A.H. Penninks

Biological activity of organotin compounds—An overview

As a consequence of the rapid expansion of the uses and applications of the organotin compounds, the concern about their environmental and health effects is increasing. The main subject of this overview is the current understanding of the mammalian toxicity of the organotin compounds. Four different types of target organ toxicity, namely neurotoxicity, hepatoxicity, immunotoxicity, and cutaneous toxicity, are discussed in more detail. The effects of the organotin compounds on the mitochondrial and cellular level are summarized and discussed in relation to the mode of action of these compounds on the central nervous system, the liver and bile duct, the immune system, and the skin.

Identification and partial characterization of multiple major allergens in peanut proteins

Peanuts are a major cause of food allergies both in children as in adults which can induce an anaphylactic shock. The identification and characterization of peanut allergens could lead to more insight into the mechanism and contribute to the improvement of diagnostic tests and treatment for peanut allergy.

Oral sensitization to food proteins: a Brown Norway rat model

Although several in vivo antigenicity assays using parenteral immunization are operational, no adequate enteral sensitization models are available to study food allergy and allergenicity of food proteins.

Dibutyltin and tributyltin compounds induce thymus atrophy in rats due to a selective action on thymic lymphoblasts

Di-n-butyltin dichloride (DBTC) or tri-n-butyltin chloride (TBTC) given in the diets of rats have previously been shown to cause atrophy of the thymus and subsequently suppression of the T-cell-dependent immune responses. To study the mechanism of the immunotoxic effects, the dose-effect relationships and the kinetics of the thymus atrophy caused by DBTC and TBTC were investigated in detail. A single oral dose of DBTC or TBTC to rats induced a dose-related reduction of relative thymus weight, which was maximal 4 days after intubation. The log dose-effect relationships for both compounds were linear and ran parallel over a dose range of 5-60 mg/kg. Dose levels calculated to cause 50% reduction of relative thymus weight were 18 mg DBTC and 29 mg TBTC per kg body wt. A single oral dose of mono-n-butyltin trichloride (MBTC), however, did not cause thymus atrophy at dose levels up to 180 mg/kg. The kinetics of the dibutyltin- and tributyltin-induced thymus atrophy in rats were investigated by measuring thymus weight, total thymic cell count, number of small, intermediate and large cells and the incorporation of DNA, RNA and protein precursors into isolated thymocytes during a period of 9 days after a single oral dose. DBTC and TBTC caused atrophy of the thymus due to a selective reduction in the number of rapidly proliferating lymphoblasts in the first 2 days after dosing. As a consequence the large pool of small lymphocytes declined in the following 2 days. On the fourth day, when atrophy was most pronounced, the frequency of the lymphoblasts increased above the controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of tri-n-butyltin chloride on energy metabolism, macromolecular synthesis, precursor uptake and cyclic AMP production in isolated rat thymocytes

The inhibitor of oxidative phosphorylation tri-n-butyltin chloride (TBTC) causes membrane damage and disintegration of isolated rat thymocytes at concentrations higher than 1 microM. From a concentration of 0.1 microM, TBTC disturbs energy metabolism as indicated by an increase in methylglucose uptake, glucose consumption and lactate production and by a decrease in cellular ATP levels. Over the same TBTC concentration range, the incorporation of DNA, RNA and protein precursors are markedly reduced. Moreover the production of cyclic AMP upon stimulation of the cells with prostaglandin E1 is effectively inhibited. These effects cannot be explained by an inhibition of nucleoside kinase activity, amino acid uptake or adenylate cyclase activity. The effects of TBTC on macromolecular synthesis and cyclic AMP production are possibly due to a disturbance of the cellular energy state.

Humoral and cellular immune responses in different rat strains on oral exposure to ovalbumin

No adequate enteral sensitization models are available to study food allergy and allergenicity of food proteins. Using a previously described oral sensitization protocol to sensitize Brown Norway rats (BN) to food proteins, the influence of genetically-based strain-specific characteristics of the immune system on the outcome of oral sensitization studies was investigated. BN, Hooded Lister (HL), Piebald Virol Glaxo (PVG) and Wistar rats were daily administered 1 mg of ovalbumin (OVA) by gavage dosing for 42 days without the use of an adjuvants. The highest OVA-specific IgG responses were detected in the BN rats followed by Wistar, HL and PVG rats. OVA-specific IgE responses were only detectable in the BN rats. The cellular immune response was examined by determination of delayed-type hypersensitivity (DTH) reactions in the animals. The response was most pronounced in the HL and Wistar rats. PVG and BN rats showed comparable DTH responses but the responses were significantly weaker than those observed in HL and Wistar rats. It was concluded that the genetic make-up of different rat strains influences the outcome of oral sensitization studies. In addition, using the described oral sensitization protocol, the BN rat seems to be the most suitable strain for inducing oral sensitization.

Effects of various inhibitors of oxidative phosphorylation on energy metabolism, macromolecular synthesis and cyclic AMP production in isolated rat thymocytes. A regulating role for the cellular energy state in macromolecular synthesis and cyclic AMP production

Inhibitors of oxidative phosphorylation such as several triorganotin compounds, oligomycin, 2,4-dinitrophenol and carbonylcyanide p-trifluoromethoxyphenylhydrazone suppress energy metabolism of isolated rat thymocytes as indicated by a reduction of ATP levels, an increase in glucose consumption and by a marked accumulation of lactate. Also these compounds effectively inhibit the incorporation of DNA, RNA and protein precursors into acid-precipitable material of thymocytes. Moreover, the prostaglandin E1-induced elevation of cAMP is markedly reduced by these inhibitors. A correlation is observed between the effects on energy metabolism, macromolecular synthesis and cAMP production, since from a series of trialkyltin chlorides, tri-n-propyltin, tri-n-butyltin and tri-n-hexyltin are very effective inhibitors of these functions, while trimethyltin and tri-n-octyltin affect neither of them; other inhibitors of oxidative phosphorylation, each of them with quite different mechanisms of action, also inhibit macromolecular synthesis and cAMP production. The finding that a rise in intracellular ATP concentrations leads to a reversion of the tri-n-butyltin-induced inhibition of cAMP production and uridine incorporation, indicates a regulating role for the cellular energy state in these aspects of cellular function.

Toxicity of organotin compounds : IV. Impairment of energy metabolism of rat thymocytes by various dialkyltin compounds

Isolated thymocytes were incubated with various carbohydrates in the presence of dimethyltindichloride (DMTC), diethyltindichloride (DETC), di-n-butyltindichloride (DBTC), and di-n-octyltindichloride (DOTC) and the substrate conversion, oxygen consumption, and cell viability were measured. All the dialkyltin compounds produced a dose-dependent stimulation of the glucose consumption, but at different concentrations. The most toxic homologs, DBTC and DETC, stimulated the glucose consumption maximally at levels of 5 and 10 μm, respectively, whereas DMTC and DOTC were less active, inducing a maximum stimulation at 120 μm. At higher exposure levels a sharp fall in the stimulation of the glucose consumption was noted together with a decrease of the oxygen consumption and viability of the thymocytes. The oxidative metabolism of glucose, lactate, and pyruvate by the TCA cycle was inhibited by dialkyltin compounds in a dose-related fashion. The glycolytic pathway was not affected, since under anaerobic conditions the glucose consumption was similar to that of the controls up to levels inducing a maximum stimulation of the glucose consumption under aerobic conditions. Probably the entrance of the glycolytic end products into the TCA cyle is disturbed by an inhibition of the pyruvate dehydrogenase system. Additional support for an interference with α-keto acid dehydrogenase complexes were obtained from mitochondrial incubations. DBTC inhibited the pyruvate and α-ketoglutarate conversion, oxygen consumption and ATP production of rat liver mitochondria in a dose-related fashion. Although in vitro the dialkyltin homologs display a comparable mode of action on the energy metabolism of rat thymocytes, in vivo especially DBTC and DOTC induce thymus involution whereas DMTC and DETC hardly decrease thymus weight. This discrepancy may be related with a different distribution pattern of the water-soluble lower homologs and the fat-soluble higher homologs. Therefore, we conclude that the inhibition of the energy metabolism of rat thymocytes by dialkyltins is related to their thymolytic effects in vivo.

Immunotoxic organotins as possible model compounds in studying apoptosis and thymocyte differentiation

In the mid-seventies it appeared that some organotin compounds selectively caused thymus atrophy. From that time onward efforts were made to reveal molecular and cellular mechanisms involved. In this review recent studies into organotin-sensitive stages and processes of thymocyte maturation are discussed. Together these studies resulted in the recognition of organotin compounds as possible model compounds in studying immature thymocyte differentiation and protein synthesis-independent apoptotic cell death of thymocytes.

Di-n-butyltindichloride uncouples oxidative phosphorylation in rat liver mitochondria

In this study di-n-butyltindichloride (DBTC) was found to inhibit alpha-ketoacid-stimulated response of rat liver mitochondria to the addition of ADP and the uncoupler carbonyl cyanide p-trifluoromethoxyphenyl hydrazone (FCCP). The alpha-ketoglutarate oxidation was already inhibited at a level of 0.8 nmol DBTC/mg protein. When succinate was used as substrate together with rotenone, the State 3 and FCCP stimulated oxidation were not inhibited by DBTC. But from a level of 8.3 nmol DBTC/mg protein, the State 4 respiration was increased. It is concluded that in low amounts DBTC specifically blocks alpha-ketoacid dehydrogenases, but higher concentrations of this compound uncouples oxidative phosphorylation. However, this uncoupling will be masked when the NADH production from substrate oxidation is decreased by DBTC as will be in case of alpha-ketoacids.