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Kupffer cells (KCs) are important in hepatic homeostasis and responses to xenobiotics. KCs are activated on interaction with endotoxin, releasing cytokines, and reactive oxygen species normally associated with increased gene expression, cellular growth, or hepatic injury. Ethanol-induced endotoxemia is one means of KC activation. We propose that KC depletion attenuates the effect of EtOH-induced endotoxemia to impact the hepatic growth response. Hepatic DNA synthesis was examined in KC competent (KC+) or KC-depleted (KC−) C57BL/6 mice fed EtOH-containing diet in the presence or absence of polyphenol-60 antioxidant. KC depletion was assessed by F4/80 antigen, and DNA synthesis was assessed by 5-bromo-2′-deoxyuridine incorporation. Tumor necrosis factor alpha (TNF-α) messenger RNA released was quantified by RT-PCR/electrophoresis. ERK1/2 phosphorylation was evaluated by Western blotting, and Nrf2 and CYP2E1protein were also assayed. Apoptosis and hepatic injury were examined by the Tunnel assay and hepatic transaminases in serum, respectively. Hepatic transaminases in serum (AST and ALT) were within normal range. Over 90% of KC was depleted by clodronate treatment. KC depletion decreased TNF-α mRNA release, ERK1/2 phosphorylation, and hepatocyte DNA synthesis. KC depletion is associated with increased numbers of apoptotic cells bodies in KC− mice. Antioxidant treatment decreased DNA synthesis, Nrf2, and CYP2E1 protein expression in EtOH-consuming mice. Our data indicate that upon ethanol exposure, KC participates in hepatic DNA synthesis and growth responses. Collectively, these observations suggest that KC depletion attenuates the downstream effect of ethanol-induced endotoxemia by reduced cytokine and reactive oxygen species production with its concomitant effect on MAPK-signaling pathway on hepatocyte DNA synthesis. © 2012 Wiley Periodicals, Inc. Environ Toxicol 29: 867-875, 2014 [ABSTRACT FROM AUTHOR]

Several therapeutic agents and industrial chemicals induce liver tumors in rodents through the activation of the peroxisome proliferator-activated receptor alpha (PPARα). The cellular and molecular events by which PPARα activators induce rodent hepatocarcinogenesis has been extensively studied and elucidated. This review summarizes the weight of evidence relevant to the hypothesized mode of action (MOA) for PPARα activator-induced rodent hepatocarcinogenesis and identifies gaps in our knowledge of this MOA. Chemical-specific and mechanistic data support concordance of temporal and dose-response relationships for the key events associated with many PPARα activators including a phthalate ester plasticizer di(2-ethylhexyl) phthalate (DEHP) and the drug gemfibrozil. While biologically plausible in humans, the hypothesized key events in the rodent MOA, for PPARα activators, are unlikely to induce liver tumors in humans because of toxicodynamic and biological differences in responses. This conclusion is based on minimal or no effects observed on growth pathways, hepatocellular proliferation and liver tumors in humans and/or species (including hamsters, guinea pigs and cynomolgous monkeys) that are more appropriate human surrogates than mice and rats at overlapping dose levels. Overall, the panel concluded that significant quantitative differences in PPARα activator-induced effects related to liver cancer formation exist between rodents and humans. On the basis of these quantitative differences, most of the workgroup felt that the rodent MOA is 'not relevant to humans' with the remaining members concluding that the MOA is 'unlikely to be relevant to humans'. The two groups differed in their level of confidence based on perceived limitations of the quantitative and mechanistic knowledge of the species differences, which for some panel members strongly supports but cannot preclude the absence of effects under unlikely exposure scenarios. [ABSTRACT FROM AUTHOR]

Neuroimaging studies have begun to uncover the neural substrates of cancer and treatment-related cognitive dysfunction, but the time course of these changes in the years following chemotherapy is unclear. This study analyzed multimodality 3T MRI scans to examine the structural and functional effects of chemotherapy and post-chemotherapy interval (PCI) in a cohort of breast cancer survivors (BCS; n = 24; PCI mean 6, range 3-10 y) relative to age- and education-matched healthy controls (HC; n = 23). Assessments included voxel-based morphometry for gray matter density (GMD) and fMRI for activation profile during a 3-back working memory task. The relationships between brain regions associated with PCI and neuropsychological performance, self-reported cognition, and oxidative and direct DNA damage as measured in peripheral lymphocytes were assessed in secondary analyses. PCI was positively associated with GMD and activation on fMRI in the right anterior frontal region (Brodmann Areas 9 and 10) independent of participant age. GMD in this region was also positively correlated with global neuropsychological function. Memory dysfunction, cognitive complaints, and oxidative DNA damages were increased in BCS compared with HC. Imaging results indicated lower fMRI activation in several regions in the BCS group. BCS also had lower GMD than HC in several regions, and in these regions, GMD was inversely related to oxidative DNA damage and learning and memory neuropsychological domain scores. This is the first study to show structural and functional effects of PCI and to relate oxidative DNA damage to brain alterations in BCS. The relationship between neuroimaging and cognitive function indicates the potential clinical relevance of these findings. The relationship with oxidative DNA damage provides a mechanistic clue warranting further investigation. [ABSTRACT FROM AUTHOR]

Oxyfluorfen is a herbicide that is not genotoxic and produces liver toxicity in rodents, following repeated administration at high dose levels. Lifetime rodent feeding studies reported in 1977 with low-purity oxyfluorfen (85%) showed no increase in any tumor type in rats (800 ppm, high dose) and only a marginally increased incidence of hepatocellular tumors in male CD-1 mice at the highest dose (200 ppm). To evaluate the potential carcinogenicity of the currently registered oxyfluorfen (> 98% purity), we conducted a series of short-term liver mode of action (MOA) toxicology studies in male CD-1 mice administered dietary doses of 0, 40, 200, 800, and 1600 ppm for durations of 3, 7, 10, or 28 days. MOA endpoints examined included liver weight, histopathology, cell proliferation, nuclear receptor-mediated gene expression, and other peroxisome proliferator-specific endpoints and their reversibility. Minimal liver effects were observed in mice administered doses at or below 200 ppm for up to 28 days. Increased liver weight, single-cell necrosis, cell proliferation, and peroxisomal acyl-CoA oxidase (ACO) were observed at 800 ppm after 28 days, but there was no increase in peroxisomes. Expression of Cyp2b10 and Cyp4a10 transcripts, markers of constitutive androstane receptor and peroxisome proliferator activated receptor a nuclear receptor activation, respectively, were increased at 800 and 1600 ppm after 3 or 10 days. Collectively, these data along with the negative genotoxicity demonstrate that oxyfluorfen (> 98% purity) has the potential to induce mouse liver tumors through a nongenotoxic, mitogenic MOA with a clear threshold and is not predicted to be carcinogenic in humans at relevant exposure levels. [ABSTRACT FROM AUTHOR]

Abstract: Perfluorooctanoic acid (PFOA) is an environmentally persistent chemical used in the manufacturing of a wide array of industrial and commercial products. PFOA has been shown to induce tumors of the liver, testis and pancreas (tumor triad) in rats following chronic dietary administration. PFOA belongs to a group of compounds that are known to activate the PPARα receptor. The PPARα activation Mode of Action was initially addressed in 2003 and further refined in subsequent reviews . In the intervening time, additional information on PFOA effects as well as a further refinement of the Mode of Action framework warrants a re-examination of this compound for its cancer induction Mode of Action. This review will address the rodent (rat) cancer data and cancer Mode of Action of PFOA for tumors of the liver, testes and pancreas. [Copyright &y& Elsevier]

The C57BL/6 mouse strain (or derivation of this strain) is used as a background for many transgenic mouse models. This strain has a relatively low susceptibility to chemically induced hepatocarcinogenesis compared with other commonly used experimental mouse strains. In the present study, the authors treated C57BL/6 mice with 25, 50, and 75 mg/kg of diethylnitrosamine (DEN) for 4 or 8 weeks by intraperitoneal injection to investigate the dose-response pattern of preneoplastic and neoplastic lesion formation in the liver. DEN induced preneoplastic lesions and cytokeratin 8/18–positive foci in a dose-dependent manner. In the 75 mg/kg for 8 weeks treatment group, hepatocellular adenoma, cholangioma and hemangioma, and cytokeratin 19–positive foci were also induced, but a significant decrease in body weight was observed. The suitable DEN treatment range for this strain was concluded to be from 75 mg/kg for 4 weeks (total amount = 300 mg/kg) to 50 mg/kg for 8 weeks (total amount = 400 mg/kg). These results should prove useful for future studies investigating hepatocarcinogenesis in both the background C57BL/6 strain and other transgenic mouse models derived from it. [ABSTRACT FROM PUBLISHER]

Abstract: Reactive oxygen species (ROS) are induced through a variety of endogenous and exogenous sources. Overwhelming of antioxidant and DNA repair mechanisms in the cell by ROS may result in oxidative stress and oxidative damage to the cell. This resulting oxidative stress can damage critical cellular macromolecules and/or modulate gene expression pathways. Cancer induction by chemical and physical agents involves a multi-step process. This process includes multiple molecular and cellular events to transform a normal cell to a malignant neoplastic cell. Oxidative damage resulting from ROS generation can participate in all stages of the cancer process. An association of ROS generation and human cancer induction has been shown. It appears that oxidative stress may both cause as well as modify the cancer process. Recently association between polymorphisms in oxidative DNA repair genes and antioxidant genes (single nucleotide polymorphisms) and human cancer susceptibility has been shown. [Copyright &y& Elsevier]

The article presents a research study that aimed to characterize dimethylaminoparthenolide's (DMAPT's) anticancer activity in tobacco-associated cancers, lung and bladder cancer. A background that focuses on statistics for bladder and lung cancer is provided along with information on parthenolide. Material and methods are presented including cell culture and treatment, western blotting, and electrophoretic mobility gel shift assay. Results are discussed regarding DMAPT's role in the generation of reactive oxygen species in transitional cell carcinoma.

Abstract: Mode of action is defined as a series of key biological events leading to an observed toxicological effect (for example, metabolism to a toxic entity, cell death, regenerative repair and tumors). It contrasts with mechanism of action, which generally involves a detailed understanding of the molecular basis for an effect. A framework to consider the weight of evidence for hypothesized modes of action in animals and their relevance to humans, has been widely adopted and used by government agencies and international organizations. The framework, developed and refined through its application in case studies for principally non-DNA-reactive carcinogens, has more recently been extended to DNA-reactive carcinogens, non-cancer endpoints and different life stages. In addition to increasing transparency, use of the framework promotes consistency in decision-making concerning adequacy of weight of evidence, facilitates peer input and review and identifies critical research needs. The framework provides an effective tool to facilitate discussion between the research and risk assessment communities on critical data gaps, which if filled, would permit more refined estimates of risk. As a basis for additionally coordinating and focusing research on critical data gaps in a risk assessment context, five key events in the mode of action for benzene-induced leukemia are proposed: (1) benzene metabolism via Cytochrome P450, (2) the interaction of benzene metabolites with target cells in the bone marrow, (3) formation of initiated, mutated target cells, (4) selective proliferation of the mutated cells and (5) production of leukemia. These key events are considered in a framework analysis of human relevance as a basis to consider appropriate next steps in developing research strategies. [Copyright &y& Elsevier]

Carcinogenesis is a multistep process involving mutation and the subsequent selective clonal expansion of the mutated cell. Chemical and physical agents including those that induce reative oxygen species can induce and/or modulate this multistep process. Several modes of action by which carcinogens induce cancer have been identified, including through production of reactive oxygen species (ROS). Oxidative damage to cellular macromolecules can arise through overproduction of ROS and faulty antioxidant and/or DNA repair mechanisms. In addition, ROS can stimulate signal transduction pathways and lead to activation of key transcription factors such as Nrf2 and NF-κB. The resultant altered gene expression patterns evoked by ROS contribute to the carcinogenesis process. Recent evidence demonstrates an association between a number of single nucleotide polymorphisms (SNPs) in oxidative DNA repair genes and antioxidant genes with human cancer susceptibility. These aspects of ROS biology will be discussed in the context of their relationship to carcinogenesis. [ABSTRACT FROM PUBLISHER]

Although rarely occurring in humans, hemangiosarcomas (HS) have become important in evaluating the potential human risk of several chemicals, including industrial, agricultural, and pharmaceutical agents. Spontaneous HS arise frequently in mice, less commonly in rats, and frequently in numerous breeds of dogs. This review explores knowledge gaps and uncertainties related to the mode of action (MOA) for the induction of HS in rodents, and evaluates the potential relevance for human risk. For genotoxic chemicals (vinyl chloride and thorotrast), significant information is available concerning the MOA. In contrast, numerous chemicals produce HS in rodents by nongenotoxic, proliferative mechanisms. An overall framework is presented, including direct and indirect actions on endothelial cells, paracrine effects in local tissues, activation of bone marrow endothelial precursor cells, and tissue hypoxia. Numerous obstacles are identified in investigations into the MOA for mouse HS and the relevance of the mouse tumors to humans, including lack of identifiable precursor lesions, usually late occurrence of the tumors, and complexities of endothelial biology. This review proposes a working MOA for HS induced by nongenotoxic compounds that can guide future research in this area. Importantly, a common MOA appears to exist for the nongenotoxic induction of HS, where there appears to be a convergence of multiple initiating events (e.g., hemolysis, decreased respiration, adipocyte growth) leading to either dysregulated angiogenesis and/or erythropoiesis that results from hypoxia and macrophage activation. These later events lead to the release of angiogenic growth factors and cytokines that stimulate endothelial cell proliferation, which, if sustained, provide the milieu that can lead to HS formation. [ABSTRACT FROM PUBLISHER]

Studies have demonstrated that the induction of oxidative stress may be involved in brain tumor induction in rats by acrylonitrile. The present study examined whether acrylonitrile induces oxidative stress and DNA damage in rats and whether blood can serve as a valid surrogate for the biomonitoring of oxidative stress induced by acrylonitrile in the exposed population. Male Sprague-Dawley rats were treated with 0, 3, 30, 100, and 200 ppm acrylonitrile in drinking water for 28 days. One group of rats were also coadministered N-acetyl cysteine (NAC) (0.3% in diet) with acrylonitrile (200 ppm in drinking water) to examine whether antioxidant supplementation was protective against acrylonitrile-induced oxidative stress. Direct DNA strand breakage in white blood cells (WBC) and brain was measured using the alkaline comet assay. Oxidative DNA damage in WBC and brain was evaluated using formamidopyrimidine DNA glycosylase (fpg)-modified comet assay and with high-performance liquid chromatography-electrochemical detection. No significant increase in direct DNA strand breaks was observed in brain and WBC from acrylonitrile-treated rats. However, oxidative DNA damage (fpg comet and 8′hydroxyl-2-deoxyguanosine) in brain and WBC was increased in a dose-dependent manner. In addition, plasma levels of reactive oxygen species (ROS) increased in rats administered acrylonitrile. Dietary supplementation with NAC prevented acrylonitrile-induced oxidative DNA damage in brain and WBC. A slight, but significant, decrease in the GSH:GSSG ratio was seen in brain at acrylonitrile doses > 30 ppm. These results provide additional support that the mode of action for acrylonitrile-induced astrocytomas involves the induction of oxidative stress and damage. Significant associations were seen between oxidative DNA damage in WBC and brain, ROS formation in plasma, and the reported tumor incidences. Since oxidative DNA damage in brain correlated with oxidative damage in WBC, these results suggest that monitoring WBC DNA damage maybe a useful tool to assess acrylonitrile-induced oxidative stress in humans. [ABSTRACT FROM PUBLISHER]