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Human liver. Small cell change comprised of a focus of small cells with an irregular margin within a cirrhotic liver. H&E.
Source publication
In this comparative review, histomorphological features of common nonneoplastic and
neoplastic hepatocyte lesions of rats and humans are examined using H&E-stained
slides. The morphological similarities and differences of both neoplastic (hepatocellular
carcinoma and hepatocellular adenoma) and presumptive preneoplastic lesions (large and
small cel...
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Citations
... Formalin-fixed liver and kidney samples were embedded in paraffin blocks, and 5 µm sections were obtained and stained with hematoxylin and eosin (HE) or Sirius Red. Histopathological alterations in both organs were identified in a section stained with HE, following the criteria established in the literature [23,55]. The incidence (% lesionbearing rats/group) was evaluated in all experimental groups. ...
Anthracycline doxorubicin (DOX) is still widely used as a chemotherapeutic drug for some solid tumors. Although DOX is highly effective, its side effects are limiting factors, such as cardio, nephro and hepatotoxicity. As such, approaches used to mitigate these adverse effects are highly encouraged. Omega 3 (ω-3), which is a class of long-chain polyunsaturated fatty acids, has been shown to have anti-inflammatory and antioxidant effects in preclinical bioassays. Thus, we evaluated the protective effects of ω-3 supplementation on hepatotoxicity and nephrotoxicity induced by multiple DOX administrations in rodents. Male Wistar rats (10 rats/group) were treated daily with ω-3 (400 mg/kg/day) by gavage for six weeks. Two weeks after the first ω-3 administration, the rats received DOX (3.5 mg/kg, intraperitoneal, 1×/week) for four weeks. DOX treatment reduced body weight gain increased systemic genotoxicity and caused liver-related (increase in serum ALT levels, thickness of the Glisson’s capsule, compensatory proliferation and p65 levels) and kidney-related (increase in serum urea and creatinine levels, and incidence of tubular dilatation) deleterious outcomes. In contrast, ω-3 supplementation was safe and abrogated the DOX-related enhancement of systemic genotoxicity, serum urea and creatinine levels. Furthermore, ω-3 intervention reduced by 50% the incidence of kidney histological lesions while reducing by 40–50% the p65 protein level, and the proliferative response in the liver induced by DOX. Our findings indicate that ω-3 intervention attenuated the DOX-induced deleterious effects in the liver and kidney. Therefore, our findings may inspire future mechanistical investigations and clinical interventions with ω-3 on the reported outcomes.
... Among these, proliferative preneoplastic lesions such as foci of cellular alteration (FCA) and early (small) hepatocellular carcinoma (HCC) are common findings [29]. In particular, the former are rarely taken into account when performing studies on the development and progression of HCC [27] unless given evidence that FCA (especially clear cell, basophilic and eosinophilic FCA) are very likely to resemble dysplastic nodules (DN) in humans and progression to HCC has been demonstrated [30]. In particular in newly designed genetic mouse models, little is known on the vasculature in early stages of liver tumorigenesis; and to date, it is not yet fully clarified if the development and progression from FCA to HCC also include mechanisms of vascular remodeling, likewise observed in human hepatocarcinogenesis and some chemically induced models [31]. ...
... These findings reflect a vascular phenotype of immature small (capillary-like) vessels. Similar to the histological appearance, the vascular profile of FCA therefore closely resembles morphology and immunophenotype of human dysplastic nodules (DN) [34], further supporting the role of FCA as the direct murine counterpart to human DN [30]. In contrast, HCCs were characterized by a lower number of vessels, larger vessel size and a higher degree of pericyte coverage. ...
The investigation of hepatocarcinogenesis is a major field of interest in oncology research and rodent models are commonly used to unravel the pathophysiology of onset and progression of hepatocellular carcinoma. HCC is a highly vascularized tumor and vascular remodeling is one of the hallmarks of tumor progression. To date, only a few detailed data exist about the vasculature and vascular remodeling in rodent models used for hepatocarcinogenesis. In this study, the vasculature of HCC and the preneoplastic foci of alteration (FCA) of different mouse models with varying genetic backgrounds were comprehensively characterized by using immunohistochemistry (CD31, Collagen IV, αSMA, Desmin and LYVE1) and RNA in situ hybridization (VEGF-A). Computational image analysis was performed to evaluate selected parameters including microvessel density, pericyte coverage, vessel size, intratumoral vessel distribution and architecture using the Aperio ImageScope and Definiens software programs. HCC presented with a significantly lower number of vessels, but larger vessel size and increased coverage, leading to a higher degree of maturation, whereas FCA lesions presented with a higher microvessel density and a higher amount of smaller but more immature vessels. Our results clearly demonstrate that vascular remodeling is present and crucial in early stages of experimental hepatocarcinogenesis. In addition, our detailed characterization provides a strong basis for further angiogenesis studies in these experimental models.
... e No data for increased foci was obtained at the carcinogenic dose levels of 2500 and 5000 ppm after 2 years. However, as described in the text, formation of preneoplastic foci is a required step in mouse liver adenoma formation (Farber and Sarma 1987;Maronpot et al. 1987;Williams 1997;Harada et al. 1999;Thoolen et al. 2012;Corton et al. 2014Corton et al. , 2018 and hence it is reasonable to consider that this stage was already passed by 2 years. f Liver tumor data are taken from the 2019 liver PWG reevaluation (Table 2) of the CD-1 mouse carcinogenicity study (Quist et al. 2019). ...
... Altered liver foci have been described as a KE for PPARa activator-induced rodent liver tumor formation Lake 2009;Corton et al. 2014Corton et al. , 2018. However, while no data for increased altered liver foci were reported at the end of the 2-year permethrin CD-1 mouse bioassay, altered liver foci are considered to be the precursor lesions for subsequent tumor formation in rodent liver (Farber and Sarma 1987;Maronpot et al. 1987;Harada et al. 1989;Williams 1997;Thoolen et al. 2012;Corton et al. 2014Corton et al. , 2018, hence it is considered that such foci would develop before the appearance of liver tumors. ...
... Like other PPARa activators Lake 2009;Corton et al. 2014Corton et al. , 2018, while increased liver weight with enzyme induction and enhanced cell proliferation were observed at an early stage of permethrin administration, the appearance of liver tumors occurred only after chronic administration of permethrin. As altered liver foci are the precursor lesions for subsequent tumor formation in rodent liver (Farber and Sarma 1987;Maronpot et al. 1987;Harada et al. 1989;Williams 1997;Thoolen et al. 2012;Corton et al. 2014Corton et al. , 2018, it is considered that such foci would develop before the appearance of liver tumors. ...
The non-genotoxic synthetic pyrethroid insecticide permethrin produced hepatocellular adenomas and bronchiolo-alveolar adenomas in female CD-1 mice, but not in male CD-1 mice or in female or male Wistar rats. Studies were performed to evaluate possible modes of action (MOAs) for permethrin-induced female CD-1 mouse liver and lung tumor formation. The MOA for liver tumor formation by permethrin involves activation of the peroxisome proliferator-activated receptor alpha (PPARα), increased hepatocellular proliferation, development of altered hepatic foci, and ultimately liver tumors. This MOA is similar to that established for other PPARα activators and is considered to be qualitatively not plausible for humans. The MOA for lung tumor formation by permethrin involves interaction with Club cells, followed by a mitogenic effect resulting in Club cell proliferation, with prolonged administration producing Club cell hyperplasia and subsequently formation of bronchiolo-alveolar adenomas. Although the possibility that permethrin exposure may potentially result in enhancement of Club cell proliferation in humans cannot be completely excluded, there is sufficient information on differences in basic lung anatomy, physiology, metabolism, and biologic behavior of tumors in the general literature to conclude that humans are quantitatively less sensitive to agents that increase Club cell proliferation and lead to tumor formation in mice. The evidence strongly indicates that Club cell mitogens are not likely to lead to increased susceptibility to lung tumor development in humans. Overall, based on MOA evaluation it is concluded that permethrin does not pose a tumorigenic hazard for humans, this conclusion being supported by negative data from permethrin epidemiological studies.
... 509 Indomethacin produces mesenteric infarcts in the intestine that may cause ileus. 510 Liver 214,295 Peliosis hepatis (telangiectasia), aging rats. Hemochromatosis in Hsd:HHCL (Wistar) rats with Tfr2 mutation. ...
Animals are valuable resources in biomedical research in investigations of biological processes, disease pathogenesis, therapeutic interventions, safety, toxicity, and carcinogenicity. Interpretation of data from animals requires knowledge not only of the processes or diseases (pathophysiology) under study but also recognition of spontaneous conditions and background lesions (pathology) that can influence or confound the study results. Species, strain/stock, sex, age, anatomy, physiology, spontaneous diseases (noninfectious and infectious), and neoplasia impact experimental results and interpretation as well as animal welfare. This review and the references selected aim to provide a pathology resource for researchers, pathologists, and veterinary personnel who strive to achieve research rigor and validity and must understand the spectrum of "normal" and expected conditions to accurately identify research-relevant experimental phenotypes as well as unusual illness, pathology, or other conditions that can compromise studies involving laboratory mice, rats, gerbils, guinea pigs, hamsters, naked mole rats, and rabbits.
... These foci have been described in several animal models and are considered as precursor lesions of HCC; 5 most of these FCAs progress to neoplasia, while some may regress. 6 Thus, detecting and guiding such hepatic pre-neoplastic growth back to normal hepatocytes would be of great clinical importance. Trichloroacetic acid (TCA) is a representative chemical carcinogen with the potential to cause experimental multistage hepatocarcinogenesis; 7 it produces pre-neoplastic lesions after a short period in the form of dysplastic tissue changes, vascular congestion, hepatocyte ballooning, and liver cell foci with extensive vacuolation. ...
... These foci could play a role in liver tumor formation through metabolic changes in carbohydrate metabolism. 6 The results of the present study approved the development of such lesions in agreement with various studies. 9 Cellular proliferation plays a principal role in the multistep carcinogenesis process, including initiation, promotion, and progression, and has emerged as an important mechanism for HCC. ...
Hepatocellular carcinoma (HCC) accounts for more than 5% of all human cancers. Diacerein (DIA), an interleukin (IL)-1β inhibitor, is used for the treatment of osteoarthritis. DIA is a potential anticancer drug acting on several protein targets in the process of apoptosis. The present study aimed to explore the molecular mechanisms underlying the effect of DIA in the treatment of trichloroacetic acid (TCA)–induced pre-neoplastic changes in rats. Rats were allocated into 5 groups and treated for 4 weeks. Group 1: control; received vehicle, Group 2: TCA group; received TCA (1 g/kg, orally for 5 days). Group 3: DIA-treated group; received TCA +DIA (50 mg/kg/day, orally, for 4 weeks). Group 4: positive control group; received TCA (1 g/kg, orally, for 5 days) + 5-fluorouracil (5-FU) (75 mg/kg) intraperitoneally (i.p.), for 4 weeks as a standard anticancer drug. Group 5: received TCA (1 g/kg, orally for 5 days) + DIA (50 mg/kg/day, orally, for 4 weeks) + 5-FU (75 mg/kg, i.p., for 4 weeks). Serum liver enzymes, oxidative stress parameters, inflammatory parameter (IL-1β), and angiogenesis marker vascular endothelial growth factor (VEGF) were assessed along with histopathological evaluation. An apoptotic marker as caspase-3 expression was measured by western blot analysis. Immunoexpression of proliferating cell nuclear antigen (PCNA) and hypoxia-inducible factor-1α (HIF-1α) was evaluated. Results and conclusion: The outcomes proved that at histological level, DIA ameliorated hepatic precancerous lesion via modulation of IL-1β–HIF-1α–VEGF pathway.
Conclusion
IL-1β mediates angiogenesis indirectly, as it has been shown to induce hypoxia-inducible factor-1α (HIF-1α) which upregulates VEGF.
... The laboratory rat (Rattus norvegicus) is a rodent model that has been faithfully used in several biomedical domains, including oncology [147]. In particular, experimental rat hepatocarcinogenesis served for a long time as a relevant model in delineating the pathogenesis of liver neoplasia, evaluating the human cancer development risk following exposure to carcinogens [148], facilitating HCC prevention strategies [149], identifying the metabolic pathways leading to liver tumorigenesis [150], and evaluating the tumor response to chemotherapy [151]. ...
Hepatocellular carcinoma (HCC), the most frequent form of primary liver carcinoma, is a heterogenous and complex tumor type with increased incidence, poor prognosis, and high mortality. The actual therapeutic arsenal is narrow and poorly effective, rendering this disease a global health concern. Although considerable progress has been made in terms of understanding the pathogenesis, molecular mechanisms, genetics, and therapeutical approaches, several facets of human HCC remain undiscovered. A valuable and prompt approach to acquire further knowledge about the unrevealed aspects of HCC and novel therapeutic candidates is represented by the application of experimental models. Experimental models (in vivo and in vitro 2D and 3D models) are considered reliable tools to gather data for clinical usability. This review offers an overview of the currently available preclinical models frequently applied for the study of hepatocellular carcinoma in terms of initiation, development, and progression, as well as for the discovery of efficient treatments, highlighting the advantages and the limitations of each model. Furthermore, we also focus on the role played by computational studies (in silico models and artificial intelligence-based prediction models) as promising novel tools in liver cancer research.
... Similarly, while much MOA data can be obtained from short-term studies, data on clonal expansion to altered hepatic foci and formation of liver tumors (adenomas and carcinomas) can only be obtained in long-term studies, and, depending on the time points selected, such increases may not be observed. However, the absence of such data does not detract from establishing a CAR-dependent rodent liver tumor MOA, as altered liver foci are considered to be precursor lesions for subsequent liver tumor formation (Thoolen et al. 2012). However, it should be noted that an increased incidence of hepatocellular foci does not always result in subsequent liver tumor formation (Sistare et al. 2011). ...
Many nongenotoxic chemicals have been shown to produce liver tumors in mice and/or rats by a mode of action (MOA) involving activation of the constitutive androstane receptor (CAR). Studies with phenobarbital (PB) and other compounds have identified the key events for this MOA: CAR activation; increased hepatocellular proliferation; altered foci formation; and ultimately the development of adenomas/carcinomas. In terms of human relevance, the pivotal species difference is that CAR activators are mitogenic agents in mouse and rat hepatocytes, but they do not stimulate increased hepatocellular proliferation in humans. This conclusion is supported by substantial in vitro studies with cultured rodent and human hepatocytes and also by in vivo studies with chimeric mice with human hepatocytes. Examination of the literature reveals many similarities in the hepatic effects and species differences between activators of rodent CAR and the peroxisome proliferator-activated receptor alpha (PPARα), with PPARα activators also not being mitogenic agents in human hepatocytes. Overall, a critical analysis of the available data demonstrates that the established MOA for rodent liver tumor formation by PB and other CAR activators is qualitatively not plausible for humans. This conclusion is supported by data from several human epidemiology studies.
... n.s.: not significant. generally regarded as a repair response after haptic injury and hepatocyte loss [25]. Additional blood tests are required to evaluate the degree of liver damage. ...
Background:
ML171 is a potent nicotinamide adenine dinucleotide phosphate oxidase (NOX) inhibitor with isoform selectivity only for NOX1. This study is aimed at investigating the safety of ML171 after a single intraperitoneal (IP) injection in mice.
Methods:
The toxicity of a single dose of ML171 was evaluated in 6-week-old Institute of Cancer Research (ICR) mice in a good laboratory practice (GLP) laboratory. Twenty-five mice of each sex were assigned to five groups: negative control, vehicle control, and 125, 250, and 500 mg/kg of ML171. All mice were acclimatized for one week before beginning the study. Mice received an IP injection of ML171 or vehicle. The general condition and mortality of the animals were observed. The mice were sacrificed to evaluate histopathology 14 days after the administration of ML171 or vehicle.
Results:
Bodyweights were not significantly different in any group. Three males and one female died due to ML171 administration in the 500 mg/kg dose group. Autopsies of the surviving mice did not reveal any significant abnormalities after the injection of 125 mg/kg of ML171. However, the anterior lobe edge of the liver was thickened and adhesions between the liver and adjacent organs were observed in mice treated with 250 or 500 mg/kg of ML171. In addition, hypertrophy of centrilobular hepatocytes and inflammatory cell infiltration were observed after injection of 250 and 500 mg/kg of ML171.
Conclusion:
Our results indicate that the lethal IP injection dose of ML171 is 500 mg/kg for both males and females. Mortality were not observed for lower doses of ML171. The safe dose of single IP ML171 in ICR mice was 250 mg/kg or less. Further studies are needed to confirm the safety of ML171 in the human body.
... For example, the occurrence of early-age forms of liver cancer has been persistently described in patients from Peru, and more broadly, in South America [31,32]. This clinical presentation is associated with a peculiar mutation spectrum and the presence of hepatic foci of cellular alteration within the liver parenchyma that could be a hallmark of chronic liver insults caused by exposure to genotoxic substances, as observed in rodent animal models [33][34][35][36]. The potential brunt of dietary mycotoxin exposure has thus been suggested to intervene as a cofactor in this phenomenon [37,38]. ...
Consumption of cereals contaminated by mycotoxins poses health risks. For instance, Fumonisins B, mainly produced by Fusarium verticillioides and Fusarium proliferatum, and the type B trichothecene deoxynivalenol, typically produced by Fusarium graminearum, are highly prevalent on cereal grains that are staples of many cultural diets and known to represent a toxic risk hazard. In Peru, corn and other cereals are frequently consumed on a daily basis under various forms, the majority of food grains being sold through traditional markets for direct consumption. Here, we surveyed mycotoxin contents of market-bought grain samples in order to assess the threat these mycotoxins might represent to Peruvian population, with a focus on corn. We found that nearly one sample of Peruvian corn out of six was contaminated with very high levels of Fumonisins, levels mostly ascribed to the presence of F. verticillioides. Extensive profiling of Peruvian corn kernels for fungal contaminants could provide elements to refine the potential risk associated with Fusarium toxins and help define adapted food safety standards.
... While data on the effect of metazachlor on rat liver foci in female Wistar rats given 8000 ppm metazachlor are not available, this is not considered to detract from the proposed MOA, as altered foci are only observed in chronic studies at extended time points and altered liver foci are considered to be precursor lesions for subsequent liver tumour formation (Thoolen et al., 2012). ...
In a 2-year study the herbicide metazachlor (BAS 479H) was shown to significantly increase the incidence of liver tumours in female Wistar rats at a dietary level of 8000 ppm. As metazachlor is not a genotoxic agent, a series of in vivo and in vitro investigative studies were undertaken to elucidate the mode of action (MOA) for metazachlor-induced female rat liver tumour formation. Male and female Wistar rats were given diets containing 0 (control), 200 and 8000 ppm metazachlor for 3, 7, 14 and 28 days. The treatment of male rats with 200 and 8000 ppm metazachlor and female rats with 8000 ppm metazachlor resulted in significant increases in relative liver weight, which was associated with a centrilobular hepatocyte hypertrophy. Hepatocyte replicative DNA synthesis (RDS) was significantly increased in male rats given 8000 ppm metazachlor for 3 and 7 days and in female rats given 200 ppm metazachlor for 7-28 days and 8000 ppm metazachlor for 3-28 days. Significant increases in relative liver weight, centrilobular hepatocyte hypertrophy and hepatocyte RDS were also observed in male and female Wistar rats given and 500 ppm sodium phenobarbital (NaPB) for 3-28 days. The treatment of female Wistar rats with either 8000 ppm metazachlor for 7 days or with 500 ppm NaPB for 3 and 7 days resulted in the nuclear translocation of the hepatic constitutive androstane receptor (CAR). Treatment of male and female Wistar rats with 8000 ppm metazachlor for 14 days resulted in significant increases in hepatic microsomal total cytochrome P450 (CYP) content, CYP2B subfamily-dependent enzyme activities and mRNA levels, together with some increases in CYP3A enzyme activity and mRNA levels. The treatment of male Wistar rat hepatocytes with metazachlor (concentration range 0.5-50 μM) and NaPB (500 μM) for 4 days resulted in increased CYP2B enzyme activities and mRNA levels; with metazachlor and NaPB also producing significant increases in hepatocyte RDS levels. Studies were also performed with hepatocytes from male Sprague-Dawley wild type (WT) rats and CAR knockout (CAR KO) rats. While both treatment with metazachlor and NaPB for 4 days increased CYP2B enzyme activities and mRNA levels in WT rat hepatocytes, only minor effects were observed in CAR KO rat hepatocytes. Treatment with both metazachlor and NaPB only increased RDS in WT but not in CAR KO rat hepatocytes. The treatment of hepatocytes from two male human donors with 0.5-25 μM metazachlor or 500 μM NaPB for 4 days resulted in increases in CYP2B6 and CYP3A4 mRNA levels but had no effect on hepatocyte RDS. EGF as concurrently used positive control demonstrated the expected RDS response in all rat and human hepatocyte cultures. In conclusion, a series of in vivo and in vitro investigative studies have demonstrated that metazachlor is a CAR activator in rat liver, with similar properties to the prototypical CAR activator phenobarbital. A robust MOA for metazachlor-induced female rat liver tumour formation has been established. Based on the lack of effect of metazachlor on RDS in human hepatocytes, it is considered that the MOA for metazachlor-induced rat liver tumour formation is qualitatively not plausible for humans.
