The Effects of Perfluorodecanoic Acid on Hepatic Stearoyl-Coenzyme A 1 Desaturase and Mixed Function Oxidase Activities in Rats

The Effects of Perfluorodecanoic Acid on Hepatic Stearoyl-CoenzymeA Desaturase and Mixed Function Oxidase Activities in Rats.VANRAFELGHAM, M. J., AND ANDERSON, M. E. (1988). Fundam. Appl.Toxicol. 11, 503-510. Perfluorodecanoic acid (PFDA) causes adioxin-lilce toxic syndrome and alters the hepatic oleate/stearateratio in rats. The acute toxic effects of a single ip dose (50mg/kg) of PFDA on hepatic stearoyl-CoA desaturase and mixedfunction oxidases were studied in male Fischer-344 rats, 14days after dosing. PFDA causes a marked decrease in food intakein rats, resulting in severe body weight loss with delayed lethality(2-3 weeks after dosing). To distinguish the effects of hypophagiafrom those caused by PFDA, pair-fed control rats were used inaddition to ad libitum-fed controls. Stearoyl-CoA desaturaseactivity, responsible for the conversion of stearoyl-CoA tooleoyl-CoA, was absent in both PFDA dosed rats and their pair-fedcontrols at Day 14. Electron transfer through the desaturasesystem was significantly reduced in PFDA-treated rats only,and in these rats there was a significant reduction in microsomalcytochrome an important component of this electron transfersystem. Pentobarbital sleeping times were significantly prolongedin both the PFDA-dosed and pairfed rats, as compared with thead libitumfed controls. This effect was more pronounced in PFDA-dosedrats. Waking plasma pentobarbital concentration was similarin all treatment groups. Hepatic microsomal cytochrome PASOcontent was unaffected. Aminopyrine N-de-methylase activitywas greatly reduced in PFDA-dosed rats. Although pairfed controlsalso had reduced demethylase activity, it was not as pronouncedas in PFDA-dosed rats, and was probably due to the fasted conditionof these animals. Although the mechanism of action of PFDA isnot known, it is possible that PFDA affects microsomal enzymesby altering the structure and/or function of the membranes inwhich they are located, through effects on lipid metabolism.     

Disposition and Elimination of Three Polychlorinated Dibenzofurans in the Liver of the Rat

Disposition and Elimination of Three Polychlorinated Dibenzofuransin the Liver of the Rat. VAN DEN BERG, M., DE JONGH, J., ECKHART,P., AND VAN DER WIELEN, F. W. M. (1989). Fundam. Appl. Toxicol.12, 738–747. The disposition and elimination of 1,2,3,6,7,8-HxCDF(HxCDF), 1,2,3,7,8-PnCDF (1-PnCDF), and 2,3,4,7,8-PnCDF (4-PnCDF)were studied in liver of female Sprague-Dawley rats after administrationof a single oral dose of 3.5–6.3 µg/kg. The dispositionof these PCDF congeners was structure and vehicle dependent.Administration in peanut oil caused the highest liver retention,compared with administration through the standard diet. Half-livesin liver for 1-PnCDF, 4-PnCDF, and HxCDF were 3.3, 108, and73 days, respectively. 4-PnCDF showed very high liver retention:70% of the dose in the first days after administration. To studykinetic interaction in the liver, mixtures of 1-PnCDF and 4-PnCDF(Experiment I) and of 4-PnCDF and HxCDF (Experiment II) wereadministered. The presence of 4-PnCDF in Experiment I did notsignificantly influence the half-life of I-PnCDF. In ExperimentII the estimated half-life of 4-PnCDF was again 108 days, butfor HxCDF an increased half-life was found, 156 days. It isconcluded that PCDFs with a chlorine substituent(s) adjacentto the oxygen bridge (4- and 6-positions) are eliminated vcryslowly with 14 much greater than that of TCDD.     

Progress in Rhesus Histocompatibility Typing Resulting from the Second International Nonhuman Primate Histocompatibility Workshop (1973)

The Second International Nonhuman Primate Histocompatibility Workshop permitted comparison of rhesus monkey alloantisera developd in various laboratories on a single common panel of related and unrelated monkeys. Analysis of the data permits the conclusion that at least nine specificities are recognized by more than one laboratory, including six at the first locus and three at the second locus.     

Susceptibility to clinically manifest cyclosporine A (CsA)-induced autoimmune disease is associated with interferon-gamma (IFN-γ)-producing CD45RC+RT6− T helper cells

Lethally irradiated Lewis (LEW) rats reconstituted with syngeneic bone marrow and given CsA for a 4-week period, develop, upon withdrawal of CsA, a graft-versus-host-like disease, so-called CsA-induced autoimmunity (CsA-AI). This T cell-mediated autoimmune disease is thymus-dependent; it is generally held that this disease is a consequence of aberrant T cell recovery brought about by CsA. In this study we determined mononuclear cell subsets phenotypically by tri-colour flow cytometry. A strong decrease in recent thymic emigrants (Thy1.1⁺, TCR αβ⁺) was observed as a consequence of CsA treatment, eventually resulting in decreased absolute peripheral T cell numbers. In these rats no altered CD4:CD8 T cell ratio was observed before onset of CsA-AI; CD4⁺ and CD8⁺ cells consisted predominantly of monocytes (CD4^dim+, TCR αβ⁻) and natural killer cells (CD8⁺, TCR αβ⁻), respectively. LEW rats, x-irradiated, syngeneic bone marrow-reconstituted and treated with CsA, showed a marked and persistent, relative expansion of mature CD45RC⁺, RT6⁻ Th cells. In contrast, Brown-Norway rats treated in a similar fashion, or LEW rats subjected to either CsA treatment or x-irradiation, did not show a comparable expansion of mature CD45RC⁺, RT6⁻ Th cells, nor did these animals develop CsA-AI. The CD45RC⁺, RT6⁻ Th cells produced IL-2, and moreover constituted the only Th subset producing IFN-γ upon stimulation, and therefore were considered as Th1-like effector cells. These results are consistent with the view that a persistent preponderance of Th1 cells and not the mere presence of autoreactive cells determines whether or not clinically manifest CsA-AI will occur.     

The Gm-Pi linkage heterogeneity in view of Pi M subtypes

In this study linkage between the loci for Gm (γ-type heavy-chain immunoglobulin markers) and Pi (α₁-antitrypsin/α₁-protease inhibitor) has been shown in families segregating for the Pi M subtypes (Ml, M2, M3 and Msal) as identified by separator isoelectric focusing. The estimate for the Gm-Pi (M-type) recombination is 0-29 (95% limits 0-24-O37) at a peak lod score of 4-31 and with no sex difference. This value is not significantly different from updated recombination frequency estimates for Gm-Pi in Pi MS (0-26) and Pi MZ, SZ and FZ families (0 21). The overall Gm-Pi recombination fraction estimate of 0 26 (95 % limits O23-0-30) at a peak lod score of 20-75 must now be considered as solid. There is a significant heterogeneity within the male Pi MZ families in that the new Finnish families show a higher recombination between Gm and Pi. There is also a possible segregation distortion (Z:M = 23:8). The heterogeneity is discussed in terms of haplotypes, the behaviour of which could be determined by linked genes or chromosomal rearrangements. The possibility that the α₁-antitrypsin level influences recombination frequency has not been ruled out, but cannot explain the heterogeneity within Pi MZ families.