.886, and 0.884, respectively. The AUROC of the ZJU index (p < 0.001) and FLI (p = 0.002) was significantly greater than that for the HSI. In subjects with a high risk of advanced fibrosis, the sensitivity of the HSI, ZJU index, and FLI were 88.8%, 94.4%, and 83.3% with a low cut-off value and the specificity was 98.5%, 100%, and 100% with a high cut-off value. In conclusion, all indexes were useful to diagnose NAFLD in the general Japanese population and in subjects with potentially advanced liver fibrosis.

Single intratracheal administration of cross-linked water-soluble acrylic acid polymer causes acute alveolo-interstitial inflammation and the subsequent fibrotic formation possibly via the TGF-ß1 pathway in the lung of rats.

In a Japanese chemical factory, a lung disease like pneumoconiosis appeared at a high rate among workers handling cross-linked water-soluble acrylic acid polymer (CWAAP). To our knowledge, no such case was known in the world until very recently. The present study was designed to elucidate the effect of single intratracheal CWAAP instillation on the lung of rats. The CWAAP group had a significant increase in relative lung weight accompanied by a significant elevation in the number of total cells, total protein concentrations, and myeloperoxidase concentrations in bronchoalveolar lavage fluid when compared to the control group. The histopathological study revealed acute lung inflammation with the destruction of alveoli. The factors promoting fibrosis, macrophages, TGF-ß1, collagen and fibronectin vs. the factors suppressing fibrosis, matrix metalloproteinases were more powerfully driven in the CWAAP group, resultantly leading to fibrotic formation. In turn, we examined if acute lung inflammation and the subsequent fibrotic formation seen in the CWAAP group appeared in the other water-soluble polymer groups. Their histopathological findings were observed only in the polyacrylic acid sodium (PAAS), a monomer of CWAAP, group. The degree of inflammation and fibrogenesis was stronger in the CWAAP group than in the PAAS group. In conclusion, the present study demonstrated the induction of acute lung inflammation and the subsequent fibrotic formation by single intratracheal CWAAP instillation. The structural features of CWAAP that contains many carboxyl groups and cross-linked chains may be responsible for enhanced inflammation and fibrogenesis in the lung.

Propofol Sedation in the Endoscopy Room versus Operation Room during Endoscopic Submucosal Dissection for Gastric Tumors: A Propensity Score-Matching Analysis.

BACKGROUND/AIMS: The present study was performed to compare the safety of sedation with propofol during endoscopic submucosal dissection (ESD) for gastric tumors under sedation in the endoscopy room by an endoscopist versus sedation in the operation room by an anesthesiologist. METHODS: In total, 638 patients with gastric tumors who underwent ESD from January 2011 to August 2017 at Ureshino Medical Center and Saga Medical Center Koseikan were retrospectively reviewed. The patients were divided into 2 groups: those who underwent ESD in the endoscopy room (Group E, n = 532) and those who underwent ESD in the operation room (Group O, n = 106). Propensity score matching was applied for evaluation. The treatment outcome of ESD and the adverse events of sedation during ESD (desaturation, hypotension, bradycardia, and arrhythmia) were compared between the 2 groups to consider the safety of ESD. RESULTS: The propensity score-matching analysis created 82 matched pairs. Adjusted comparisons between Groups E and O showed similar treatment outcomes of ESD for gastric tumors. There were no significant differences in the treatment outcomes, anesthesia time, and mean propofol dose between the 2 groups. With respect to adverse events, desaturation occurred more often in Group E than Group O (18.3 vs. 3.7%, respectively; p = 0.005). There were no significant differences in other adverse events (hypotension, bradycardia, and arrhythmia) between the 2 groups. CONCLUSION: Sedation with propofol in the operation room might be required to ensure safer application of ESD for gastric tumors. However, a decrease in the desaturation rate was the only disadvantage of sedation in the endoscopy room.

Colorectal endoscopic mucosal resection with submucosal injection of epinephrine versus hypertonic saline in patients taking antithrombotic agents: propensity-score-matching analysis.

BACKGROUND: Endoscopic mucosal resection (EMR) to remove colon polyps is increasingly common in patients taking antithrombotic agents. The safety of EMR with submucosal saline injection has not been clearly demonstrated in this population. AIMS: The present study aimed to evaluate the efficacy and safety of submucosal injection of saline-epinephrine versus hypertonic saline in colorectal EMR of patients taking antithrombotic agents. METHODS: This study enrolled 204 patients taking antithrombotic agents among 995 consecutive patients who underwent colonic EMR from April 2012 to March 2018 at Ureshino Medical Center. Patients were divided into two groups according to the injected solution: saline-epinephrine or hypertonic (10%) saline (n = 102 in each group). Treatment outcomes and adverse events were evaluated in each group and risk factors for immediate and post-EMR bleeding were investigated. RESULTS: There were no differences between groups in patient or polyp characteristics. The main antithrombotic agents were low-dose aspirin, warfarin, and clopidogrel. Propensity-score matching created 80 matched pairs. Adjusted comparisons between groups showed similar en bloc resection rates (95.1% with saline-epinephrine vs. 98.0% with hypertonic saline). There were no significant differences in adverse events (immediate EMR bleeding, post-EMR bleeding, perforation, or mortality) between groups. Multivariate analyses revealed that polyp size over 10 mm was associated with an increased risk of immediate EMR bleeding (odds ratio 12.1, 95% confidence interval 2.0-74.0; P = 0.001). CONCLUSIONS: Two tested solutions in colorectal EMR were considered to be both safe and effective in patients taking antithrombotic agents.

Cardiotoxicity induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin exposure through lactation in mice.

Dioxins are a group of structurally related chemicals that persist in the environment. Exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), the most toxic congener, is a suspected risk factor for cardiac diseases in humans. TCDD induces signs of cardiotoxicity in various animals. Mouse models of TCDD exposure suggest cardiotoxicity phenotypes develop differently depending on the timing and time-course of exposure. In order to clarify and characterize the TCDD-induced cardiotoxicity in the developing period, we utilized mouse pups exposed to TCDD. One day after delivery, groups of nursing C57BL/6J dams were orally administered TCDD at a dose of 0 (Control), 20 (TCDD-20), or 80 µg/kg (TCDD-80) body weight (BW). On postnatal days (PNDs) 7 and 21, pups' hearts were examined by histological and gene expression analyses. The TCDD-80 group was found to have a left ventricular remodeling on PND 7, and to develop heart hypertrophy on PND 21. It was accompanied by fibrosis and increased expression of associated genes, such as those for atrial natriuretic peptide (ANP), ß-myosin heavy chain (ß-MHC), and endothelin-1 (ET-1). These results revealed that TCDD directly induces cardiotoxicity in the postnatal period represented by progressive hypertrophy in which ANP, ß-MHC, and ET-1 have potentials to mediate the cardiac hypertrophy and heart failure.

Significance of AHR nuclear translocation sequence in 2,3,7,8-tetrachlorodibenzo-p-dioxin-induced cPLA2α activation and hydronephrosis.

The aryl hydrocarbon receptor (AHR) plays a major role in 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced toxicity phenotypes. TCDD bound to AHR elicits both genomic action in which target genes are transcriptionally upregulated and nongenomic action in which cytosolic phospholipase A2α (cPLA2α) is rapidly activated. However, how either of these actions, separately or in combination, induces toxicity phenotypes is largely unknown. In this study, we used AHRnls/nls mice as a model in which AHR was mutated to lack nuclear translocation sequence (NLS), and AHRd/- mice as the corresponding control. Using this model, we studied TCDD-induced alterations in cPLA2α activation and related factors because of the pivotal roles of cPLA2α both in AHR's nongenomic action and in regulation of causative genes of TCDD-induced hydronephrosis. Dams were orally administered TCDD at a dose of 300 µg/kg body weight on postnatal day 1, and pups subsequently exposed to TCDD via milk were examined for gene expression on PND 7 and for histological changes on PND 14. The activation of the AHR genomic action and hydronephrosis onset were observed in the control group but not in the AHRnls/nls group. An ex vivo experiment using peritoneal macrophages exposed to 100 nM TCDD resulted in rapid activation of cPLA2α, an indicator of the nongenomic action, only in the control group but not in the AHRnls/nls group. These results indicated that an NLS is required for the AHR's genomic and nongenomic actions.

Mechanisms of Developmental Toxicity of Dioxins and Related Compounds.

Dioxins and related compounds induce morphological abnormalities in developing animals in an aryl hydrocarbon receptor (AhR)-dependent manner. Here we review the studies in which 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is used as a prototypical compound to elucidate the pathogenesis of morphological abnormalities. TCDD-induced cleft palate in fetal mice involves a delay in palatogenesis and dissociation of fused palate shelves. TCDD-induced hydronephrosis, once considered to be caused by the anatomical obstruction of the ureter, is now separated into TCDD-induced obstructive and non-obstructive hydronephrosis, which develops during fetal and neonatal periods, respectively. In the latter, a prostaglandin E2 synthesis pathway and urine concentration system are involved. TCDD-induced abnormal development of prostate involves agenesis of the ventral lobe. A suggested mechanism is that AhR activation in the urogenital sinus mesenchyme by TCDD modulates the wingless-type MMTV integration site family (WNT)/ß-catenin signaling cascade to interfere with budding from urogenital sinus epithelium. TCDD exposure to zebrafish embryos induces loss of epicardium progenitor cells and heart malformation. AHR2-dependent downregulation of Sox9b expression in cardiomyocytes is a suggested underlying mechanism. TCDD-induced craniofacial malformation in zebrafish is considered to result from the AHR2-dependent reduction in SRY-box 9b (SOX9b), probably partly via the noncoding RNA slincR, resulting in the underdevelopment of chondrocytes and cartilage.

A long-term survivor of undifferentiated carcinoma of the liver successfully treated with surgical treatments: A case report and literature review.

INTRODUCTION: Undifferentiated carcinoma of the liver is extremely rare. The biological characteristics and standard strategy for its treatment have not been established yet. PRESENTATION OF CASE: A 45-year-old man was admitted because of fever elevation and shivering. Abdominal computed tomography revealed a hypovascular cystic mass in segments 6 and 7 of the liver measuring 11.5 × 9.0 cm with ring enhancement and partial solid component. A diagnosis of liver abscess was made, and percutaneous transhepatic abscess drainage was performed. Reddish brown-colored pus showed no bacteria or amoebas. However, cytology demonstrated malignant cells. After additional examinations of magnetic resonance imaging and the positron emission tomography, extended posterior sectionectomy with cholecystectomy was performed. The excised specimen showed a solid and irregular tumor with extensive central necrosis. A pathological examination revealed diffuse proliferation of oval- and spindle-shaped malignant cells. Immunohistochemically, the malignant cells were diffusely positive for AE1/AE3 and vimentin and focally positive for granulocyte colony-stimulating factor and cytokeratin 19; however, hepatocyte-specific antigen, glypican 3, cytokeratin 7, and CD56 were negative. Therefore, a diagnosis of undifferentiated carcinoma of the liver was made. He has remained well without any recurrence for three years since the operation. DISCUSSION: Undifferentiated carcinoma of the liver might grow rapidly, resulting in necrosis with a cystic component. Therefore, it can be difficult to distinguish from liver abscess. CONCLUSION: This disease has markedly different clinical and biological features from common primary malignant tumor of the liver. However, if the tumor is a solitary mass, surgical resection might lead to a good prognosis.

Diet-induced hyperhomocysteinemia impairs vasodilation in 5/6-nephrectomized rats.

Plasma homocysteine is elevated in patients with impaired renal function, and markedly so at end-stage renal disease. As chronic kidney disease and hyperhomocysteinemia are also independent risk factors for cardiovascular disease, the latter is hypothesized to accelerate vascular abnormalities following renal failure. This study aimed to investigate the combined effect of impaired renal function and hyperhomocysteinemia on vascular function. We show that in 5/6-nephrectomized rats, a model of chronic kidney disease, a methionine-rich diet for 8 weeks induces moderate hyperhomocysteinemia, exacerbates hypertension, and attenuates the vascular response to acetylcholine, sodium nitroprusside, 8-bromo-cGMP, and isoprenaline. However, plasma nitrate/nitrite and total NOS activity in the thoracic aorta were not affected. Collectively, the data imply that hyperhomocysteinemia and end-stage renal disease synergistically impair endothelium-dependent and endothelium-independent vasodilatation by blocking the cGMP/protein kinase G and/or cAMP/protein kinase A pathways. 5/6-Nephrectomized rat with hyperhomocysteinemia induced by a methionine-rich diet would be a useful model for elucidating the pathogenesis of vascular impairment in patients with end-stage renal disease.

Roles of cytosolic phospholipase A2α in reproductive and systemic toxicities in 2,3,7,8-tetrachlorodibenzo-p-dioxin-exposed mice.

Exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) induces a variety of toxicities upon binding of TCDD to aryl hydrocarbon receptor. Although this binding upregulates the synthesis of prostaglandins and their related lipid mediators via cytosolic phospholipase A2α (cPLA2α), toxicological significance of this signaling pathway remains elusive. Herein, we investigated the roles of cPLA2α in TCDD toxicities using cPLA2α-null mice. In a first set of experiments, pregnant mice were orally administered TCDD at a dose of 40 µg/kg on gestation day (GD) 12.5, and fetuses were collected on GD 18 for subsequent analyses. The number of live male fetuses of cPLA2α-null type was significantly less than that of wild-type in TCDD-exposed litters. TCDD-induced hydronephrosis was more severe in wild-type fetuses than in cPLA2α-null fetuses regardless of sex, and kidney expression levels of the inflammatory cytokines interleukin-1ß and tumor necrosis factor-α were increased in a cPLA2α-dependent manner in TCDD-exposed fetuses. In a second set of experiments, following intraperitoneal administration of TCDD at 50 µg/kg, body weight of the male adult mice was decreased within 2 days in wild-type mice but was not changed in cPLA2α-null mice. In addition, TCDD-induced lipid accumulation in the livers of cPLA2α-null mice was at an intermediate level compared with TCDD-exposed wild-type and vehicle-control mice. In conclusion, the present results show that cPLA2α is involved in TCDD-induced body weight loss, lipid accumulation in the liver, fetal hydronephrosis, and cytokine gene expression, and that the molecular basis of TCDD toxicity differs considerably between target tissues and life stages.