Gingival Carcinogenicity in Female Harlan Sprague-Dawley Rats following Two-Year Oral Treatment with 2,3,7,8-Tetrachlorodibenzo-p-dioxin and Dioxin-Like Compounds
ABSTRACT We evaluated gingival toxicities induced by chronic exposure of female Harlan Sprague-Dawley rats to dioxin and dioxin-like compounds (DLCs) and compared them to similarly induced oral lesions reported in the literature. This investigation represents part of an ongoing initiative of the National Toxicology Program to determine the relative potency of chronic toxicity and carcinogenicity of polychlorinated dioxins, furans, and biphenyls. For two years, animals were administered by gavage 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD); 3,3',4,4',5-pentachlorobiphenyl (PCB126); 2,3,4,7,8-pentachlorodibenzofuran (PeCDF); 2,2',4,4',5,5'-hexachlorobiphenyl (PCB153); a tertiary mixture of TCDD, PCB126, and PeCDF; a binary mixture of PCB126 and 153; or a binary mixture of PCB126 and 2,3',4,4',5-pentachlorobiphenyl (PCB118); control animals received corn oil-acetone vehicle (99:1) alone. A full complement of tissues, including the palate with teeth, was examined microscopically. In the groups treated with TCDD and the mixtures of TCDD, PCB126, and PeCDF; PCB126 and 153; and PCB126 and 118, the incidences of gingival squamous hyperplasia increased significantly. Moreover, in the groups treated with TCDD, PCB126, and the mixture of PCB126 and 153, squamous cell carcinoma (SCC) in the oral cavity increased significantly. This investigation constitutes the first report documenting that chronic administration of dioxin-like PCBs can induce gingival SCC in rats. These results indicate that dioxin and DLCs target the gingiva of the oral cavity, in particular the junctional epithelium of molars.
- SourceAvailable from: Venkatesha Venkatasubbaiah
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- "Exposure to PCB-153 has been reported to cause a wide array of biological effects, such as perturbations of endocrine functions and sex hormone synthesis, reproductive defects, DNA damage, nephro-, immuno-and lung-toxicities (Chen et al., 2006; Craft et al., 2002; Johansson et al., 2006; Jung et al., 2005; Lyche et al., 2006; Oskam et al., 2005; Sipka et al., 2008; Venkatesha et al., 2008). Furthermore, the evidence for liver toxicity, tumor promotion, and oral squamous cell carcinoma formation suggests that PCB-153 exposures could perturb cellular proliferation (Glauert et al., 2008; Strathmann et al., 2006; Yoshizawa et al., 2005). "
ABSTRACT: 2,2',4,4',5,5'-Hexachlorobiphenyl (PCB-153) is a non-metabolizable environmental chemical contaminant commonly found in breast milk of PCB exposed individuals, suggesting that chronic exposure to PCB-153 could have adverse health effects. We have shown previously that PCB-153 increased reactive oxygen species levels in non-tumorigenic MCF-10A human mammary epithelial cells, which were associated with DNA damage, growth inhibition, and cytotoxicity. This study investigates the hypothesis that PCB-153 exposure coordinates cell cycle progression and cellular metabolism by inhibiting cyclin D1 accumulation. PCB-153 treated MCF-10A cells exhibited a dose and time dependent decrease in cyclin D1 protein levels. The decrease in cyclin D1 protein levels was associated with an inhibition in AKT and GSK-3beta phosphorylation, which correlated with an increase in cyclin D1-T286 phosphorylation. Fibroblasts carrying a mutant form of cyclin D1 (T286A) were resistant to PCB-153 induced degradation of cyclin D1. Pre-treatment of cells with a proteasome inhibitor (MG132) suppressed PCB-153 induced decrease in cyclin D1 protein levels. Interestingly, suppression in cyclin D1 accumulation was associated with an increase in cellular glucose consumption, and hexokinase II and pyruvate kinase protein levels. These results suggest that cyclin D1 coordinates cell cycle progression and cellular metabolism in PCB-153 treated non-tumorigenic human mammary epithelial cells.Toxicology Letters 07/2010; 196(2):110-6. DOI:10.1016/j.toxlet.2010.04.005 · 3.36 Impact Factor
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- "The National Toxicology Program (NTP) recently conducted 2-year bioassays in female rats to evaluate the chronic pathology and carcinogenicity induced by dioxin, DLCs, structurallyrelated PCBs, and mixtures of these compounds, including TCDD; 3,3′,4,4′,5- pentachlorobiphenyl (PCB126); 2,3,4,7,8-pentachloro-dibenzifyran (PeCDF); and the Toxic Equivalency Factor (TEF) ternary mixture of TCDD, PCB126, and PeCDF (National Toxicology Program,2004a,b,c,d). In these studies, there was an increase in the incidence of neoplasms and non-neoplastic lesions in several organs notably the liver, lung and oral mucosa (National Toxicology Program, 2004a,b,c,d; Walker et al., 2005, 2006; Hailey et al., 2005; Jokinen et al., 2003; Nyska et al., 2004, 2005; Tani et al., 2004; Yoshizawa et al., 2005a, b). This present article, one of a series of works highlighting specific findings from NTP dioxin- TEF-evaluation studies, focuses on a comparative analysis of pulmonary effects across these studies. "
ABSTRACT: Dioxin and dioxin-related compounds have been associated with high incidences of pulmonary dysfunctions and/or cancers in humans. To evaluate the relative potencies of effects of these compounds, the National Toxicology Program completed a series of two-year bioassays which were conducted using female Harlan Sprague-Dawley rats. The rats were treated orally for up to 2 years with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), 3,3',4,4',5-pentachlorobiphenyl (PCB126), 2,3,4,7,8-pentachlorodibenzofuran (PeCDF), and a ternary mixture of TCDD, PCB126 and PeCDF. In addition to treatment-related effects reported in other organs, a variety of pulmonary lesions were observed that were related to exposure. Pulmonary CYP1A1-associated 7-ethoxyresorufin-O-deethylase (EROD) activity was increased in all dosed groups. The most common non-neoplastic lesions, which occurred in all studies, were bronchiolar metaplasia and squamous metaplasia of the alveolar epithelium. Cystic keratinizing epithelioma was the most commonly observed neoplasm which occurred in all studies. A low incidence of squamous cell carcinoma was associated only with PCB126 treatment. Potential mechanisms leading to altered differentiation and/or proliferation of bronchiolar and alveolar epithelia may be through CYP1A1 induction or disruption of retinoid metabolism.Toxicologic Pathology 02/2007; 35(7):880-9. DOI:10.1080/01926230701748396 · 1.92 Impact Factor
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- "— — HSD (TR520) Walker et al., 2005; Yoshizawa et al., 2005a — Squamous hyperplasia/gum swelling/gum pigmentation — HSD (TR521) Yoshizawa et al., 2005a — Asahi, 1993 ATSDR, 1998; Brouwer et al., 1998; Guo et al., 1999, 2004; Hashiguchi et al., 1995, 1997; HSD (TR520) Yoshizawa et al., 2005a — "
ABSTRACT: 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, or dioxin) and dioxin-like compounds (DLCs) induce numerous toxicities, including developmental, endocrine, immunological, and multi-organ carcinogenic, in animals and/or humans. Multiple studies completed by the National Toxicology Program (NTP) focused on the effects caused in Harlan Sprague-Dawley rats by specific DLCs, among them the prototypical dioxin, TCDD. Because humans are exposed daily to a combination of DLCs, primarily via ingestion of food, the Toxic Equivalency Factor (TEF) was developed in order to evaluate health hazards caused by these mixtures. Herein we review the pathological effects reported in humans exposed to TCDD; 3,3',4,4',5-pentachlorobiphenyl (PCB 126); and 2,3,4,7,8,-pentachlorodibenzofuran (PeCDF) and compare them to similar changes seen in NTP murine studies performed with the same compounds. While there were differences in specific pathologies observed, clear consistency in the target organs affected (liver, oral cavity, cardiovascular system, immune system, thyroid, pancreas, and lung) could be seen in both human studies and rodent toxicity and carcinogenicity investigations.Toxicologic Pathology 02/2007; 35(7):865-79. DOI:10.1080/01926230701618516 · 1.92 Impact Factor