Diagnostic criteria are presented for degenerative, inflammatory, nonneoplastic proliferative, and neoplastic lesions in the liver of medaka (Oryzias latipes), a small fish species frequently used in carcinogenesis studies. The criteria are the consensus of a Pathology Working Group (PWG) convened by the National Toxicology Program. The material examined by the PWG was from medaka exposed to N-nitrosodiethylamine for 28 days, removed to clean water, and sacrificed 4, 6, or 9 mo after initiation of exposure. Degenerative lesions included hepatocellular intracytoplasmic vacuolation, hepatocellular necrosis, spongiosis hepatis, hepatic cysts, and hepatocellular hyalinization. Inflammatory lesions consisted of granulomas, chronic inflammation, macrophage aggregates, and focal lymphocytic infiltration. Nonneoplastic proliferative lesions comprised foci of cellular alteration (basophilic focus, eosinophilic focus, vacuolated focus, and clear cell focus) and bile duct hyperplasia. Neoplastic lesions included hepatocellular adenoma, hepatocellular carcinoma, cholangioma, and cholangiocarcinoma. Two lesions composed mainly of spindle cells were noted, hemangiopericytoma and spindle cell proliferation. Rather than being an exhaustive treatment of medaka liver lesions, this report draws from the published literature on carcinogen-induced liver lesions in medaka and other fish species and attempts to consolidate lesion criteria into a simplified scheme that might be useful to pathologists and other researchers using medaka lesions for risk assessment or regulatory purposes.
Hepatic drug-metabolizing enzyme (DME) induction is an adaptive response associated with changes in preclinical species; this response can include increases in liver weight, hepatocellular hyperplasia and hypertrophy, and upregulated tissue expression of DMEs. Effects of DME induction on clinical pathology markers of hepatobiliary injury and function in animals as well as humans are not well established. This component of a multipart review of the comparative pathology of xenobiotically mediated induction of hepatic metabolizing enzymes reviews pertinent data from retrospective and prospective preclinical and clinical studies. Particular attention is given to studies with confirmation of DME induction and concurrent evaluation of liver and/or serum hepatobiliary marker enzyme activities and histopathology. These results collectively indicate that in the rat, when histologic findings are limited to hepatocellular hypertrophy, DME induction is not expected to be associated with consistent or substantive changes in serum or plasma activity of hepatobiliary marker enzymes such as alanine aminotransferase, alkaline phosphatase, and gamma glutamyltransferase. In the dog and the monkey, published studies also do not demonstrate a consistent relationship across DME-inducing agents and changes in these clinical pathology parameters. However, increased liver alkaline phosphatase or gamma glutamyltransferase activity in dogs treated with phenobarbital or corticosteroids suggests that direct or indirect induction of select hepatobiliary injury markers can occur both in the absence of liver injury and independently of induction of DME activity. Although correlations between tissue and serum levels of these hepatobiliary markers are limited and inconsistent, increases in serum/plasma activities that are substantial or involve changes in other markers generally reflect hepatobiliary insult rather than DME induction. Extrahepatic effects, including disruption of the hypothalamic-pituitary-thyroid axis, can also occur as a direct outcome of hepatic DME induction in humans and animals. Importantly, hepatic DME induction and associated changes in preclinical species are not necessarily predictive of the occurrence, magnitude, or enzyme induction profile in humans.
Hepatic steatosis, or fatty liver, is commonly observed during the animal phase of drug safety studies. A noninvasive threedimensional (3D) three-point Dixon method was used to quantitatively evaluate the fatty livers of rats induced by an experimental microsomal transfer protein (MTP) inhibitor, in an effort to develop a safety biomarker that could be translated to human studies. The method was implemented at 2.0 T for in vivo studies, and at 7.1 T for higher-resolution magnetic resonance (MR) histologic studies. In three separate protocols to study dose response and longitudinal evolution, intrahepatic fatty accumulation was detected by this method and confirmed by chemical and histologic assessments. Consistent with the pathologic changes, the fat/water ratios estimated by the MR technique increased significantly at doses of 1 mg/kg and 100 mg/kg of MTP inhibitor after 14 days of continuous administration. Among the more important findings were: 1) with the 3D threepoint Dixon method, in vivo longitudinal studies of liver fat distribution can be conducted at significantly higher resolution than has previously been reported; 2) MR histology allows delineation of distribution at the microscopic scale of 0.0024 mm 3 resolution; and 3) the 3D three-point Dixon technique provides relative estimates of liver fat content and distribution at a high confidence level. This technique will be applicable in future studies in which fatty liver is a potential safety issue. A common finding in drug safety studies is fatty liver, which is the result of diet, stress, or compounds that modify lipid metabolism in the liver. The development of noninvasive methods to detect the onset and progression of, and recovery from fatty liver would be a valuable aid for the early determination of compound toxicity.The use of decomposing fat and water signals to discriminate between fat and water protons based on their resonant frequency difference was first introduced by Dixon (1). This method uses two acquisitions with a delay between the radiofrequency (RF) and gradient echoes, such that the phase shift between water and fat is either 0 or radians (in-phase and out-of-phase, respectively). Separate water and fat images can be obtained by adding and subtracting the in-phase and out-of-phase images. This method was subsequently enhanced to accommodate magnetic field (B 0 ) and RF inhomogeneity through the use of a third acquisition, leading to the three-point Dixon method (2,3).The microsomal transfer protein (MTP) inhibitor family of drugs has subnanomolar potency in the inhibition of lipid transfer and apolipoprotein B secretion of hepatocytes. Thus, MTP inhibitors have a potential application as therapeutic agents to lower atherogenic lipoprotein in humans. MTP inhibitor studies (both experimental and clinical) (4 -6) have provided visual and biochemical evidence of hepatocellular triglyceride (TG) accumulation. Quantification of the TG-filled droplets within the hepatocytes is of interest in the evaluation of MTP inhibitors under metabo...
Abstract. Accidental intra-airway exposure of dogs with pure oleic acid produced bronchiolitis obliterans and bronchopneumonia. Pulmonary changes included multifocal to coalescing necrosis of bronchioles and adjacent alveoli, hemorrhage, inflammation, and exudation of fibrin. Hyperplasia of bronchiolar and alveolar epithelial cells and proliferation of loose fibrovascular connective tissue formed polyps or plugs of variable size and shape. Polyps in the airways primarily consisted of fibroblasts with loose or myxoid stroma and were variably covered with attenuated epithelial cells. Some polyps had prominent vasculature, mixed inflammatory cell infiltration, and/or necrosis. Polyps or plugs variably effaced bronchioles and adjacent alveoli. The changes closely resembled human bronchiolitis obliteransorganizing pneumonia (BOOP). Controlled intra-airway delivery of oleic acid in dogs may be a potential animal model of obstructive pulmonary diseases such as BOOP or bronchiolitis obliterans.
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