Anaemia is a significant prognostic factor in cancer patients receiving anticancer drugs such as methotrexate (MTX). This study focuses on the effects of toxicological changes on the hematopoietic systems in male and female Wistar Hannover rats when MTX is orally administered at a dose of 0, 0.05, 0.15, or 0.45 mg/(kg·day) for a period of 28 days. Both male and female rats receiving 0.45 mg/kg MTX showed a decrease in the haemoglobin concentration (Hb), haematocrit, and erythrocyte count. Female rats showed a decrease in mean corpuscular volume (MCV) and an increase in cell mean Hb (CHCM) in total erythrocytes, including the mature erythrocytes. These results indicate that MTX causes the production of small, mature erythrocytes that contain a high concentration of Hb. MTX reduced the number of peripheral reticulocytes but produced the cells with a large size and a high concentration of Hb, as demonstrated by the reticulocyte MCV and CHCM as well as the content of haemoglobin per reticulocyte (CHr). Consistent with these findings, bone marrow haematopoiesis was impaired by MTX, as there was a reduction in erythroid count in rats of both sexes. The number of cells of the myeloid lineage reduced in female rats, followed by a reduction in the total leukocyte and neutrophil counts in peripheral blood. Thrombocytopenia was detected in a small population of rats. These results indicate that MTX induces hyperchromic microcytic anaemia and pancytopenia, and the use of MCV and CHCM in mature erythrocytes and reticulocytes, along with the CHr, gives a better understanding of the development and nature of anaemia.

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 1500μg/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 150μg/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 150μg/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-1β, 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.

Chromated copper arsenate, which is used worldwide as a wood preservative, can adversely affect human health. Accumulating evidence suggests that chromium (Cr) and arsenic (As) can potentially disrupt the redox balance and cause respiratory diseases and cancer in humans. The present study was designed to determine the combined toxic effects of these metals in the lungs and to clarify the specific molecules that are stimulated by combined exposure to both metals. Male C57BL/6J mice were intratracheally instilled with arsenate [As(V)], hexavalent chromium [Cr(VI)], or a combination of both metals. Mice were sacrificed 2 days after treatment to collect bronchoalveolar lavage fluid and lung tissue samples. Inflammation, cytotoxicity, apoptosis, and oxidative stress markers were measured. Our results indicated that administration of Cr(VI) alone or in combination with As(V) induced neutrophil-dominant inflammation as well as phosphorylation of mitogen-activated protein kinases; effects of treatment with As(V) alone were comparatively less potent. By analyzing the production of interleukin-6 and activity of lactate dehydrogenase and caspase, we confirmed that co-treatment intensified pulmonary injury and that it was accompanied by oxidative stress, as confirmed by marked increases in the production of reactive oxygen species, reduced glutathione content, and thioredoxin reductase (TRXRD) activity. Expressed mRNA levels of heme oxygenase-1, glutamylcysteine ligase, glutathione peroxidase 2, thioredoxin (TRX) 1, and TRXRD1 were also enhanced by co-treatment, whereas treatment with As(V) alone reduced the mRNA expression level of TRX2. Our data suggest that co-treatment with As(V) exacerbated Cr(VI)-induced pulmonary injury and that this effect may be exerted through a disruption in the balance among several antioxidant genes.

A 4-week repeated dose oral toxicity study of phenobarbital (PB) sodium was conducted in F344 rats of both sexes at PB doses of 0.8, 8, and 80 mg/kg/day to fully elucidate its general toxicity including hematological changes. Both sexes in the 80 mg/kg/day group showed staggering gait, lacrimation, and/or sedation, which were more evident in the early stage of treatment. The body weight gain and food consumption were greater in these animals than in controls. Hematology revealed a significant reduction in the hematocrit (Ht), hemoglobin concentration (Hb), and erythrocyte count (RBC) in both sexes at 80 mg/kg/day, which was accompanied by a decrease in the cell mean Hb (CHCM) in mature erythrocytes with an increase in unsaturated iron binding capacity. Female rats also showed reduction in the CHCM in reticulocytes, content of hemoglobin per reticulocyte, and transferrin saturation. PB prolonged the activated partial thromboplastin time and inversely increased the platelet count with no evidence of platelet activation. Well-known toxic effects of PB on the liver and thyroid were observed in a dose-dependent manner, along with altered lipid, glucose, and electrolyte metabolism. The serum levels of PB increased dose-dependently, when examined in females received 8 and 80 mg/kg/day on day 1 and 28; there were no difference in C-max and AUC(0-24) values between day 1 and day 28. These results indicated that PB has the potential to elicit multiple organ toxicity including an effect on the hematopoietic system. The hematological analysis provided evidence for hypochromic anemia, plausibly caused by the impairment of iron utility.

We previously demonstrated that rat offspring exposed perinatally to methoxychlor (MXC) still exhibited immunotoxic changes in young adulthood at 10 weeks of age. That result led us to further investigate whether the influence of perinatal exposure to MXC on the rat immune system persistently remains in adult life. Sprague-Dawley rat offspring of both sexes from dams receiving MXC at dietary dose levels of 0, 30, 100, 300, and 1000 ppm were used for the present study. The pups exposed to MXC through the placenta, milk, and/or direct intake during the gestation and lactation periods were maintained on a normal diet from weaning up to 52 weeks of age. At the termination, a significant increase in plasma chloride was noted in both sexes at 300 and 1000 ppm MXC exposure. Females at 1000 ppm MXC exposure showed increases in serum IgM and urinary protein and had significantly increased relative weights (ratio to body weight) of the spleen and kidneys. An increased relative kidney weight was also noted in females at 300 ppm MXC exposure. Histopathologically, the incidence and severity of chronic nephropathy tended to be higher in females at 1000 ppm MXC exposure, and their kidneys had enlarged glomeruli with increased IgG and IgM deposits. In the immune system, however, there were neither notable histological changes nor significant alterations in the splenic lymphocyte subsets for any dose group of either sex. These results indicate that the immunotoxic damage caused by pre- and post-natal MXC exposure appears to be repaired during the process of growth, although the effect seems to remain in females even at 52 weeks after birth and consequently may accelerate the progression of chronic nephropathy.

We have performed a Monte Carlo simulation of an isotropic Heisenberg antiferromagnet with dipolar interactions on the triangular lattice. The model exhibits three phase transitions at T-KT1, T-KT2 and T-c. A Kosterlitz-Thouless-like phase of the spins initially appears at T-KT1 and disappears at T-KT2 The low-temperature phase occurring below T-c is a long-range ordered phase which is characterized by the ordering of the chiral vectors for every plaquette and the exponential decay of the spin correlation. This novel phase is realized as the result of the cooperation between the exchange and dipolar interactions.

We make for the first time a large-scale Monte-Carlo simulation of a ferromagnetic Heisenberg model with dipolar interactions on a two dimensional square lattice with open boundaries using an efficient new technique. We find that a phase transition occurs in the model and the ordered phase is characterized by a circular arrangement of the spins.