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Titolo:
NONLINEARITIES IN 2-ACETYLAMINOFLUORENE EXPOSURE RESPONSES FOR GENOTOXIC AND EPIGENETIC EFFECTS LEADING TO INITIATION OF CARCINOGENESIS IN RAT-LIVER
Autore:
WILLIAMS GM; IATROPOULOS MJ; WANG CX; JEFFREY AM; THOMPSON S; PITTMAN B; PALASCH M; GEBHARDT R;
Indirizzi:
AMER HLTH FDN,NAYLOR DANA INST DIS PREVENT,1 DANA RD VALHALLA NY 10595 UNIV TUBINGEN,INST PHYSIOL CHEM D-7400 TUBINGEN GERMANY
Titolo Testata:
TOXICOLOGICAL SCIENCES
fascicolo: 2, volume: 45, anno: 1998,
pagine: 152 - 161
SICI:
1096-6080(1998)45:2<152:NI2ERF>2.0.ZU;2-0
Fonte:
ISI
Lingua:
ENG
Soggetto:
DNA-ADDUCT FORMATION; CELL-PROLIFERATION; N-NITROSODIETHYLAMINE; NEOPLASTIC CONVERSION; GLUTAMINE-SYNTHETASE; IRON ACCUMULATION; EPITHELIAL-CELLS; TUMOR INITIATION; MECHANISTIC DATA; RISK ASSESSMENT;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Citazioni:
55
Recensione:
Indirizzi per estratti:
Citazione:
G.M. Williams et al., "NONLINEARITIES IN 2-ACETYLAMINOFLUORENE EXPOSURE RESPONSES FOR GENOTOXIC AND EPIGENETIC EFFECTS LEADING TO INITIATION OF CARCINOGENESIS IN RAT-LIVER", TOXICOLOGICAL SCIENCES, 45(2), 1998, pp. 152-161

Abstract

The dose responses for several effects of low-level limited exposuresto 2-acetylaminofluorene (AAF) in the livers of male Fischer 344 ratswere measured and a subsequent phenobarbital tumor promotion regimen was used to manifest initiation of carcinogenesis. Three doses over a 10-fold range yielding cumulative total exposures of 0.126, 0.42, and 1.26 mmol AAF/kg body weight were achieved by daily intragastric instillation for up to 12 weeks with interim terminations. This was followed by 24 weeks administration of 500 ppm phenobarbital (PB) in the dietto promote liver tumor development. At 12 weeks at the end of AAF administration, all exposures produced adducts in liver DNA, measured by P-32 postlabeling, and the level of adducts increased with exposure, except that the high exposure did not produce a dose proportional increase. Measurement of arylsulfotransferase activity, a key enzyme in themetabolic activation of AAF, revealed that in livers from the high exposure animals, the enzyme was inhibited. To assess for toxicity, the centrilobular zone of glutamine synthetase-positive hepatocytes was quantified immunohistochemically at 12 weeks. The area of the zone was reduced in the high exposure group and there was a trend to reduction in relationship to exposure. The two lower exposures to AAF produced noincrease in cell proliferation, whereas the high exposure resulted ina marked increase, about 8-fold over controls. Initiation was assessed by induction of hepatocellular altered foci (HAF) that expressed theplacental form of glutathione S-transferase. AAF induced HAF in the high exposure group, 9-fold at 8 weeks and 170-fold at 12 weeks compared to controls. In rats maintained on PB for 24 weeks after exposure, the multiplicity of HAF increased in controls and comparably in the lowand mid exposure groups, but remained at the about the same high level in the high exposure group. The high exposure produced a substantialincidence of benign neoplasms by 12 weeks, and with promotion by 36 weeks, all rats developed hepatocellular neoplasia. In the mid exposuregroup, only one adenoma occurred at 36 weeks in 17 rats, while in thelow exposure group, no liver tumor occurred in 23 rats. Thus, these findings document nonlinearities for some of the effects of AAF, with supralinear effects at the high exposure for cell proliferation and induction of HAF, and a no-observed-effect level for induction of promotable liver neoplasms at the lowest cumulative exposure of 0.126 mmol/kg, in spite of the formation of DNA adducts. We conclude that the effects of this DNA-reactive hepatocarcinogen leading to initiation exhibitnonlinearities and possible thresholds. (C) 1998 Society of Toxicology.

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Documento generato il 30/11/20 alle ore 16:12:46