Polyorchidism in a young Sprague-Dawley rat.

Duplicate testes lined in series were observed in the right scrotum of a 6-week-old Sprague-Dawley rat in a single-dose toxicity study. Of the two right testicles, one was spherical and less than half the size of a normal testis. The other was oval-shaped, slightly smaller than a normal testis, and possessed clear, tortuous blood vessels similar to those of a normal testis.

A-910823, a squalene-based emulsion adjuvant, induces T follicular helper cells and humoral immune responses α-tocopherol component.

Background: Adjuvants are chemical or biological materials that enhance the efficacy of vaccines. A-910823 is a squalene-based emulsion adjuvant used for S-268019-b, a novel vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that is currently in clinical development. Published evidence has demonstrated that A-910823 can enhance the induction of neutralizing antibodies against SARS-CoV-2 in humans and animal models.

Suspected spontaneous hyperadrenocorticism in a young experimental beagle dog.

A 6-month-old female beagle dog, assigned to the low-dose group in a toxicity study, was evaluated for compound toxicity, and spontaneous hyperadrenocorticism was suspected. The animal had an externally apparent distended abdomen on clinical examination upon arrival. Pre-dose clinical pathology showed slightly higher erythroid parameters and stress leukogram on hematology; plasma biochemistry showed higher total protein, gamma-glutamyl transferase, total cholesterol, and triglyceride levels than the reference data.

Current status of pathological image analysis technology in pharmaceutical companies: a questionnaire survey of the Japan Pharmaceutical Manufacturers Association.

The Japan Pharmaceutical Manufacturers Association (JPMA) has instituted a task force (TF) for the "development of image analysis technology for histopathological changes" as part of the collaboration for realizing cutting-edge drug development since 2016. In recent years, there has been progress in the digital pathology technology; however, few applications in nonclinical drug development studies have been observed. Therefore, TF performed a questionnaire survey to investigate the current status, needs, possibility, and development of image analysis.

Spontaneous hemangioendothelial cell hyperplasia of the heart in a young ICR mouse.

Spontaneous nonneoplastic proliferative lesions of the cardiac hemangioendothelium are extremely rare in humans and animals. Here, we describe a spontaneous hemangioendothelial cell hyperplasia in the heart of a 9-week-old male ICR mouse. The lesion was observed focally in the interventricular septum, with no compression of the surrounding tissues.

Adrenal dysplasia in a young SD rat.

The present report describes an adrenal dysplasia in which developmental abnormality was observed in the adrenal gland of a six-week-old male Crl:CD(SD) rat. Microscopically, a localized lesion composed of mildly vacuolated adrenal fasciculata cells with a slightly disturbed cord structure and containing areas with high cell density was observed in a unilateral adrenal gland; no macroscopical changes were detected in the organ. The areas with high cell density consisted of two cell types.

Gene expression profiles in auricle skin as a possible additional endpoint for determination of sensitizers: A multi-endpoint evaluation of the local lymph node assay.

The murine local lymph node assay (LLNA) is widely used to test chemicals to induce skin sensitization. Exposure of mouse auricle skin to a sensitizer results in proliferation of local lymph node T cells, which has been measured by in vivo incorporation of H-methyl thymidine or 5-bromo-2'-deoxyuridine (BrdU). The stimulation index (SI), the ratio of the mean proliferation in each treated group to that in the concurrent vehicle control group, is frequently used as a regulatory-authorized endpoint for LLNA.

Aminoglutethimide-induced lysosomal changes in adrenal gland in mice.

Aminoglutethimide is a steroidogenesis inhibitor and inhibits a cholesterol side-chain cleavage enzyme (CYP11A1) that converts cholesterol to pregnenolone in mitochondria. We investigated histopathological changes induced by 5-day administration of AG in mice. Cytoplasmic vacuoles of various sizes and single cell necrosis were found in zona fasciculata cells in AG-treated mice.

Analysis of gene expression for microminipig liver transcriptomes using parallel long-read technology and short-read sequencing.

The microminipig is one of the smallest minipigs that has emerged as a possible experimental animal model, because it shares many anatomical and/or physiological similarities with humans, including the coronary artery distribution in the heart, the digestive physiology, the kidney size and its structure, and so on. However, information on gene expression profiles, including those on drug-metabolizing phase I and II enzymes, in the microminipig is limited. Therefore, the aim of the present study was to identify transcripts in microminipig livers and to determine gene expression profiles.

Histopathological image analysis of chemical-induced hepatocellular hypertrophy in mice.

Chemical-induced hepatocellular hypertrophy is frequently observed in rodents, and is mostly caused by the induction of phase I and phase II drug metabolic enzymes and peroxisomal lipid metabolic enzymes. Liver weight is a sensitive and commonly used marker for detecting hepatocellular hypertrophy, but is also increased by a number of other factors. Histopathological observations subjectively detect changes such as hepatocellular hypertrophy based on the size of a hepatocyte.

Evaluation of the repeated-dose liver micronucleus assay using 2,4-dinitrotoluene: a report of a collaborative study by CSGMT/JEMS.MMS.

The liver micronucleus assay using young adult rats has the potential to detect liver carcinogens by repeated dosing, and could be expected to be integrated into repeated-dose toxicity studies using a hepatocyte isolation method without the traditional in situ collagenase perfusion. In this study, to assess the performance of the repeated-dose liver micronucleus assay, 2,4-dinitrotoluene (DNT), which is a rodent liver carcinogen, was administered orally to male rats at doses of 50, 100 and 200 mg/kg/day once daily for 14 or 28 consecutive days, and the frequencies of micronucleated hepatocytes (MNHEPs) and micronucleated immature erythrocytes (MNIMEs) were examined. Significant increases in the MNHEPs were observed at 50 mg/kg/day or more in the 14-day treatment, and 50 and 100 mg/kg/day in the 28-day treatment.

Spontaneous Accumulation of Globotriaosylceramide (Gb3) in Proximal Renal Tubules in an ICR Mouse.

This report describes spontaneous cytoplasmic vacuolation in the proximal renal tubules of a 7-week-old male ICR [Crlj:CD1(ICR)] mouse. The contents of vacuoles were positively stained with periodic acid-Schiff (PAS) and Sudan black, and the membranes were positive on immunohistochemical staining for lysosomal-associated membrane protein-2 (LAMP-2), a marker of lysosomal membrane. Electron microscopy revealed electron-dense lamellar bodies in the proximal tubular epithelial cells.

Nrf2 activators attenuate the progression of nonalcoholic steatohepatitis-related fibrosis in a dietary rat model.

Oxidative stress is considered to be a key mechanism of hepatocellular injury and disease progression in patients with nonalcoholic steatohepatitis (NASH). The transcription factor Nrf2 (nuclear factor-erythroid-2-related factor 2) plays a central role in stimulating expression of various antioxidant-associated genes in the cellular defense against oxidative stress. As the cytosolic repressor kelch-like ECH-associated protein 1 (Keap1) negatively regulates Nrf2, activation of Nrf2 facilitated by its release from Keap1 may represent a promising strategy in the treatment of NASH.

Immunohistochemistry of LAMP-2 and adipophilin for phospholipidosis in liver and kidney in ketoconazole-treated mice.

Drug-induced phospholipidosis is an abnormal accumulation of phospholipids in the lysosomes following repeated administration of cationic amphiphilic drugs. Phospholipidosis is detected histopathologically as cytoplasmic vacuolation; however, it is difficult to distinguish from lipid accumulation since their morphological features are similar. In this study, we investigated the usefulness of immunohistochemistry for lysosome-associated membrane protein-2 (LAMP-2) and adipophilin, a membrane protein of cytosolic non-lysosomal lipid droplets, in the liver and kidneys of mice orally administered ketoconazole, an inducer of hepatic phospholipidosis.

A possible mechanism for hepatotoxicity induced by BIRB-796, an orally active p38 mitogen-activated protein kinase inhibitor.

BIRB-796, a selective inhibitor of p38 mitogen-activated protein kinase, has entered clinical trials for the treatment of autoimmune diseases. Levels of alanine transaminase, a biomarker of hepatic toxicity in clinical pathology, were found to be increased in Crohn's disease patients treated with BIRB-796. The purpose of the present study was to clarify the molecular mechanism(s) of this hepatotoxicity.

Changes in the gene expression and enzyme activity of hepatic cytochrome P450 in juvenile Sprague-Dawley rats.

The developmental changes in the hepatic cytochrome P450 (CYP) content, mRNA expression of 12 hepatic CYP subtypes, and the enzyme activities of 5 hepatic CYP subfamilies in rats were investigated using non-treated male and female Sprague-Dawley rats of ages postnatal day (PD) 4, 16, 30 and 8 and 12 weeks. The hepatic proliferation kinetics was also determined by using the phospho-histone H3 (p-histon)-labeled hepatocyte index. The developmental changes in the enzyme activities of hepatic expression of CYP1A and CYP3A in rats were similar to those in humans, although there is no fetal-neonatal dominant CYP3A subtype in rat livers unlike human CYP3A7.

Detection of initiation activity of 1,2-dimethylhydrazine in in vivo medium-term liver initiation assay system using 4-week-old rats without hepatocellular proliferative stimuli during the test chemical treatment period.

We have developed an in vivo medium-term liver initiation assay system to detect initiation activities of chemicals on multi-organ carcinogenesis. However, cell proliferation stimuli during the test chemical treatment period, required in the previously used assay models using adult rats, are laborious; moreover, those cause decrease of hepatic metabolic enzymes and psychological and physical discomfort to animals resulting in inaccurate interpretation. Therefore, we investigated the utility of another in vivo medium-term liver initiation assay model using 4-week-old rats without the cell proliferation stimuli.

Intraperitoneal injection of D-galactosamine provides a potent cell proliferation stimulus for the detection of initiation activities of chemicals in rat liver.

In an in vivo 5-week initiation assay model, chemical hepatectomy by hepato-toxicant administration was utilized as a cell proliferation stimulus as an alternative to the two-thirds partial hepatectomy. The study investigated the effect of an intraperitoneal (i.p.

Proventricular adenocarcinoma in a Humboldt penguin (Spheniscus humboldti) and a great horned owl (Bubo virginianus); identification of origin by mucin histochemistry.

Cases of proventricular neoplasm in a Humboldt penguin (Spheniscus humboldti) and a great horned owl (Bubo virginianus) were observed. Microscopically, the neoplastic cells formed branching tubules or acini in both cases. Galactose oxidase-Schiff (GOS) staining revealed that the cytoplasm of the normal surface epithelium and surface mucosubstances of the proventriculus adjacent to the neoplasm were positive in both cases.

Fatal necrotic enteritis associated with Clostridium perfringens in wild crows (Corvus macrorhynchos).

Sporadic outbreaks of fatal enteritis occurred among free-living wild crows ('large billed' or 'wok' crow; Corvus macrorhynchos) in an open-air park in Japan in 2002. Eight crows were found dead during February, followed by two more in September, and five of the eight were examined histopathologically. At necropsy, all cases showed a markedly dilated small intestine, especially the jejunum and ileum, with large amounts of gas, and dark red to greenish-brown soft content.