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1.
Photochem Photobiol ; 93(4): 1096-1114, 2017 07.
Article in English | MEDLINE | ID: mdl-28130778

ABSTRACT

Cosmetic products that contain retinyl palmitate are popular as antiaging skin treatments; however, recent studies suggest a risk for enhanced skin tumor development with topical retinyl palmitate applications and exposure to solar ultraviolet radiation (UVR). In this study, we investigated the potential of retinyl palmitate to enhance UVR-induced photo-co-carcinogenesis. Groups of 36 male and 36 female SKH-1 hairless mice were exposed to simulated solar light (SSL) and treated with the control cream or creams containing retinyl palmitate, 5 days per week for 40 weeks. Other groups of mice were exposed to SSL and received no cream treatment or received cream treatments and were exposed to ultraviolet-A or ultraviolet-B. Mice were monitored for the development of skin tumors, and the incidences and multiplicities of squamous cell neoplasia were determined by histopathology. In both the absence and presence of SSL, mice administered the control cream developed skin tumors earlier and had higher incidences and multiplicities of skin squamous cell neoplasms than mice that received no cream treatment. Compared to the control cream groups, mice exposed to SSL and administered the retinyl palmitate creams demonstrated earlier onsets of skin tumors and had increased incidences and multiplicities of squamous cell skin neoplasms.


Subject(s)
Carcinoma, Squamous Cell/etiology , Cocarcinogenesis , Neoplasms, Radiation-Induced/chemically induced , Neoplasms, Radiation-Induced/etiology , Skin Neoplasms/etiology , Sunlight/adverse effects , Ultraviolet Rays/adverse effects , Vitamin A/analogs & derivatives , Administration, Topical , Animals , Diterpenes , Female , Male , Mice, Hairless , Retinyl Esters , Vitamin A/administration & dosage , Vitamin A/toxicity
2.
Toxicol Sci ; 131(1): 26-39, 2013 Jan.
Article in English | MEDLINE | ID: mdl-22968693

ABSTRACT

Aloe barbadensis Miller (Aloe vera) is an herbal remedy promoted to treat a variety of illnesses; however, only limited data are available on the safety of this dietary supplement. Drinking water exposure of F344/N rats and B6C3F1 mice to an Aloe vera whole-leaf extract (1, 2, and 3%) for 13 weeks resulted in goblet cell hyperplasia of the large intestine in both species. Based upon this observation, 2-year drinking water studies were conducted to assess the carcinogenic potential of an Aloe vera whole-leaf extract when administered to F344/N rats (48 per sex per group) at 0.5, 1, and 1.5%, and B6C3F1 mice (48 per sex per group) at 1, 2, and 3%. Compared with controls, survival was decreased in the 1.5% dose group of female rats. Treatment-related neoplasms and nonneoplastic lesions in both species were confined primarily to the large intestine. Incidences of adenomas and/or carcinomas of the ileo-cecal and cecal-colic junction, cecum, and ascending and transverse colon were significantly higher than controls in male and female rats in the 1 and 1.5% dose groups. There were no neoplasms of the large intestine in mice or in the 0 or 0.5% dose groups of rats. Increased incidences of mucosa hyperplasia of the large intestine were observed in F344/N rats, and increased incidences of goblet cell hyperplasia of the large intestine occurred in B6C3F1 mice. These results indicate that Aloe vera whole-leaf extract is an intestinal irritant in F344/N rats and B6C3F1 mice and a carcinogen of the large intestine in F344/N rats.


Subject(s)
Aloe/chemistry , Intestinal Mucosa/drug effects , Intestinal Neoplasms/chemically induced , Intestine, Large/drug effects , Plant Extracts/toxicity , Administration, Oral , Animals , Body Weight/drug effects , Carcinogenicity Tests , Dose-Response Relationship, Drug , Female , Hyperplasia , Intestinal Mucosa/pathology , Intestinal Neoplasms/pathology , Intestine, Large/pathology , Male , Mice , Mice, Inbred Strains , Plant Extracts/isolation & purification , Plant Leaves/chemistry , Rats , Rats, Inbred F344 , Species Specificity , Survival Analysis
3.
Food Chem Toxicol ; 51: 149-59, 2013 Jan.
Article in English | MEDLINE | ID: mdl-23009883

ABSTRACT

Acrylamide is a component of roasted coffee and certain baked and fried carbohydrate-rich foods prepared at high temperatures. We have assessed the carcinogenicity of acrylamide in male and female B6C3F(1) mice and F344/N rats administered 0, 0.0875, 0.175, 0.35, or 0.70mM acrylamide in the drinking water ad libitum for 2 years. Acrylamide caused significant dose-related decreasing trends in the body weights of F344/N rats. Acrylamide administration resulted in significant dose-related decreasing trends in survival in both sexes of B6C3F(1) mice and in female F344/N rats. Histopathological analyses indicated significant dose-related increases in Harderian gland and lung tumors in male and female B6C3F(1) mice. Male B6C3F(1) mice also had a significantly increased incidence of forestomach tumors, while female B6C3F(1) mice had significant dose-related increases in mammary gland, ovary, and skin tumors. In male and female F344/N rats, there were significant increases in thyroid tumors. Male F344/N rats also had significant dose-related increases in testes, heart, and pancreas tumors, while female F344 rats demonstrated significant increases in clitoral gland, mammary gland, oral cavity, and skin tumors. These results, combined with previous mechanistic studies, provide strong support for the concept that acrylamide is activated to a carcinogen through metabolism to glycidamide.


Subject(s)
Acrylamide/toxicity , Carcinogens/toxicity , Drinking Water/chemistry , Toxicity Tests, Chronic/methods , Animals , Body Weight/drug effects , Carcinogenicity Tests , Dose-Response Relationship, Drug , Female , Harderian Gland/drug effects , Harderian Gland/pathology , Lung Neoplasms/chemically induced , Lung Neoplasms/mortality , Male , Mammary Neoplasms, Animal/chemically induced , Mice , Mice, Inbred Strains , Mortality , Ovarian Neoplasms/chemically induced , Rats , Rats, Inbred F344 , Skin Neoplasms/chemically induced
4.
Mol Carcinog ; 47(11): 822-34, 2008 Nov.
Article in English | MEDLINE | ID: mdl-18381587

ABSTRACT

The p53 codon 270 CGT to TGT mutation was investigated as a biomarker of sunlight-induced mutagenesis and carcinogenesis. The relationship between tumor development and abundance of this hotspot mutation was analyzed in mouse skin tumors induced by chronic exposure to simulated solar light (SSL). The 24 tumors analyzed had similar growth kinetics, with an average doubling time of approximately 16.4 d. Levels of the p53 codon 270 mutation were quantified in the 24 mouse skin tumors using allele-specific competitive blocker-polymerase chain reaction (ACB-PCR). All tumors contained measurable amounts of the mutation. The p53 codon 270 CGT to TGT mutant fraction (MF) ranged from 2.29 x 10(-3) to 9.42 x 10(-2), with 3.26 x 10(-2) as the median. These p53 MF measurements are lower than expected for an initiating mutation involved in the development of tumors of monoclonal origin. There was no evidence of a correlation between p53 codon 270 MF and either tumor area or an estimate of tumor cell number. Thus, the data do not support the idea that p53 mutation accumulates linearly during tumor development. To investigate how p53 mutation was distributed within tumors, 19 needle biopsies from seven different tumors were analyzed by ACB-PCR. This analysis demonstrated that p53 codon 270 mutation is heterogeneously distributed within tumors. The long-term goal of this research is to combine morphological and p53 MF measurements from tissues corresponding to the various stages of tumor development, in order to derive mathematical models relating the p53 codon 270 mutation to the development of SSL-induced skin tumors.


Subject(s)
Codon/genetics , Neoplasms, Radiation-Induced/metabolism , Neoplasms, Radiation-Induced/pathology , Skin Neoplasms/metabolism , Skin Neoplasms/pathology , Tumor Suppressor Protein p53/genetics , Tumor Suppressor Protein p53/metabolism , Animals , Base Sequence , Cell Transformation, Neoplastic/genetics , Cell Transformation, Neoplastic/metabolism , Cell Transformation, Neoplastic/radiation effects , Mice , Mutation/genetics , Neoplasms, Radiation-Induced/genetics , RNA, Messenger/genetics , Skin Neoplasms/genetics , Sunlight
5.
Toxicology ; 248(1): 8-17, 2008 Jun 03.
Article in English | MEDLINE | ID: mdl-18423834

ABSTRACT

Non-clinical studies were conducted to evaluate the toxicity of Antalarmin, a corticotropin-releasing hormone type 1 receptor antagonist being developed for therapy of stress-related pathologies. Antalarmin was not genotoxic in bacterial mutagenesis assays, mammalian cell mutagenesis assays, or in vivo DNA damage assays. In a 14-day range-finding study in rats, Antalarmin doses >or=500 mg/kg/day (3,000 mg/m(2)/day) induced mortality. In a 90-day toxicity study in rats, no gross toxicity was seen at doses of 30, 100, or 300 mg/kg/day (180, 600, or 1,800 mg/m(2)/day, respectively). Antalarmin (300 mg/kg/day) induced mild anemia, increases in serum gamma-glutamyl transferase activity, and microscopic hepatic pathology (bile duct hyperplasia and epithelial necrosis, periportal inflammation). Microscopic renal changes (cortical necrosis, inflammation, hypertrophy, nephropathy) were observed in rats at all Antalarmin doses. In a 14-day range-finding study in dogs, Antalarmin doses >or=50mg/kg/day (1,000 mg/m(2)/day) induced repeated emesis and bone marrow suppression. In a 90-day toxicity study in dogs, Antalarmin (4, 8, or 16 mg/kg/day (80, 160, or 320 mg/m(2)/day, respectively)) induced bone marrow and lymphoid depletion, but no gross toxicity. Comparative in vitro studies using rat, dog, and human neutrophil progenitors demonstrated that canine bone marrow cells are highly sensitive to Antalarmin cytotoxicity, while rat and human bone marrow cells are relatively insensitive. As such, the bone marrow toxicity observed in dogs is considered likely to over-predict Antalarmin toxicity in humans. The hepatic and renal toxicities seen in rats exposed to Antalarmin identify those tissues as the most likely targets for Antalarmin toxicity in humans.


Subject(s)
Pyrimidines/toxicity , Pyrroles/toxicity , Receptors, Corticotropin-Releasing Hormone/antagonists & inhibitors , Animals , Bone Marrow Cells/drug effects , Bone Marrow Cells/pathology , Cell Line, Tumor , Colony-Forming Units Assay , Dogs , Female , Humans , Kidney/drug effects , Kidney/pathology , Liver/drug effects , Liver/pathology , Male , Mice , Mutagenicity Tests , No-Observed-Adverse-Effect Level , Rats , Rats, Inbred F344 , Salmonella typhimurium/drug effects , Salmonella typhimurium/genetics , Vomiting/chemically induced
6.
Food Chem Toxicol ; 44(8): 1204-12, 2006 Aug.
Article in English | MEDLINE | ID: mdl-16554117

ABSTRACT

Malachite green is a triphenylmethane dye used in the fish industry as an anti-fungal agent. Leucomalachite green is formed by the metabolic reduction of malachite green and persists in the tissues of exposed fish. In this study, we examined the carcinogenicity of malachite green chloride and leucomalachite green. Female F344 rats (48 per group) were fed diets containing 0, 100, 300, or 600 ppm malachite green chloride for 104 weeks, at which time the extent of tumorigenesis was assessed. Additional groups of 48 female and 48 male F344 rats were fed diets containing 0, 91, 272, or 543 ppm leucomalachite green for 104 weeks. Groups of 48 female B6C3F1 mice were fed diets containing 0, 100, 225, or 450 ppm malachite green chloride or 0, 91, 204, or 408 ppm leucomalachite green for 104 weeks. For each of the exposures, food consumption in the treatment groups was similar to the controls. Rats fed malachite green chloride or leucomalachite green had dose-dependent reductions in body weight; in mice, there were no consistent effects upon body weights with either compound. Female rats exposed to malachite green chloride had increased incidences of thyroid gland follicular cell adenoma or carcinoma and hepatocellular adenoma, and a dose-related increasing trend in mammary gland carcinoma. Female rats fed malachite green chloride and female and male rats fed leucomalachite green had a dose-related decreasing trend in the incidence of mononuclear cell leukemia. In male rats fed leucomalachite green there was a decreasing trend in pituitary gland adenoma and an increasing trend in interstitial cell adenoma of the testis. There were no treatment-related neoplasms in female B6C3F1 mice fed malachite green chloride. Female mice fed leucomalachite green had a dose-related increasing trend in the incidence of hepatocellular adenoma or carcinoma, with the incidence being significant in the highest dose group.


Subject(s)
Aniline Compounds/toxicity , Fungicides, Industrial/toxicity , Neoplasms, Experimental/chemically induced , Rosaniline Dyes/toxicity , Animals , Body Weight/drug effects , Carcinogenicity Tests , Eating/drug effects , Female , Male , Mice , Mice, Inbred C57BL , Neoplasms, Experimental/pathology , Rats , Rats, Inbred F344 , Statistics, Nonparametric , Survival Analysis
7.
Food Chem Toxicol ; 43(1): 1-19, 2005 Jan.
Article in English | MEDLINE | ID: mdl-15582191

ABSTRACT

Urethane is a carcinogen to which there is widespread exposure through the consumption of fermented foods and alcoholic beverages. In this study, we have assessed the carcinogenicity of urethane in combination with ethanol. Male and female B6C3F(1) mice (48 mice per sex per group) were exposed to 0, 10, 30, or 90 ppm urethane in the presence of 0%, 2.5%, or 5% ethanol in drinking water ad libitum for two years, at which time the extent of tumorigenesis was assessed. Additional mice (four per sex per group) received the same doses for four weeks to assess serum levels of urethane and ethanol, DNA adduct formation, and the induction of microsomal cytochromes P450, cell proliferation, and apoptosis. Urethane decreased cell replication in the livers of female, but not male, mice, decreased cell replication in the lungs of both sexes, and induced cytochrome P450 2E1 in the livers of female mice. Hepatic levels of the DNA adduct 1,N(6)-ethenodeoxyadenosine were increased by exposure to urethane and decreased by treatment with ethanol. Animal weights and survival were not affected by ethanol; in contrast, urethane administration decreased body weights and survival. Urethane caused dose-dependent increases in liver, lung, and harderian gland adenoma or carcinoma and hemangiosarcoma of the liver and heart in both sexes, mammary gland and ovarian tumors in females, and squamous cell papilloma or carcinoma of the skin and forestomach in males. The increase in hepatocellular tumors occurred in a relatively linear manner and was attributed to the formation of 1,N(6)-ethenodeoxyadenosine in hepatic DNA coupled with an increase in cell replication. Hemangiosarcomas were observed only at the 90 ppm urethane dose and were probably a result of high-dose urethane-induced toxicity. Lung alveolar/bronchiolar and harderian gland adenoma or carcinoma increased in a relatively linear manner, suggestive of a genotoxic mechanism for tumor induction. Ethanol induced a dose-dependent trend in hepatocellular adenoma or carcinoma in male mice, with the incidence being marginally increased at the highest dose. In female mice administered 10 ppm and 90 ppm urethane, ethanol caused dose-related increases in alveolar/bronchiolar adenoma or carcinoma and hemangiosarcoma of the heart, respectively. This may be due to ethanol decreasing the first-pass clearance of urethane, thus, increasing systemic distribution. In male mice a different relationship was observed: ethanol caused a dose-related decrease in alveolar/bronchiolar and harderian gland adenoma or carcinoma in mice administered 30 ppm urethane.


Subject(s)
Carcinogens/toxicity , Ethanol/toxicity , Neoplasms, Experimental/chemically induced , Urethane/toxicity , Animals , Apoptosis/drug effects , Body Weight/drug effects , Carcinogenicity Tests , Carcinogens/analysis , Cell Division/drug effects , Cytochrome P-450 Enzyme System/metabolism , DNA Adducts , Dose-Response Relationship, Drug , Ethanol/blood , Female , Liver/drug effects , Liver/enzymology , Liver/pathology , Lung/drug effects , Lung/pathology , Male , Mice , Mice, Inbred Strains , Neoplasms, Experimental/epidemiology , Random Allocation , Sex Factors , Survival Analysis , Urethane/blood
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