Biomedical subjects

M A Hayes

Publications and source records attributed to M A Hayes.

At least 73 records · Page 4Linked to original sources

PubMed1988

Depletion of salivary gland epidermal growth factor by sialodacryoadenitis virus infection in the Wistar rat.

Male and female Wistar rats 2 to 15 months of age were inoculated intranasally with sialoda-cryoadenitis (SDA) virus and killed at 8 to 21 days post-inoculation (PI). Submandibular glands were evaluated by light and electron microscopy, and levels of salivary gland epidermal growth factor (EGF) were quantitated by cytochemistry and competitive radioreceptor assay. Apical granules in the epithelial cells of the granular convoluted tubules (GCT) were selectively depleted during the acute and convalescent stages of the disease. In addition, levels of immunoreactive EGF were reduced in affected submandibular glands, especially at 8 to 14 days PI with SDA virus, but some evidence of EGF depletion was seen at up to 3 weeks PI. A corresponding transient depletion of EGF receptor reactive salivary EGF was seen between 1 and 3 weeks after experimental SDA infection. These studies suggest that a clinical (or subclinical) infection with SDA virus could have significant effects on experimental studies on EGF-dependent functions, including reproductive physiology and carcinogenesis.

Animals↗

PubMed1987

Inhibition of proliferation of normal, preneoplastic, and neoplastic rat hepatocytes by transforming growth factor-beta.

The influences of purified transforming growth factor beta (TGF-beta) on proliferation of normal, preneoplastic, and neoplastic rat hepatocytes were examined in primary monolayer culture with or without prior stimulation with epidermal growth factor (EGF). Hepatocytes from normal livers or discrete preneoplastic nodules or carcinomas generated in F344 rats by the Solt-Farber model were isolated and cultured in serum-free modified Williams' E. medium for up to 72 h. Proliferation was quantified by labeling index by [3H]thymidine autoradiography. The majority of normal hepatocytes became labeled in response to EGF (20 ng/ml) between 24 and 72 h. TGF-beta had a dose-dependent inhibitory effect which was virtually complete at concentrations above 0.5 ng/ml added at 0 h together with EGF. Hepatocytes from all nodule and carcinoma populations were less stimulated by EGF but also strongly inhibited by TGF-beta. Hepatocytes isolated from normal livers 24 h after partial hepatectomy were similarly inhibited by TGF-beta. The minimal initial exposure period for TGF-beta to maximally inhibit was 2 h. TGF-beta added at various times between 8 and 48 h after EGF partially inhibited the labeling index to levels that were constant but substantially greater than the labeling index at the time TGF-beta was added. A proportion of hepatocytes from normal and nodular livers became resistant to the inhibitory effects of TGF-beta between 48 and 72 h, suggesting that the inhibitory effect is transient. TGF-beta added at 0 h also virtually completely inhibited the labeling of normal and nodular hepatocytes that were not exposed to EGF. These studies demonstrate that TGF-beta is a potent negative regulator of proliferation of normal, regenerating, preneoplastic, and neoplastic hepatocytes. This suggests that persistent proliferation of neoplastic hepatocytes in vivo cannot be explained by a difference in response to TGF-beta.

Animals↗

PubMed1987

Alternative methods of selecting rat hepatocellular nodules resistant to 2-acetylaminofluorene.

Dietary 2-acetylaminofluorene (2-AAF) coupled with a stimulus for cell proliferation such as a 2/3 partial hepatectomy (PH) or a necrotizing dose of carbon tetrachloride is frequently employed to generate nodules of resistant ("initiated") rat hepatocytes. This regimen is a useful model for experimental analysis of alterations in hepatocytes during carcinogenesis, and also as an assay for initiation by various carcinogens. Because of the decreasing availability of carcinogen-containing diets from commercial sources, we have developed alternative methods of 2-AAF administration to generate nodules in rats initiated with N-nitrosodiethylamine. This study compared the nodule-selecting and cancer-promoting efficacy of 2-AAF administered by the Solt-Farber procedure (0.02% in diet for 2 weeks) with 2-AAF administered by gavage, as a suspension in 1% aqueous carboxymethyl-cellulose (CMC). Three or 4 daily administrations of 2-AAF by gavage (20 mg/kg/day) followed by PH on day 4 were equivalent to the dietary regimen in generating early resistant nodules, late persistent nodules and hepatocellular carcinomas. These regimens were similar to the dietary regimen of 2-AAF in inhibiting virtually all normal hepatocyte proliferation. These regimens permit control over the duration and level of 2-AAF exposure and the resulting size of selected nodules.

2-Acetylaminofluorene↗

PubMed1987

Mitogenic activity in platelet-poor plasma from rats with persistent liver nodules or liver cancer.

Platelet-poor plasma (PPP) from F-344 rats with chemically-induced preneoplastic liver nodules or hepatocellular carcinoma stimulated S-phase DNA synthesis in monolayer cultures of normal rat hepatocytes. Similar mitogenic activity was detected in PPP 6 hrs to 1 week after partial hepatectomy (PH) or after necrotizing doses of CCl4 or diethylnitrosamine (DENA). Very little activity was found in PPP4 from control rats. The mitogenic activity in PPP from animals with nodules was non-dialyzable (greater than 14 kd) and bound to a heparin-sepharose affinity column. None of the mitogenic PPPs competed with [125I] epidermal growth factor (EGF) for binding sites on A431 cells or normal rat hepatocytes. These studies indicate that persistent proliferation of preneoplastic and neoplastic hepatocytes is associated with increased circulating levels of mitogenic hepatocyte growth factor.

Animals↗

PubMed1987

Progression in hepatocarcinogenesis: differences in growth and behavior of transplants of early and later hepatocyte nodules in the rat spleen.

Hepatocyte nodules were induced in Fischer 344 rats using the resistant hepatocyte model. Nodules harvested at 5, 24, or 25 weeks after initiation were isolated, diced, and transplanted into the spleen of normal rats and observed for periods up to 104 weeks. In the first experiment, 50% of the animals developed hepatocellular carcinoma, some with invasion and metastasis, by 70 to 104 weeks. In the second experiment, transplants of 5-week nodules grew very slowly and diffusely in the spleen, as did normal liver, but retained at least some of their phenotypic properties. In contrast, transplants of 25-week nodules grew into nodules up to 2.5 cm in diameter by 70 weeks. Two of the larger nodules had smaller nodules within resembling trabecular carcinoma. Transplants from the liver surrounding the 25-week nodules did not grow and produced no nodules by 70 weeks after transplantation. The implications of these observations in the study of progression in hepatocarcinogenesis are discussed briefly.

Animals↗

PubMed1987

Influences of diethylnitrosamine on longevity of surrounding hepatocytes and progression of transplanted persistent nodules during phenobarbital promotion of hepatocarcinogenesis.

The possibility that phenobarbital (PB) selectively promotes liver nodule development by decreasing survival of surrounding hepatocytes previously exposed to diethylnitrosamine (DENA) was evaluated. Livers of F-344 rats were labelled with [3H-methyl]-thymidine (3H-TdR) during developmental or regenerative growth. Neonatal rats given 3H-TdR between days 3 and 12 were subjected at 12 weeks of age to partial hepatectomy (PH) followed 24 hr later by DENA (10 mg/kg) or saline. Subsequent administration of PB (0.1% in drinking water) for 28 weeks reduced total liver label to 46 +/- 10% (saline group) or 40 +/- 4% (DENA group). Adult male rats initiated with DENA (200 mg/kg) and later labelled with 3H-TdR after PH also lost total liver label during 28 weeks' promotion with PB (0.05% in water) at rates similar to those exhibited by noninitiated rats given PB, and by DENA-treated or control rats not given PB. Large persistent (12 weeks) liver nodules generated by DENA in the Solt-Farber model were transplanted as small fragments into the spleens of syngeneic rats previously given 0, 100 or 200 mg/kg of DENA. Subsequent exposure to PB (0.05% in drinking water for 40 weeks) or Aroclor 1254 (6 X 300 mg/kg per month) promoted nodule and cancer development only in livers of DENA-initiated recipients. Surviving transplanted nodules remained as small microscopic clusters even after 40 weeks of promotion. However, PB increased transplant survival (50% vs. 21% in controls) whereas Aroclor reduced it to 8%. These findings indicate that promotion of liver nodules by PB occurs without enhanced mortality of surrounding hepatocytes previously damaged by DENA. They further suggest that promoters such as PB and PCBs do not directly influence the progression of established persistent nodules.

Animals↗

PubMed1987

Aflatoxin B1 and acetaminophen induce different cytoskeletal responses during prelethal hepatocyte injury.

Primary monolayer cultures of adult rat hepatocytes exposed to the hepatocarcinogen aflatoxin B1 (AFB1) undergo a characteristic prelethal cytomorphological change that is distinct from their response to the necrogenic noncarcinogenic hepatotoxin, acetaminophen (AAP). Since changes in cell shape are mediated, at least in part, by the F-actin cytoskeleton, we designed experiments to study early prelethal alterations in the distribution of actin microfilaments in monolayer rat hepatocytes exposed to AFB1 (100 microM) or AAP (16 mM). Using rhodamine-phalloidin fluorescence microscopy, we observed that normal hepatocytes showed a submembranous F-actin distribution with focal short microfilaments extending into filopodia along the periphery of the cell. Hepatocytes exposed to AFB1 for several hours exhibited retraction of their cytoplasm within a prominent circumferential peripheral band of F-actin microfilament bundles. Retraction of focal areas of peripheral cytoplasm was associated with an increased prominence of the radial F-actin-containing filopodia. Subsequently, there appeared peripheral blebs containing very little F-actin. Hepatocytes exposed to equivalently lethal concentrations of AAP initially remained structurally normal. After several hours, the cells exhibited a prominent polar aggregate of short microfilament bundles without the formation of blebs. Both the blebbing and the polar aggregation of F-actin bundles occurred prior to cell death as shown by lactate dehydrogenase release and trypan blue exclusion. These studies support the hypothesis that the lethal effects of these two agents may occur by different biological mechanisms that are associated with remarkably distinct prelethal cytoskeletal responses.

Acetaminophen↗

PubMed1987

Inhibition of hepatocarcinogenic responses to 1,2-dimethylhydrazine by diallyl sulfide, a component of garlic oil.

The mechanisms by which diallyl sulfide (DAS), a component of garlic oil, inhibits hepatocarcinogenicity of 1,2-dimethylhydrazine (DMH) were examined in male Fischer 344 rats. Rats were subjected to partial hepatectomy to stimulate hepatocellular proliferation required for initiation by DMH (50-200 mg/kg i.p.) given 12 h later. Initiation was assessed by the numbers of foci and nodules of hepatocytes that were positive for gamma-glutamyl transpeptidase (gamma-GT) or glutathione-S-transferase-P (GST-P) after 6 weeks promotion by orotic acid (1% in semi-purified diet). DAS at doses above 50 mg/kg (by gavage) administered 1 h before DMH (50 mg/kg) partially reduced the numbers of gamma-GT and GST-P-positive foci. By comparison, all doses of DAS (25-100 mg/kg) completely prevented liver necrosis by DMH (200 mg/kg). DAS substantially reduced macromolecular binding of [14C]DMH in cultured liver cells, but had no effect on their levels of glutathione-S-transferase, glutathione reductase or glutathione peroxidase at 18 h. These findings suggest that low dosages of DAS which reduce DMH binding appear more likely to inhibit hepatocarcinogenicity by reducing the promoting influences of post-necrotic regeneration than by preventing initiation.

Allyl Compounds↗

PubMed1986

Influences of glutathione status on different cytocidal responses of monolayer rat hepatocytes exposed to aflatoxin B1 or acetaminophen.

In short-term primary monolayer cultures of rat hepatocytes, aflatoxin B1 (AFB1) causes a characteristic prelethal cytomorphological response in which peripheral attached cytoplasm contracts segmentally to form finger-like blebs. This response precedes lethal injury as detected by release of lactate dehydrogenase (LDH) into culture medium. We compared the influences of various modifiers of cellular glutathione (GSH) status on cytocidal responses of Fischer 344 rats hepatocytes exposed to AFB1 or acetaminophen (AAP), a hepatotoxin which does not produce segmental cytoplasmic contraction. N-Acetylcysteine (4 mM) reduced the degree of LDH release by AAP (4 to 16 mM) but was not protective against cell killing by AFB1, although it slightly reduced the percentage of hepatocytes with segmental cytoplasmic contraction at 6 hr. BCNU (1,3-bis(2-chloroethyl)-1-nitrosourea) at 40 microM markedly inhibited glutathione reductase and also strongly potentiated cell killing by AAP but did not significantly influence segmental cytoplasmic contraction or LDH release in response to AFB1. Diethylmaleate (40 to 160 microM), a depletor of hepatocellular GSH, and buthionine-D,L-sulfoximine (4 mM), an inhibitor of GSH synthesis, each did not alter hepatocyte killing by AFB1 but were strong potentiators of toxicity of AAP. AAP inhibited glutathione reductase but AFB1 did not. Total GSH concentrations at 6 and 18 hr were reduced by AAP and to a lesser extent by AFB1 in comparison with control cultures. These findings demonstrate that, in contrast to AAP toxicity, the characteristic mode of hepatocyte killing by AFB1 in monolayer cultures is substantially independent of induced alterations in GSH. These results indicate that GSH-dependent detoxification mechanisms do not play a major role in removing necrogenic metabolites of AFB1 in Fischer 344 rat hepatocytes. They further suggest that prelethal responses of AFB1-injured hepatocytes are not affected by GSH-dependent cytoprotective mechanisms.

Acetaminophen↗

PubMed1986

Influences of different polychlorinated biphenyls on cytocidal, mitoinhibitory, and nodule-selecting activities of N-2-fluorenylacetamide in rat liver.

The influences of different polychlorinated biphenyl (PCB) isomers and congeners on distinct hepatotoxic responses to the hepatocarcinogen N-2-fluorenylacetamide [(2-FAA) CAS: 53-96-3] were examined in F344 rats. Cytocidal toxicity of 2-FAA (25-400 microM), determined by lactate dehydrogenase release during 20 hours in primary monolayer cultures of isolated rat hepatocytes, was reduced by in vivo pretreatment with either phenobarbitone [(PB) CAS: 50-06-6] or 2,2',4,4',5,5'-hexachlorobiphenyl (HCBP), a PB-type PCB inducer. However, cytocidal toxicity of 2-FAA was substantially potentiated by either 3-methylcholanthrene [(MCA) CAS: 56-49-5] or 3,3',4,4'-tetrachlorobiphenyl [(TCBP) CAS: 32598-13-3], an MCA-type PCB. In the same cell culture assays, all four pretreatments similarly reduced cytocidal toxicity of N-hydroxy-N-2-fluorenylacetamide (0.32-32 microM; CAS: 53-95-2). By comparison, pretreatments with either the PB-type or MCA-type PCB's (50-200 mumol/kg) diminished mitoinhibitory toxicity of 2-FAA in vivo, as measured by hepatic regenerative growth and hepatocyte labeling indices 7 days after partial hepatectomy (PH) in rats given 3 consecutive daily doses of 2-FAA (20/mg/kg/day) before PH. This regimen of 2-FAA and PH promoted rapid selective growth of gamma-glutamyltranspeptidase-positive (gamma-GT+) nodules at 2 and 4 weeks after PH in rats previously given an initiating hepatocarcinogen, diethylnitrosamine [(DENA) CAS: 55-18-5]. However, various PCB's, including 2,2',4,4',5,5'-HCBP, 3,3',4,4'-TCBP, 2,2',4,4'-TCBP, 2,2',5,5'-TCBP, and the commercial mixture Aroclor 1254, each given as a single dose of 50 mumol/kg by gavage 10 days after DENA and 7 days before 2-FAA, all reduced the size of 2-FAA-selected gamma-GT+ nodules during the 4-week period after PH. These results indicate that, in spite of predictable inducer-specific opposite influences of different types of PCB's on cytocidal toxicity of 2-FAA, all PCB's similarly reduce nodule selection by 2-FAA in initiated livers. Reduced growth of 2-FAA-selected nodules correlated with the consistent ability of all PCB's to enhance regeneration of liver mass after 2-FAA and PH.

2-Acetylaminofluorene↗

PubMed1985

Comparative cytopathology of primary rat hepatocyte cultures exposed to aflatoxin B1, acetaminophen, and other hepatotoxins.

The cytomorphological alterations in primary monolayer cultures of Fischer 344 rat hepatocytes exposed continuously to lethal concentrations of various hepatotoxins were compared. Aflatoxin B1 (AFB1) at concentrations of 1 and 10 microM killed 67 and 97% hepatocytes, respectively, at 48 hr, as determined by release of lactate dehydrogenase (LDH) into culture medium, or by trypan blue uptake. AFB1 produced numerous radial finger-like projections (blebs) at attached margins of cytoplasm in almost all hepatocytes between 6 and 24 hr. Formation of blebs was dose dependent and preceded release of LDH and trypan blue uptake. Similar marginal blebs were produced by cycloheximide, 2-acetylaminofluorene, N-hydroxy-2-acetylaminofluorene, and senecionine. By comparison, acetaminophen, at equivalently lethal concentrations (4 or 16 mM) did not cause marginal blebs, but resulted in a similar time course of LDH release and trypan blue uptake. Carbon tetrachloride and bromobenzene also failed to produce blebs at lethal concentrations. Phalloidin and cytochalasin B rapidly produced smaller spherical blebs over the entire surface of all hepatocytes, distinct from the finger-like blebs produced only at the free attached margins of cells exposed to AFB1. Blebs and lethal injury by AFB1 were reduced by phenobarbitone or 3-methylcholanthrene pretreatments and by SKF-525-A in culture. The demonstration of morphological prelethal changes in hepatocytes injured by different classes of hepatotoxins in culture provides a means of differentiating the early biochemical mechanisms by which hepatotoxins and hepatocarcinogens lethally injure hepatocytes before membrane permeability to LDH and trypan blue is detectable.

Acetaminophen↗

PubMed1985

Influence of cell proliferation on initiating activity of pure polychlorinated biphenyls and complex mixtures in resistant hepatocyte in vivo assays for carcinogenicity.

The abilities of various pure polychlorinated biphenyls (PCB) and complex mixtures to generate resistant gamma-glutamyltransferase (GGT)-positive hepatocellular nodules was evaluated in F344 rats in which hepatocytes were proliferating. The PCB examined were 2,2',4,4',5,5'-hexachlorobiphenyl (CAS: 35065-27-1), 2,2',4,4'-tetrachlorobiphenyl, 2,2',5,5'-tetrachlorobiphenyl, Aroclor 1254 (CAS: 11097-69-1), and a prepared mixture of pure PCB isomers and congeners similar to those found in human breast milk. The PCB were administered either to male and female suckling rats (weekly for 3 wk) during liver growth or to adult male rats (150-160 g body wt) previously subjected to two-thirds partial hepatectomy (PH). Rats were subsequently given a selection regimen consisting of 3 daily doses (20 mg/kg) of 2-acetylamino-fluorene (2-FAA; CAS: 53-96-3) followed by either PH or necrotizing carbon tetrachloride (CAS: 56-23-5) in adult rats that previously underwent PH. None of the PCB exposures generated GGT-positive nodules after selection, whereas known initiators such as diethylnitrosamine (CAS: 55-18-5), 3-methylcholanthrene (CAS: 56-49-5), benzo[a]pyrene (CAS: 50-32-8), and 2-FAA were active initiators of nodules in suckling or hepatectomized rats. These findings indicate that short-term exposures to these PCB during liver cell proliferation do not show initiating action in an in vivo assay that detects both hepatic and nonhepatic initiating carcinogens.

Animals↗

PubMed1985

Initiation and selection of resistant hepatocyte nodules in rats given the pyrrolizidine alkaloids lasiocarpine and senecionine.

The biological mechanisms by which pyrrolizidine alkaloids contribute to initiation and nodule selection (promotion) steps in hepatic carcinogenesis were studied in male Fischer 344 rats. Lasiocarpine at single or double dosages (up to 80 mumol/kg) delayed hepatic regeneration for at least 8 weeks after partial hepatectomy (PH). This regimen of lasiocarpine and PH had a strong selective influence on the growth of gamma-glutamyltranspeptidase (gamma-GT)-positive hepatocyte nodules in rats previously initiated with diethylnitrosamine. However, both lasiocarpine (up to 80 mumol/kg) and senecionine (up to 160 mumol/kg) were inactive as initiators of gamma-GT-positive nodules in rats exposed to a similar selection regimen consisting of 2-acetylaminofluorene and PH. When lasiocarpine or senecionine was given 12 h after PH, very few nodules were initiated. Lasiocarpine pretreatments reduced the initiating activity of diethylnitrosamine and N-nitrosomethylurea in rats subsequently selected with 2-acetylaminofluorene and PH. Resistant nodules selected with lasiocarpine had the typical resistant nodule phenotype (positive for gamma-GT and epoxide hydrolase) and also lacked pyrrolizidine alkaloid-induced megalocytosis. Lasiocarpine treatment also resulted in small regenerative nodular proliferations of hepatocytes that were distinct from resistant nodules because they were negative for gamma-GT and epoxide hydrolase and unrelated to diethylnitrosamine pretreatments. These studies suggest that the hepatocarcinogenicity of pyrrolizidine alkaloids can be better explained by their strong selection (promotion) influence on initiated hepatocytes, rather than by their very weak initiating activity.

Animals↗

PubMed1984

Comparative influences of different PB-type and 3-MC-type polychlorinated biphenyl-induced phenotypes on cytocidal hepatotoxicity of bromobenzene and acetaminophen.

The influences of in vivo treatment with two pure PCB congeners, 2,2',4,4',5,5'-hexachlorobiphenyl (HCBP) and 3,3',4,4'-tetrachlorobiphenyl (TCBP), on the lethal cytotoxicity of bromobenzene and acetaminophen were examined in short-term primary cultures of isolated rat hepatocytes. Lethal injury was measured by release of lactate dehydrogenase (LDH) into culture medium after 20 hr exposure to the hepatotoxins. The HCBP, a PB-type inducer of cytochrome P-450, resembled phenobarbitone (PB) in its ability to increase susceptibility of hepatocytes to bromobenzene (0.5 to 1.6 mM) and acetaminophen (1 to 16 mM). This induced sensitivity was consistently inhibited by SKF-525-A (10 microM) but not alpha-naphthoflavone (ANF, 10 microM) in culture. The 3,3',4,4'-TCPB, a 3-MC-type inducer of cytochrome P-450, resembled 3-methylcholanthrene (3-MC) in its inability to induce susceptibility to bromobenzene. TCBP and 3-MC each increased (20- to 30-fold) cytotoxicity of acetaminophen by a mechanism substantially inhibitable by ANF but not SKF-525-A. These results demonstrate that categorizing pure PCB isomers and congeners into groups according to their different induction capabilities is predictive for their ability to modulate acute hepatocellular necrosis by bromobenzene and acetaminophen.

Acetaminophen↗

PubMed1984

Influences of various xenobiotic inducers on cytocidal toxicity of lasiocarpine and senecionine in primary cultures of rat hepatocytes.

The influences of in vivo pretreatment with phenobarbitone (PB), 3-methylcholanthrene (3-MC), 2,2',4,4',5,5'-hexachlorobiphenyl (HCBP), and 3,3',4,4'-tetrachlorobiphenyl (TCBP) on cytocidal hepatotoxicity of two pyrrolizidine alkaloids, lasiocarpine (LC) and senecionine (SC), were compared in short-term primary cultures of rat hepatocytes. Toxicity was measured by release of lactate dehydrogenase (LDH) into culture medium at 24 h. LC was slightly more toxic to control hepatocytes than SC in the graded response range of 10-160 microM. PB and HCBP (a PB-type polychlorobiphenyl inducer) similarly potentiated toxicity of SC, and each diminished the degree to which cell killing by LC and SC was inhibited by SKF-525-A. By comparison, 3-MC and TCBP (a 3-MC-type PCB inducer) each diminished toxicity of SC but had little effect on toxicity of LC. Alpha-naphthoflavone (ANF) potentiated toxicity of both LC and SC in hepatocytes induced by 3-MC or TCBP but had little effect on responses of hepatocytes induced by either PB or HDBP. These results indicate that xenobiotics that induce similar patterns of cytochrome P-450 isozymes have qualitatively similar modulating influences on cytocidal hepatotoxicity of pyrrolizidine alkaloids in primary cultures. However, the observed modulating effects could not be explained solely on the basis of altered activation rates by the cytochrome P-450 species known to be induced by the various xenobiotics.

Animals↗

PubMed1984

Chemical carcinogenesis: hepatocyte nodules with a special phenotype as a common step at the crossroads.

Unlike the great heterogeneity and diversity in the initial interactions of a chemical carcinogen with DNA and in the phenotypes of the late malignant neoplasms, the intermediate steps in liver carcinogenesis, the hepatocyte nodules, are remarkably similar. This commonality is seen in six different models of liver cancer development using carcinogens and promoters of quite different chemical structure and properties. The hepatocytes in the nodules show a similar arrangement and architecture, cytology and cytochemistry, blood supply, biological behavior, and biochemical pattern. These observations, coupled with the program nature of the remodeling of the hepatocyte nodules, strongly suggest that at least some of the earlier steps in carcinogenesis are of a physiological adaptive nature.

Adaptation, Physiological↗

PubMed1983

Subacute toxic effects of dietary T-2 toxin in young mallard ducks.

Young Mallard ducks (Anas platyrhynchos) were fed diets containing purified T-2 toxin at levels of 20 or 30 ppm for two or three weeks. Ingestion of T-2 toxin was associated with reduced weight gain and delayed development of adult plumage. Affected ducks developed caseonecrotic plaques throughout the upper alimentary tract, especially in oropharynx and ventriculus. Several ducks also developed severe ulcerative, proliferative esophagitis and proventriculitis. Generalized atrophy of all lymphoid tissues consistently occurred. The manifestations of T-2 mycotoxicosis in Mallard ducks were mostly attributable to irritant toxicity to the alimentary mucosa. The T-2 toxin caused neither hematopoietic suppression nor a hemorrhagic syndrome in ducks. These alimentary lesions of T-2 mycotoxicosis in ducks do not resemble diseases of native waterfowl presently being recognized in routine surveillance of waterfowl mortality in Saskatchewan.

Animal Feed↗

PubMed1982

Comparative toxicity of dietary T-2 toxin in rats and mice.

The subacute toxic effects of dietary T-2 toxin were compared in young male Wistar rats, young male Swiss mice and juvenile Swiss mice. Purified T-2 toxin was fed in the diet at levels of 10 or 20 ppm for 2 or 4 weeks. Dose-related depressions in food consumption and weight gain consistently occurred in all animals fed T-2 toxin. Hyperkeratosis of the squamous gastric mucosa, atrophy of the thymus and thymus-dependent lymphoid tissues, and lymphopenia occurred in all animals exposed to T-2 toxin. These effects were most severe in juvenile mice, and least severe in rats. In addition, juvenile mice fed the 20-ppm level developed erythroid hypoplasia and became severely anemic by 4 weeks. These results demonstrate that dietary T-2 toxin at levels up to 20 ppm cause similar effects attributable to food refusal and alimentary irritation in both species. However, mice and rats were relatively resistant to hematopoietic suppression. Only the juvenile mice fed 20 ppm developed this potentially lethal toxic effect.

Animals↗