Trihalomethanes in liver pathology: Mitochondrial dysfunction and oxidative stress in the mouse.

Trihalomethanes (THMs) are disinfection byproducts found in chlorinated water, and are associated with several different kinds of cancer in human populations and experimental animal models. Metabolism of THMs proceeds through enzymes such as GSTT1 and CYP2E1 and gives rise to reactive intermediates, which form the basis for their toxic activities. The aim of this study was to assess the mitochondrial dysfunction caused by THMs at low levels, and the resulting hepatic histological and biochemical changes in the mouse. Male ICR mice were administered with two THMs: dibromochloromethane (DBCM) and bromodichloromethane (BDCM); once daily, by gavage, to a total of four administrations. Animals were sacrificed four weeks after DBCM and BDCM administrations. Blood biochemistry was performed for alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), total bilirubin (TB), albumin (Alb), total protein (TP), creatinine, and urea. Animals exposed to DBCM and BDCM showed elevated ALT and TB levels (p < 0.05) as compared with controls. Histological analysis confirmed the presence of vacuolar degenerescence and a multifocal necrotizing hepatitis in 33% of animals (n = 2). Mitochondrial analysis showed that THMs reduced mitochondrial bioenergetic activity (succinate dehydrogenase (SQR), cytochrome c oxidase (COX), and ATP synthase) and increased oxidative stress (glutathione S-transferase (GST)) in hepatic tissues (p < 0.05). These results add detail to the current understanding of the mechanisms underlying THM-induced toxicity, supporting the role of mitochondrial dysfunction and oxidative stress in liver toxicity caused by DBCM and BDCM. © 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 1009-1016, 2016.

MNU-induced rat mammary carcinomas: immunohistology and estrogen receptor expression.

Environmental exposure to nitrosamines is associated with the development of cancer in a variety of target organs. One such carcinogen, N-methyl-N-nitrosurea (MNU), has long been used to induce mammary tumors in rats, which provide a useful model to study mammary carcinogenesis. However, some poorly clarified issues remain, such as the lack of a clear description of morphological patterns of tumors and the distribution and role of estrogen receptors (ERs) during tumor progression, as tumors overexpressing ERs show a paradoxical tendency to recur after ovariectomy. Mammary carcinomas were induced in Sprague-Dawley rats using MNU. The tumors were studied histologically and distribution of smooth muscle actin and ERs was studied immunohistochemically. All tumors presented both an epithelial and a myoepithelial component, demonstrated by immunohistochemical detection of smooth muscle actin. Tumors showed distinct histological patterns: well-differentiated papillary and adenoid areas and poorly differentiated solid and spindle-cell foci. Overexpression of ERs (>75% of labelled cells vs. 0-75% in control tissue) occurred in papillary and adenoid areas but not in solid and spindle-cell foci. Poorly differentiated tumor foci are likely to represent a more advanced, estrogen-independent phase in cancer progression and constitute the basis for tumor recurrence after ovariectomy.