Clinical and pathological characteristics of acute myelogenous leukemia in a female koala with diabetes mellitus.

A female koala presented with hyperglycemia related to diabetes mellitus diagnosed at 9 years and treated with insulin. She presented with nasal hemorrhage, anemia, leukocytosis, and tachypnea at 10 years. A blood smear examination revealed scattered, atypical large myeloid cells and a clinical diagnosis of myelogenous leukemia was made. White blood cell count reached a maximum of 295 × 102/µl, with evidence of severe regenerative anemia and thrombocytopenia. Grossly, systemic lymph node enlargement, fragile liver with hemorrhage, and bloody ascites were observed. Histopathologically, atypical myeloid cells, including myelocytic and metamyelocytic cells, were scattered in the vasculature and surrounding tissues throughout the organs. The patient was infected with a koala retrovirus, which might have caused the myelogenous leukemia.

p,p'-DDT induces microcytic anemia in rats.

Emerging evidence suggests that chronic exposure to DDT and its derivatives is associated with a variety of human disorders such as anemia. The present study demonstrated that p,p'-DDT caused microcystic anemia in a dose-dependent manner (0, 5, 50, and 500 ppm) in the long-term study up to 2 years. To elucidate the mechanism(s) by which p,p'-DDT induces anemia, certain hematological parameters were assessed in rats fed specific doses of p,p'-DDT for 2 weeks, and the effect of lipopolysaccharide on anemia of inflammation was also examined in p,p'-DDT-treated rats. The parameters included the content of hemoglobin per reticulocyte, mean corpuscular volume of reticulocytes and mature erythrocytes, corpuscular hemoglobin concentration mean of mature erythrocytes, and saturation levels of transferrin and iron. During the 2-week treatment period, hypochromic microcytic reticulocytes and hypochromic normocytic mature erythrocytes were observed in p,p'-DDT-treated rats, with no evidence of alteration in plasma iron levels. p,p'-DDT enhanced microcytosis of reticulocytes, as well as mature erythrocytes, which occurred due to severe hypoferremia resulting from anemia of inflammation; however, plasma iron levels were attenuated probably through the inhibition of interleukin-6. Our data suggests that long-term treatment with p,p'-DDT induces microcytic anemia, possibly because of the impairment of iron utility in erythrocytes.

Altered pulmonary defense system in lung injury induced by didecyldimethylammonium chloride in mice.

Didecyldimethylammonium chloride (DDAC), a representative dialkyl-quaternary ammonium compound (QAC), could contaminate working atmospheres when used in disinfectant operation and adversely affect human health. Furthermore, the development of bacteria resistant to DDAC might become public health concern. We postulated that DDAC instillation in the lungs alters pulmonary antioxidant and antimicrobial responses and increases susceptibility to systemic administration of a bacterial component lipopolysaccharide (LPS). Mice were intratracheally instilled with DDAC and sacrificed 1, 3, or 7 days after treatment. Pulmonary cytotoxicity in recovered bronchoalveolar lavage was evident on Days 1 and 7, and inflammatory cell influx and interleukin-6 expression peaked on Day 7, in association with altered antioxidant and antimicrobial responses, as demonstrated by measuring heme oxygenase-1, glutathione peroxidase 2, lactoferrin, and mouse ß-defensin-2 and -3 mRNA in the lung samples. The impaired defense system tended to enhance the inflammatory reaction caused by a systemic administration of LPS; the effect was in association with increased expression of toll-like receptor-4 mRNA. The results suggest that DDAC alters pulmonary defense system, which may contribute to susceptibility to an exogenous infectious agent.

Didecyldimethylammonium chloride induces pulmonary inflammation and fibrosis in mice.

Didecyldimethylammonium chloride (DDAC) is used worldwide as a germicide, in antiseptics, and as a wood preservative, and can cause adverse pulmonary disease in humans. However, the pulmonary toxicity of DDAC has not yet been thoroughly investigated. Mice were intratracheally instilled with DDAC to the lung and the bronchoalveolar lavage (BAL) fluid and lung tissues were collected to assess dose- and time-related pulmonary injury. Exposure to 1500 µg/kg of DDAC caused severe morbidity with pulmonary congestive oedema. When the BAL fluid from survivors was examined on day 3 after treatment, exposure to 150 µg/kg of DDAC caused weakly induced inflammation, and exposure to 15µg/kg did not cause any visible effects. Next, we observed pulmonary changes that occurred up to day 20 after 150 µg/kg of DDAC exposure. Pulmonary inflammation peaked on day 7 and was confirmed by expression of interleukin-6, monocyte chemotactic protein-1, macrophage inflammatory protein (MIP)-1α, MIP-1ß, and regulated upon activation, normal T-cell expressed and secreted in the BAL fluid; these changes were accompanied by altered gene expression of their chemokine (C-C motif) receptor (Ccr) 1, Ccr2, Ccr3, and Ccr5. Cytotoxicity evoked by DDAC was related to the inflammatory changes and was confirmed by an in vitro study using isolated mouse lung fibroblasts. The inflammatory phase was accompanied or followed by pulmonary remodeling, i.e., fibrosis, which was evident in the mRNA expression of type I procollagen. These results suggest that administering DDAC by intratracheal instillation causes pulmonary injury in mice, and occupational exposure to DDAC might be a potential hazard to human health.

Mechanisms of promotion and progression of preneoplastic lesions in hepatocarcinogenesis by DDT in F344 rats.

Time-related changes in potential factors involved in hepatocarcinogenesis by DDT were investigated in a 4-week and a 2-year feeding studies of p,p'-DDT with F344 rats. In the 4-week study with males at doses of 50, 160, and 500 ppm, cell proliferation and gap junctional intercellular communication (GJIC) were examined after 1, 2, 3, 7, 14, and 28 days. Cell proliferation was enhanced within 3 days at any dose level, but returned to normal after 7 days, whereas GJIC was inhibited throughout the study. In the 2-year study with both sexes at doses of 5, 50, and 500 ppm, cell proliferation, GJIC, enzyme induction, and oxidative stress were investigated after 26, 52, 78, and 104 weeks. Males and females showed an inhibition of GJIC and increases in P450 isozymes (CYP2B1 and CYP3A2) in a dose-dependent manner at all time points, but no significant change in cell proliferation. Lipid peroxide for males at 50 and 500 ppm and 8-hydroxydeoxyguanosine for both sexes at 500 ppm were elevated throughout the study. Histologically, eosinophilic foci and hepatocellular adenomas increased in males at 50 ppm and both sexes at 500 ppm. Hepatocellular carcinomas also developed in males at 500 ppm. These results indicate that DDT may induce eosinophilic foci as a result of oxidative DNA damage and leads them to neoplasms in combination with its mitogenic activity and inhibitory effect on GJIC. Oxidative stress could be a key factor in hepatocarcinogenesis by DDT.