Archives of toxicology. Supplement. = Archiv fur Toxikologie. Supplement最新文献

Double transgenic mice bearing fusion genes consisting of mouse albumin enhancer/promoter-mouse c-myc cDNA and mouse metallothionein 1 promoter-human TGF-alpha cDNA were generated to investigate the interaction of these genes in hepatic oncogenesis and to provide a general paradigm for characterizing both the interaction of nuclear oncogenes and growth factors in tumorigenesis as well as to produce an experimental model to test how environmental chemicals might interact with these genes during the neoplastic process. Coexpression of c-myc and TGF-alpha as transgenes in the mouse liver resulted in a tremendous acceleration of neoplastic development in this organ as compared to expression of either of these transgenes alone. The two distinct cellular reactions that occurred in the liver of the double transgenic mice prior to the appearance of liver tumors were dysplastic and apoptotic changes in the existing hepatocytes followed by emergence of multiple focal lesions composed of both hyperplastic and dysplastic cell populations. These observations suggest that the interaction of c-myc and TGF-alpha, during development of hepatic neoplasia contributes to the selection and expansion of the preneoplastic cell populations which consequently increases the probability of malignant conversion. Treatment of the double transgenic mice with both genotoxic agents such as diethylnitrosamine and IQ as well as the tumor promoter phenobarbital greatly accelerated the neoplastic process. These results suggest that selective transgenic mouse models may provide important tools for testing both the carcinogenic potential of environmental chemicals and the interaction/cooperation of these compounds with specific genes during the neoplastic process.

The usefulness of transgenic E mu-pim-1 mice bearing in their genome the pim-1 oncogene supplemented with an upstream immunoglobulin enhancer and a downstream murine leukaemia virus long terminal repeat, as sensitive test organisms was studied in two short-term carcinogenicity studies. The mice were fed standard diet Altromin 1314 supplemented either with 0.03% 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) for 7 months or with 0.03% 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) for 6 months. PhIP and IQ are heterocyclic amines formed during cooking of meat and fish and are mutagenic to bacteria and cultured mammalian cells. PhIP is a potent mouse lymphomagen, while IQ is a liver, lung and forestomach carcinogen in mice. We found that transgenic E mu-pim-1 mice are highly susceptible to PhIP induced lymphomagenesis but do not respond to IQ treatment. PhIP feeding of E mu-pim-1 mice not only increased the total number of T-cell lymphomas but also decreased the latency time compared to either transgenic or wild-type controls. The effect was most pronounced in the treated female E mu-pim-1 mice, which showed a higher incidence of PhIP induced T-cell lymphomas than transgenic males and a strongly reduced latency period after PhIP treatment compared to non-transgenic mice. Our results suggest that the transgenic E mu-pim-1 mouse may be a useful model for short-term carcinogenicity screening of potential genotoxic carcinogens having the lymphoid system as target tissue. Carcinogens that do not target this tissue, like IQ, however will not be recognised.

Cyanobacterial toxins are produced by terrestrial- fresh-, brackish- and sea-water cyanobacteria of cosmopolitan occurrence. These toxins present acute and chronic hazards to human and animal health and are responsible for isolated, sporadic animal fatalities (mammals, fish, birds) each year. Human health problems are associated with the ingestion of, and contact with cyanobacterial blooms and their toxins. Modes of action of cyanobacterial neurotoxins, hepatotoxins and skin irritants are considered. Recent indications of the accumulation of cyanobacterial toxins in fish, their effect on crop plants and their association with the deaths of human dialysis patients are discussed. These findings and events indicate an incomplete understanding of the exposure routes of these natural toxins and the need for greater awareness of their occurrence and properties among users of waterbodies which are prone to cyanobacterial bloom development.

Allergic diseases are partly genetically determined, but environmental factors have a strong influence on the expression of allergic symptoms in genetically predisposed subjects. In particular, outdoor air pollution has received widespread attention as a potential manifestation factor. The unification of Germany provided a unique opportunity to study the impact of radically different environmental and social conditions on the development of allergies in two genetically homogeneous populations. A high car density and NO2 exposure were typical for many West German cities. Severe pollution due to heavy industrialization and private coal burning for heating purposes were the main sources of air pollution in East German cities. We assessed the prevalence of asthma and allergic disorders in 9-11 year old children in in East Germany (Leipzig and Halle) and in West Germany (Munich). All fourth grade pupils in Munich (n = 7,445) were compared with those in Leipzig and Halle 1991 (n = 3,105). Hay fever, skin test reactivity to common aeroallergens and asthma were considerably more prevalent in West Germany as compared to East Germany. When atopy was taken into account, there was no longer a significant difference in the prevalence of asthma between the two parts of the country.

Many factors determine individual susceptibility to toxic agents in addition to their primary interaction with the target site. Absorption, delivery to target tissues, bio-activation, bio-inactivation, elimination, and adaptive or protective responses all play important parts in determining the overall response of the individual. In addition changes in the physiological significance of the function which is disrupted may be crucially important. Pulmonary absorption can be limited by ventilation or perfusion, both of which increase with work rate. Tissue uptake can be limited by local blood flow, which is strongly influenced by local functional activity. In areas with a blood-tissue barrier, such as brain and testis, tissue uptake can be strongly influenced by developmental state, protein binding or vascular damage. Metabolic transformation can show marked inter-individual variations at both hepatic and extra-hepatic sites, due to genetic or nutritional influences. The capacity for adaptation to toxicological insult can also vary markedly, depending on functional reserve capacity as well as on inherent plasticity. Examples used to illustrate these factors include: the influence of motor activity on the toxicity of carbon monoxide; of noise on the ototoxicity of aminoglycoside antibiotics; of brain activity on the neurotoxicity of dinitrobenzene; of acid-base balance on the toxicity of nicotine; and of developmental stage on the neurotoxicity of haloperidol. In addition disease states can influence sensitivity. Thus anaemia sensitises to manganese; calcium deficiency to lead; nerve trauma to hexane; and Wilson's disease to copper overload.