RESUMO
Gingival lesions of squamous hyperplasia, cystic keratinizing hyperplasia (CKH), and squamous cell carcinoma (SCC) can be induced in rats treated by chronic gavage with 10-100 mg/kg 3,3',4,4'-tetrachloroazobenzene. We evaluated gingival squamous hyperplasia (GSH), CKH, and SCC for the immunohistochemical pattern of expression of carcinogenesis-associated markers. The 3 types of lesions and controls were stained with proliferation markers (proliferating cell nuclear antigen [PCNA] and cyclin-D1), tumor-suppressor markers (ß-catenin and mammary serine protease inhibitor [maspin]) and stroma-related markers (α-smooth muscle actin [SMA] and osteonectin/SPARC). The lesions had common immunohistochemical characteristics that differed in their expression patterns among the various diagnoses. PCNA and cyclin-D1 expression was higher in GSH, CKH, and SCC than in controls. The normal membranous expression of ß-catenin was lower in GSH, and almost absent in CKH and SCC. Maspin expression was similar in GSH and controls, whereas both CKH and SCC showed decreased expression. SMA and/or osteonectin/SPARC were seen in stromal cells in CKH and SCC. Collectively, there appears to be a progression from hyperplastic and cystic lesions toward malignancy based on the morphological changes, supported by the expression of carcinogenesis-associated proteins. The exact sequence of events leading to SCC remains to be defined in a time-dependent manner.
Assuntos
Compostos Azo/toxicidade , Carcinoma de Células Escamosas/induzido quimicamente , Carcinoma de Células Escamosas/metabolismo , Clorobenzenos/toxicidade , Neoplasias Gengivais/induzido quimicamente , Neoplasias Gengivais/metabolismo , Análise de Variância , Animais , Biomarcadores Tumorais/química , Biomarcadores Tumorais/metabolismo , Carcinoma de Células Escamosas/química , Carcinoma de Células Escamosas/patologia , Ciclina D1/química , Ciclina D1/metabolismo , Epitélio/química , Epitélio/metabolismo , Feminino , Gengiva/química , Gengiva/metabolismo , Gengiva/patologia , Neoplasias Gengivais/química , Neoplasias Gengivais/patologia , Hiperplasia/induzido quimicamente , Hiperplasia/metabolismo , Hiperplasia/patologia , Imuno-Histoquímica , Masculino , Antígeno Nuclear de Célula em Proliferação/química , Antígeno Nuclear de Célula em Proliferação/metabolismo , Ratos , Ratos Sprague-Dawley , Estatísticas não ParamétricasRESUMO
To investigate the toxicity and carcinogenic potential of indole-3-carbinol (I3C), the National Toxicology Program has conducted 13-week subchronic studies in Fisher 344 rats and B6C3F1 mice, and chronic 2-year bioassays in Sprague-Dawley rats and B6C3F1 mice. While the chronic study results are not yet available, subchronic study results and short-term special evaluations of interim sacrifices in the 2-year rat bioassay are presented. F344 rats were orally gavaged ≤300 mg I3C/kg body weight 5 days a week for 13 weeks. Rats treated with ≥150 mg/kg demonstrated a dose-related dilation of lymphatics (lymphangiectasis) of the duodenum, jejunum, and mesenteric lymph nodes. Material within dilated lacteals stained positively for Oil Red O and Sudan Black, consistent with lipid. Electron microscopic evaluation confirmed extracellular lipid accumulation within the villar lamina propria, lacteals, and within villar macrophages. Analyses of hepatic and pulmonary CYP1A enzymes demonstrated dose-dependent I3C induction of CYP1A1 and 1A2. B6C3F1 mice orally gavaged ≤250 mg I3C/kg body weight did not demonstrate histopathological changes; however, hepatic CYP induction was similar to that in rats. The histopathologic changes of intestinal lymphangiectasis and lipidosis in this study share similarities with intestinal lymphangiectasia as observed in humans and dogs. However, the resultant clinical spectrum of protein-losing enteropathy was not present.
