Cancer is due to multiple inherited or acquired mutations occurring in a single cell. DNA replication, although incredibly precise, results in spontaneous errors. A chemical can increase the number of errors per DNA replication by increasing damage to DNA, or it can increase the probability for spontaneous errors by increasing the number of DNA replications. A model has been developed which takes into account the role of DNA reactivity and increased DNA replication in the pluripotential cell population of a tissue on the development of cancer. This model can be used to assess the mode of action of chemicals which are carcinogenic in animal models and to access the relevance of that mode of action to human risk. By using this mode of action-based model, it may then be possible to replace the 2-year cancer bioassay with shorter-term assays which assess DNA reactivity, immunosuppression and estrogenic activity of the chemical and the effects of the chemical on toxicity and cell proliferation.
Drug-induced phospholipidosis (PLDsis) is an excessive accumulation of polar phospholipids in cells or tissues/organs caused by xenobiotics. Numerous drugs and chemicals are capable of inducing the storage disorder in animals and humans; however, despite their diverse pharmacological activities, each of these drugs shares common physicochemical properties: a hydrophobic aromatic ring structure on the molecule and a hydrophilic side chain with a charged cationic amine group and therefore are in the group of cationic amphiphilic drugs. In affected cells the appearance of membrane-bound inclusions, primarily lysosomal in origin, with a lamellar structure (lamellar bodies) is a definitive morphologic hallmark. Massive accumulations can occur in animal tissues such as the lung with little effect on organ function. The inducing drug also accumulates in association with the excess phospholipid. Although these alterations are generally reversible after cessation of drug treatment, PLDsis is of regulatory concern and an issue for drug safety for pharmaceutical companies. Thus, the assessment of potential target organ dysfunction and the identification of clinical biomarkers are important objectives for new drug development. Recent advances in biotechnology such as metabonomics and toxicogenomics have been providing novel tools to elucidate the mechanisms of PLDsis and to establish biomarkers for screening tests in the preclinical stages and for monitoring in the clinical phases in addition to conventional approaches such as morphology (lamellar bodies) and biochemical methods including assays of specific metabolites and phospholipase inhibition.
Seventy years ago it was discovered that glutamate is abundant in the brain and that it plays a central role in brain metabolism. However, it took the scientific community a long time to realize that glutamate also acts as a neurotransmitter. Glutamate is an amino acid and brain tissue contains as much as 5 - 15 mM glutamate per kg depending on the region, which is more than of any other amino acid. The main motivation for the ongoing research on glutamate is due to the role of glutamate in the signal transduction in the nervous systems of apparently all complex living organisms, including man. Glutamate is considered to be the major mediator of excitatory signals in the mammalian central nervous system and is involved in most aspects of normal brain function including cognition, memory and learning. In this review, the basic biology of the excitatory amino acids glutamate, glutamate receptors, GABA, and glycine will first be explored. In the second part of this review, the known pathophysiology and pathology will be described.
In the present survey, the historical data for spontaneous tumors observed in our laboratory was compared in relation to the time-related changes between recent (2000-2004) and past (1990-1999) samples from Fischer 344 rats used in carcinogenicity studies. In the recent samples, there were statistically increased incidences of islet cell adenomas in males and uterine adenocarcinomas in females. On the other hand, there were decreased incidences of pheochromocytomas, prostatic adenomas, pituitary anterior adenomas, large granular lymphocytic (LGL) leukemias and Leydig cell tumors in males and pituitary anterior adenomas in females. Furthermore, there were decreases in the body weights of both sexes at 58 weeks of age in the recent samples, and this may have been related to the decreases in the incidences of pheochromocytomas, Leydig cell tumors, prostatic adenomas and LGL leukemias. Moreover, the decreased incidence of pheochromocytoma in males revealed a positive correlation with a decreased percentage of severe chronic progressive nephropathy (CPN). On the other hand, there were no distinct factors responsible for increased incidences of tumors observed in the recent samples, suggesting a possible genetic drift. In conclusion, the incidences of spontaneous tumors obtained in our laboratory have been changed with time. Smaller body weights in both sexes and reduction in the number of male cases with severe CPN might be related to the reduced incidence of certain types of tumors in recent animals.
A tissue engineering approach using human mesenchymal stem cells (MSCs) can be used to regenerate bone/cartilage tissue. For effective tissue regeneration, cell cultivation under biologically safe conditions is essential. The objective of this study was to determine suitable antibiotic concentrations in culture media for MSCs while maintaining their inherent capabilities for proliferation and osteogenic/chondrogenic differentiation. When human MSCs were cultured with over 200 μg/mL of gentamicin, the rate of cell growth decreased significantly. In contrast, a concentration of 20 μg/mL gentamicin supported cell proliferation and differentiation capability very well and did not change the expression patterns of cell surface antigens (CD44+, CD105+, CD34-, CD45-). The concentration of 20 μg/ml is much higher than that of the MIC (Minimum Inhibition Concentration) of common bacteria, such as Staphylococcus aureus, Haemophilus influenzae and Escherichia coli. Therefore, we recommend 20 μg/mL of gentamicin in culture media for effective tissue regeneration to avoid bacterial contamination and maintain the osteogenic/chondrogenic capability of MSCs.
Histiocytic sarcoma is characterized by a malignant invasive proliferation of atypical cells showing morphologic and immunophenotypic features similar to those of mature tissue histiocytes. We report a case of histiocytic sarcoma in 11-year-old male cynomolgus macaque fed with a high-fat diet for 6 years. Invasive proliferation of neoplastic cells was localized in systemic organs such as liver, spleen, aorta, kidney, lung, peritonea, and mesenterium. Diffuse cellular foci of invasive proliferation were mainly observed in the peri/intra vascular area, sinus and serous membrane frequently accompanying arteriosclerosis. The tumor cells showed a round to spindle or polygonal shape with abundant foamy to vacuolated cytoplasm. Hemophagocytosis was noted infrequently. In immunohistochemical examinations, some medium to large-sized histiocytic atypical cells were positive for histiocytic markers such as CD68 and Lysozyme. Our case raises the possibility that histiocytic proliferation might be related to hypercholesterolemia and atherosclerosis. This is the first case report of histiocytic sarcoma in non-human primates.
The purpose of this study was to determine the relation between administration of a large amount of Di (2-ethylhexyl) phthalate (DEHP) and peroxisome proliferation in cynomolgus monkey (Macaca fascicularis) hepatocytes. DEHP was administered orally to four cynomolgus monkeys, once daily for 28 days at dose levels of 1,000 and 2,500 mg/kg/day. Enlargement of the mitochondria, and lamellar orientation of the cristae along the major axis of the mitochondria were observed in the hepatocytes; however, we did not observe clear proliferation of peroxisomes.