November 2004
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39 Reads
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3 Citations
Toxicological Sciences
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November 2004
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39 Reads
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3 Citations
Toxicological Sciences
July 2004
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51 Reads
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2 Citations
Toxicologic Pathology
The use of a bitransgenic mouse model for cancer is an effective approach for studying the impact of specific carcinogens and the occurrence of tissue-specific lesions. We studied the novel p53 heterozygous zeta globin-promoted Tg.AC (v-Ha-ras) mouse model because these mice contain a carcinogen-inducible ras oncogene and one functional p53 tumor suppressor allele, both of which occur frequently in human cancers. Our aim was to characterize the short-term control and chemically induced tumor spectrum in this novel model. Mice were placed on basal semipurified diet containing 20% soy protein for 2 weeks prior to random allocation to groups. Subsequently, 15 male and 15 female mice were administered corn oil vehicle alone or containing benzo(a)pyrene (20 mg/kg body weight) via oral gavage 2 times per week for 10 weeks with subsequent observation for 18 weeks. Mice exhibited lesions characteristic of FVB/N, p53 heterozygous and Tg.AC mouse models. However, an array of unique, novel lesions were observed including uterine leiomyosarcomas, mammary gland carcinomas, mammary squamous cell carcinomas, and parotid salivary gland carcinomas suggesting tissue-specific interactions of the 2 genotypes. Thus, this bitransgenic model may provide further insight into the mechanistic interaction of 2 genes commonly mutated in neoplasia.
February 2002
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100 Reads
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14 Citations
Epidemiological studies support the protective role of dietary antioxidants in preventing cancer. However, emerging evidence suggests that antioxidant supplements may actually exacerbate carcinogenesis. We explored this paradox in a model containing two common genotypic characteristics of human cancers. We selected p53 haploinsufficient Tg.AC (v-Ha-ras) mice as a model, because it contains an activated, carcinogen-inducible ras oncogene and an inactivated p53 tumor suppressor gene. These mice develop chemically induced benign and malignant skin tumors rapidly. Mice were fed basal diet with or without 3% N-acetyl-L-cysteine (NAC) before and after topical application of the carcinogen benzo[a]pyrene (64 micrograms twice per week for 7 wk) until 50% of mice within a group displayed at least one lesion. Half each of mice fed the basal and the NAC-supplemented diet were then switched to the alternate diet. Mice fed the NAC-supplemented diet or switched from the NAC-supplemented to the basal diet displayed 38% and 26% reductions, respectively, in tumor multiplicity and a 15% reduction if switched from the basal to the NAC-supplemented diet. Although latency was unaffected, NAC induced a lag in tumor incidence, which exceeded 90% at 10 wk for all groups. The timing of NAC supplementation did not affect malignant progression. Thus dietary NAC was chemoprotective by slowing tumorigenesis but did not affect malignant conversion.
September 2001
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43 Reads
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15 Citations
Carcinogenesis
Epidemiologic studies support the protective role of dietary antioxidants in preventing cancer. However, emerging evidence from clinical trials and laboratory data suggest that in some cases individual antioxidant supplements may actually exacerbate carcinogenesis. Our goal was to explore these paradoxical activities in a rodent model that possesses genotypic characteristics of human cancers. We selected the p53 haploinsufficient Tg.AC ( v-Ha-ras ) mouse as a model, because it contains an activated, carcinogeninducible ras oncogene and an inactivated p53 tumor suppressor gene, which are frequent genetic alterations in human cancers. These mice develop chemically induced benign and malignant skin tumors rapidly which can easily be quantified. Mice were fed basal diets with or without 3% N -acetyl-L-cysteine (NAC), a well-recognized antioxidant, prior to, during and after topical application of the carcinogen benzo[ a ]pyrene (64 μg/mouse) applied twice per week for 7 weeks. Tumor incidence exceeded 90% for both groups, and NAC did not reduce tumor latency. Mice fed NAC displayed a 43% reduction ( P < 0.05) in tumor multiplicity and delayed the appearance of lesions ( P < 0.05). Dietary NAC also significantly ( P < 0.05) improved group survival by 5 weeks. Total tumor yields were reduced in both dietary groups but malignant spindle cell tumors (SCT) increased by 25% in NAC-fed mice. The v-Ha-ras oncogene and p53 protein products were clearly co-expressed in both benign and malignant lesions from both dietary groups. In summary, dietary supplementation with NAC was chemopreventive, but the marginal increase in SCT suggests a paradoxical effect.
January 2001
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34 Reads
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18 Citations
Environmental Health Perspectives
Caloric restriction has been shown to alter a broad range of immunological end points in both experimental animals and humans. The objective of this study was to investigate the effect of short-term moderate feed restriction (25% reduction) on allergic immune responses in Brown Norway rats. After 3 weeks of acclimation to their feed regimens, rats were sensitized and 2 weeks later challenged with house dust mite (HDM) antigen via intratracheal instillation. Feed restriction resulted in lower levels of antigen-specific IgE in serum and reduced antigen specific lymphoproliferative activity in pulmonary lymph nodes. Feed restriction also attenuated pulmonary inflammation, as evidenced by lower levels of lactate dehydrogenase and total protein, decreased infiltration of neutrophils and eosinophils, and reduced secretion of pro-inflammatory cytokine tumor necrosis factor (TNF)-[alpha] in bronchoalveolar lavage fluid. In addition, feed restriction decreased TNF-[alpha] secretion in serum and decreased mRNA expression of TNF-[alpha] and interleukin-6 in pulmonary lymph nodes. We conclude that feed restriction strongly dampened the allergic immune responses to HDM in rats and that this attenuation was associated with decreased expression and secretion of pro-inflammatory cytokines.
February 2000
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20 Reads
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11 Citations
In Vitro & Molecular Toxicology
Recent epidemiological evidence suggests that antioxidants may enhance carcinogenesis by promoting cellular proliferation and/or impeding programmed cell death. We examined the effect of N-acetyl-l-cysteine (NAC) on mitogenesis and apoptosis in splenocytes from p53 haploinsufficient Tg.AC (v-Ha-ras) mice. This model contains genetic lesions found frequently in human cancer and is predisposed to develop carcinogen-induced cancer. Splenocytes were incubated with NAC alone or with the B- and T-cell-specific mitogens Concanavalin A (Con A) and E. coli lipopolysaccharide (LPS), respectively. Mitogenesis increased 17-fold in mitogen-stimulated cultures and 10-fold in cultures incubated with NAC alone. Co-incubation with both NAC (1000 microg/mL) and mitogen increased mitogenesis by 33-fold without changing apoptosis rates. Strikingly, incubation with NAC and LPS attenuated LPS-induced apoptosis. Mitogen alone did not affect GSH levels but NAC-induced increases were significantly depleted by co-incubation with mitogen. Furthermore, NAC increased the number of CD45R+ B cells, but decreased CD3+ T cells showing enhanced survival of B cells under these conditions. These results demonstrate concurrent reduced apoptosis and increased mitogenesis in B lymphocytes that may favor clonal selection of preneoplastic cells.
August 1999
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17 Reads
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70 Citations
Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
February 1999
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50 Reads
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94 Citations
The Journal of Nutrition Health and Aging
This paper focuses on the role of insulin-like growth factor-1 (IGF-1) and its associated regulatory apparatus as a key endocrine, autocrine, and paracrine signalling system involved in mediating the anti-carcinogenic activity of dietary restriction. Literature is reviewed showing that the inhibitory action of dietary restriction on carcinogenesis is global and pervasive--it is effective in several laboratory species, for a variety of tumor types, and for both spontaneous tumors and tumors caused by different types of tumor-inducing agents. Evidence is presented showing the IGF-1 pathway responds appropriately to nutritional interventions including diet restriction. Recent evidence points to an obligatory role for the IGF-1 receptor in the establishment and maintenance of the transformed phenotype and reveals that IGF-1 in concert with insulin-like binding protein 3 and p53 is involved in autocrine/paracrine growth signaling pathways as adaptive responses to environmental stimuli. Considered together these works show that the IGF-1 pathway is uniquely poised to influence cellular transformation leading to the malignant phenotype by modulating the balance of cellular proliferation and cell death (apoptosis) in precancerous and cancerous cells and by influencing metastasis of nascent tumors. We evaluated these hypotheses directly using animal models of mononuclear cell leukemia, bladder transitional cell carcinogenesis, and breast cancer. Our studies demonstrate that manipulation of IGF-1 level through dietary intervention influences tumor growth and metastasis. Upregulation of this pathway demonstrated that increased IGF-1 stimulates tumor proliferation, progression and metastasis. Conversely, downregulation of this pathway in vivo as a consequence of dietary restriction results in antitumorigenic activity. We found that the functional disruption of IGF-1R markedly influences breast cancer metastasis in nude mice by suppressing cellular adhesion, invasion, and metastasis of breast cancer cells to the lung, lymph nodes, and lymph vessels. Epidemiological observations and clinical oncology results support the involvement of IGF-1 in carcinogenesis and anticarcinogenesis. This leads to the hypothesis that factors such as IGF-1 which regulate body size and composition may be related to human cancer incidence or prognosis. Additional understanding of this pathway and its interactions with other signaling pathways will advance our ability to develop new interventions towards decreased cancer risk in humans.
October 1998
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85 Reads
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57 Citations
American Journal of Respiratory Cell and Molecular Biology
Alveolar macrophage functions associated with clearance of bacteria from the lung were assessed in male Fischer 344 rats maintained on a 25% calorie-restricted diet. Calorie-restricted and ad libitum-fed (control) rats were exposed to concentrations of ozone known to compromise phagocytic function of alveolar macrophages. Ozone suppressed alveolar macrophage phagocytosis of latex beads in vitro in ad libitum-fed rats, but not in calorie-restricted rats. In fact, caloric restriction enhanced phagocytic function in both control and ozone-exposed animals. Ad libitum-fed rats exposed to ozone and challenged with Streptococcus zooepidemicus experienced a prolonged infection and influx of polymorphonuclear leukocytes (PMN), whereas calorie-restricted rats exposed to ozone cleared the bacteria in 24 h without an inflammatory response. Bacterial endotoxin-stimulated in vitro production of nitric oxide and tumor necrosis factor (TNF)-alpha as well as expression of TNF-alpha and interleukin-6 messenger RNAs were all lower in alveolar macrophages isolated from calorie-restricted rats. Together, the data suggest that caloric restriction enhances resistance to gram-positive bacteria, while lowering the production of proinflammatory mediators elicited by endotoxin, a component of gram-negative bacteria. Although increased bacterial resistance is considered beneficial, reduction in the lung's ability to induce inflammatory mediators can have both positive and pathophysiologic consequences.
January 1998
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44 Reads
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38 Citations
American Journal of Respiratory Cell and Molecular Biology
Studies were undertaken to determine whether dietary restriction protects against acute pulmonary oxidant challenge. Male F344 rats were fed NIH-31 diet either ad libitum or at restricted levels equal to 75% that of ad libitum intake. After 3 wk of dietary adaptation, animals were exposed by inhalation to 2.0 ppm ozone (O3) for 2 h or chamber air and evaluated for cellular and biochemical indices of pulmonary toxicity. Compared to air controls, bronchoalveolar lavage fluid (BALF) from O3 exposed ad libitum fed rats contained increased protein (145 versus 380 microg/ml), PMN infiltration (0 versus 11%) and fibronectin (45 versus 607 U/ml). Diet restriction abrogated these indicators of pulmonary inflammation induced by ozone. Binding of 18O3 to BALF protein and cells was significantly decreased in diet restricted rats while BALF ascorbate and glutathione levels, but not alpha-tocopherol or urate, were elevated compared to ad libitum fed rats. Taken together, these results indicate that dietary restriction affords protection against O3-induced oxidant toxicity. Protection is mediated partially by increases in ascorbate in the fluid bathing the lung surface, thereby providing an antioxidant sink which minimizes the ability of O3 to reach biological targets.
... Rats exhibited an increased number of benign mammary tumours and an increased incidence of salivary gland sarcomas in males with DCM at levels of 500, 1500 and 3500 ppm was reported (Serota et al 1986). A safe dose of DCM in drinking water was recommended to be less than 10 mg/L per day or 2 mg/L in 10 days (Kanno et al 1993) and less than 5 mg/kg/day (Serota et al 1986). ...
December 1993
Environmental Health Perspectives
... NAC, a well-recognized antioxidant, modulates BaP-induced skin tumors (Martin et al., 2001) and inhibit BaP-induced lung tumorigenesis (Yang et al., 2002). To determine whether NAC induces similar antioxidant effects in muscle, we treated C2C12 cells with either 10 µm BaP for 72 h (the BaP group) or BaP followed by 4 mM NAC harvested at 24 and 48 h (the BaP + NAC group). ...
September 2001
Carcinogenesis
... Catecol has strong cancer promoting potentials and was reported to increase the occurrence of initiator-targeted tumors of the stomach, tongue and esophagus in mice [57,58]. Hydroquinone was reported to cause kidney tumors in male and female rats, leukemia in female rats, thyroid follicular cell hyperplasia in mice and liver tumors in male and female mice [5,59,60]. Phenol has been reported to promote skin cancer in mouse. Phenol in conjunction with benzo(a)-pyrene showed increased carcinogenicity of benzo[a)-pyrene by sixfold [57]. ...
October 1992
Food and Chemical Toxicology
... The database of dichloromethaneinduced chromosomal instability and DNA damage supports a mutagenic mode of carcinogenic action for dichloromethane, with a primary role for the GST metabolic pathway in carcinogenesis. This evidence includes a) in vivo evidence of chromosomal aberrations and micronuclei in mouse lung and peripheral red blood cells, tissues with a high availability of GST, without concurrent cytotoxicity (Allen et al. 1990), along with negative findings in bone marrow cells that have comparatively low availability of GST (Allen et al. 1990;Gocke et al. 1981;Sheldon et al. 1987;Westbrook-Collins et al. 1990); b) in vitro evidence of micronuclei (Doherty et al. 1996) and sister chromatid exchanges (Olvera-Bello et al. 2010) in human cells, mutation and DNA breaks in Chinese hamster ovary cells with GST-competent mouse liver cytosol (Graves and Green 1996), and mutation in bacterial strains that possess GST metabolic activity (in strains lacking GST, results were negative unless transfected with a mammalian GST gene) (DeMarini et al. 1997;Graves et al. 1994a;Pegram et al. 1997;Thier et al. 1993); and c) in vivo and in vitro DNA damage indicator assays, including the comet and sister chromatid exchange assays, with positive results in mouse red blood cells, liver, and lung, but not in bone marrow, where there is limited availability of GST (Allen et al. 1990;Graves et al. 1994bGraves et al. , 1995Sasaki et al. 1998;Westbrook-Collins et al. 1990). This targettissue site specificity is a key consideration in the evaluation of the available data. ...
January 1990
Environmental and Molecular Mutagenesis
... Gram-negative bacteria are normally inherently resistant to VAN and DOC (21,22), but the enhanced efficacy of the combination provides an opportunity to expand the use of these normally Gram-positive-only antibacterials to Gram-negative bacteria (6). Additionally, the possibility of dose reduction could mitigate nitrofuran's reported mutagenicity (23,24). The triple combination, therefore, shows considerable potential as a viable antibacterial treatment option. ...
March 1989
Food and Chemical Toxicology
... Scientists conducted experiments using experimental rats (2 years chronic studies) and documented carcinogenic effects (renal tubular cell adenomas and carcinomas) of phenylbutazone in male F344/N rats. Some evidence of carcinogenic activity for female F344/N rat also reported by other research scientist in the form of transitional cell carcinomas at high dose levels (Kari et al., 1995). ...
April 1995
Japanese Journal of Cancer Research
... This work was part of a broader investigation aimed at evaluating the alternative hypotheses of an oxidative stress–related or directly mutagenic MOA for EO-induced lung carcinogenesis (SupplementaryFigure S1). The effect of EO inhalation was examined in the lung tissue of 12-to 16-week-old mice, ages at which other studies have found relatively low, but measureable levels of cell proliferation in untreated controls (Kanno et al., 1993; Yu et al., 2002). Results describing EO-induced lung histopathology, DNA strand breaks, DNA adducts, markers of oxidative stress, ROS, and cII mutation will be published separately, with time and dose concordance between endpoints integrated into a MOA analysis. ...
January 1994
Environmental Health Perspectives
... Foster et al. (1994) also showed that increased DNA synthesis occurred after exposure to z1000 ppm DCM. Foley et al. (1993) demonstrated a burst of cell proliferation in hepatocytes of mice exposed 14 days earlier to 2000 ppm DCM. These data contrast with those of Kanno et al. (1993) and Maronpot et al. (1995) who described decreases in lung cell proliferation following exposure to 2000 or 8000 ppm DCM. ...
June 1993
Carcinogenesis
... Haseman et al. 1985Haseman 1983Haseman et al. 1998Rao & Haseman 1993 Diet -Commercial rodent chow versus NIH-07 72% increased incidence in males fed NIH-07 diet Rao & Haseman 1993 Diet -NIH-07 versus NTP-2000 Slight decreased incidence in males and females in NTP 2000 diet feeding studies but not in inhalation studies Haseman et al. 2003 Diet restriction Decreased incidence. Progression is retarded but rats live longer and eventually develop MNCL Hursting et al. 1993Imai et al. 1990Shimokawa et al. 1993Thurman et al. 1994Turturro et al. 1994Lipman et al. 1999Stefanski et al. 1990 Corn oil gavage Safflower oil gavage Tricaprylin gavage Decreased incidence in males (up to 57% lower compared to non-gavage NIH-07 diet or water gavage); females not affected Hursting et al. 1994Rao & Haseman 1993Haseman et al. 1985Haseman & Rao 1992 Body weight at 14 weeks Positive correlation with MNCL as adult Turturro et al. 1994 Body weight at 12 months Slight increased incidence in both sexes Haseman et al. 2003 Inhalation chamber control Increased incidence in females versus feeding study Haseman et al. 1985Haseman et al. , 1998Haseman et al. , 2003 Splenectomy at 1-2 months of age Significant decreased incidence later in life Moloney & King 1973 Splenic toxicity Significant decreased incidence in both sexes Elwell et al. 1996. ...
March 1994
Carcinogenesis
... Similar results were obtained in several studies performed in different rodent models and the underline mechanisms could be mediated by the decrease in blood glucose, IGF-1 and insulin levels, the increase in glucocorticoids and insulin sensitivity as a result of the homeostatic response to reduced body fat stores and an increase in gluconeogenesis [77,83]. Long-term CR is reported to reduce IGF-1 serum levels in rodents by~30-40%, protecting them against several types of cancers, while treatments with GH or IGF-1 can reverse this protective effect mediated by CR, confirming the important role of these factors in cancer pathogenesis [84][85][86][87]. The NF-E2-related factor 2 (Nrf2) transcription factor has been shown to mediate, in part, the CR anticancer effects. ...
July 1993
Cancer Research