Barbara M. Nolan

The role of cell death and cell proliferation in the promotion of rat liver tumours by tamoxifen

Administration of tamoxifen to rats results in liver tumours with a latency time that is dependent on the strain of rat used. Wistar and Lewis rats develop liver tumours more rapidly than Fischer rats. Significant increases in the number of apoptotic hepatocytes were found in the Wistar and Lewis strains of rats after they were fed tamoxifen for up to 6 months, but not in Fischer rats. By 6 months of exposure to tamoxifen there were liver tumours in the Wistar and Lewis rats, but not the Fischers. Sustained elevations of the PCNA labelling index were found in the livers of tamoxifen-treated Wistar and Lewis rats, over the first 6 months of tamoxifen treatment, but not Fischers. It is proposed that sustained cell death by apoptosis may play a role in the mechanism of promotion of tamoxifen-induced liver tumours, by causing liver hyperplasia. To support this concept it has been shown that cyloheximide, which causes apoptosis but not necrosis in the rat liver, causes DNA synthesis and cell division in hepatocytes.

A GC–MS metabolic profiling study of plasma samples from mice on low- and high-fat diets☆

Metabolic profiling of biofluids, based on the quantitative analysis of the concentration profile of their free low molecular mass metabolites, has been playing increasing role employed as a means to gain understanding of the progression of metabolic disorders, including obesity. Chromatographic methods coupled with mass spectrometry have been established as a strategy for metabolic profiling. Among these, GC-MS, targeting mainly the primary metabolism intermediates, offers high sensitivity, good peak resolution and extensive databases. However, the derivatization step required for many involatile metabolites necessitates specific data validation, normalization and analysis protocols to ensure accurate and reproducible performance. In this study, the GC-MS metabolic profiles of plasma samples from mice maintained on 12- or 15-month long low (10 kcal%) or high (60 kcal%) fat diets were obtained. The profiles of the trimethylsilyl(TMS)-methoxime(MeOx) derivatives of the free polar metabolites were acquired through GC-(ion trap)MS, using [U-(13)C]-glucose as the internal standard. After the application of a recently developed data correction and normalization/filtering protocol for GC-MS metabolomic datasets, the profiles of 48 out of the 77 detected metabolites were used in multivariate statistical analysis. Data mining suggested a decrease in the activity of the energy metabolism with age. In addition, the metabolic profiles indicated the presence of subpopulations with different physiology within the high- and low-fat diet mice, which correlated well with the difference in body weight among the animals and current knowledge about hyperglycemic conditions.

Method for Determining Whether the Number of Hepatocytes in Rat Liver is Increased after Treatment with the Peroxisome Proliferator Gemfibrozil

A histological method has been developed for determining the absolute numbers of rodent hepatocytes after treatment with the hypolipodemic drug gemfibrozil. It can be applied to distinguish between the enlargement of the liver that commonly occurs in rodents after treatment with chemicals, due to changes in the size of cells (hypertrophy), rather than an increase in the number of cells caused by cell division (hyperplasia). In the case of gemfibrozil the liver enlargement was found to be partly due to hypertrophy and partly to hyperplasia. The induction of hyperplasia can be associated with an increased risk of eventual liver tumour formation, and the distinction of hypertrophy from hyperplasia using a purely histological method, for the determination of increases in hepatocyte cell numbers, will be useful in the assessment of compounds which cause liver enlargement that could precede neoplasia. © 1997 by John Wiley & Sons, Ltd.

Articular chondromatosis and chrondroid metaplasia in transgenic TAg mice.

The C3(1)/SV40 T antigen transgenic mouse model for which rapid mammary and prostate tumor development has been documented uses the FVB/N mouse as a background strain. In this study, where the background strain used was the C57BL/6J mouse, neither mammary nor prostate tumors developed over periods of up to 40 weeks. However, a disturbance of hyaline cartilage in joints was observed similar to that found in synovial chondromatosis in humans. In addition, cartilage thickening in the external ears and cartilaginous metaplasia of the ascending aorta also occurred. This suggests that rearrangement of the transgene occurred in breeding on the C57BL background, thus modifying its expression. It raises the possibility that the genetic changes induced by the SV40 T antigen transforming sequence are important in cartilage homeostasis.