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At least 19 recordsLinked to original sources
PubMed1990

Behavioral deficits in rats with minimal cortical hypoplasia induced by methylazoxymethanol acetate.

Methylazoxymethanol, a short-acting antimitotic agent, produces marked cortical hypoplasia in fetuses when injected into pregnant rats. These offspring also have increased cortical concentrations of biogenic amines associated with hyperactivity and learning deficits. In this experiment, rats with a relatively mild degree of methylazoxymethanol-induced cortical hypoplasia were studied to determine whether these neurochemical and behavioral abnormalities persisted. Sprague-Dawley pregnant rats were injected intraperitoneally on day 15 of gestation with methylazoxymethanol acetate (25 mg/kg). Total brain weight was reduced by 12% and cortical slab weight by 28% in methylazoxymethanol-exposed offspring. They were more active than control rats and showed a trend toward slower learning in a swim maze. Affected offspring had increased cortical concentrations of norepinephrine, 5-hydroxyindoleacetic acid, and glycine. There was no significant difference in the concentrations of serotonin gamma-aminobutyric acid, aspartic acid, glutamic acid, or glutamine. Methylazoxymethanol-lesioned animals with mild cortical hypoplasia remained measurably hyperactive and may serve as a model for the study of neurotransmitter and neuropathologic abnormalities associated with hyperactivity in children with microcephaly.

Animals↗
PubMed1990

Morphometrical and microdensitometrical studies on peptide- and tyrosine hydroxylase-like immunoreactivities in the forebrain of rats prenatally exposed to methylazoxymethanol acetate.

Methylazoxymethanol acetate (MAM Ac) injected into pregnant rats at a dose of 25 mg/kg at gestational day 15 causes microcephaly due to an atrophy of various telencephalic areas, mainly neocortex, hippocampus and basal ganglia. Previous studies demonstrated alterations in various neurochemical markers of classical transmitter systems in these regions. The present paper deals with changes in peptide and tyrosine hydroxylase (TH)-containing neurons in MAM Ac-induced microcephaly using immunocytochemistry coupled with computer-assisted morphometry and microdensitometry. No change in the number of vasoactive intestinal polypeptide (VIP)-immunoreactive neurons in the neocortex and neuropeptide Y (NPY)-immunoreactive neurons in the nucleus caudatus-putamen was found whereas cholecystokinin (CCK)-and NPY-immunoreactive neurons in the neocortex and CCK- and VIP-immunoreactive neurons in the hippocampus were decreased. The reduction of the latter peptide containing neuronal populations led to a maintained density of cells in MAM Ac-exposed rats, due to the parallel reduction of the overall mass of these regions. TH immunoreactivity was found to be unchanged in the basal ganglia, and increased in the cerebral cortex in agreement with previous reports on noradrenaline cortical system after MAM Ac exposure. The present results show a heterogenous vulnerability of different peptide immunoreactive neuronal populations to MAM Ac exposure. The sparing of VIP- and NPY-immunoreactive neurons may be due to their late development in the neocortex and striatum, respectively. The hypothesis is introduced that cortical VIP interneurons can develop independent of marked alterations in the intrinsic circuitry of the cortical region.

Animals↗
PubMed1977

Tumor induction in intact and regenerating liver of adult rats by a single treatment with methylazoxymethanol acetate.

Methylazoxymethanol (MAM) acetate was given once i.p. to intact adult rats and to rats at 24 h after partial hepatectomy. In each group, tumors developed as early as 10 months. The incidence of neoplastic nodules and of hepatocellular carcinomas in the carcinogen-treated intact adult rats was approximately 70% and, in the rats treated after partial hepatectomy, it was approximately 80%. The data suggest that both dividing and resting liver cells are sensitive to the tumor-initiating effects of methylazoxymethanol acetate.

Animals↗
PubMed1981

Tumors of the anal region induced in mice painted with methylazoxymethanol acetate.

The carcinogenicity of methylazoxymethanol acetate (MAM acetate) was examined in 91 BALB/c mice by painting it on the anal region. Carcinomas and adenomas of the perianal sebaceous gland were induced in 23 of 24 male (96%) and 16 of 30 female (53%) mice and keratoacanthoma developed in one of 24 male mice within 30 weeks after treatment with MAM acetate. Vascular tumors of the liver and fat issue of the abdominal cavity also developed in 16 of 24 male (67%) and 3 of 30 female (10%) mice treated with this drug. Microscopic adenocarcinomas were found in the rectal mucosa of 3 of 24 male mice adjacent to the anorectal junction. The sex difference in the incidence of tumors is briefly discussed.

Adenoma↗
PubMed1977

Differences in the acute response of the various segments ofrat intestine to treatment with the intestinal carcinogen, methylazoxymethanol acetate.

Previous work has shown that single injections of methylazoxymethanol acetate in rats induce tumors predominantly in the colon, occasionally in the duodenum, and rarely in the jejunum and ileum. These studies describe the acute pathological and biochemical, alterations induced by this carcinogen in the different segments of rat small intestine and colon. Karyorrhexis was found in crypts of duodenum, cecum, and all segments of colon at 6 hr after treatment. Much of the cellular debris was removed by 24 hr, although mitoses did not return to normal levels until the third day after treatment. No pathological alterations were found in jejunum or ileum, even as late as 24 hr after treatment. Studies of DNA synthesis at 24 hr after treatment indicated that jejunum and ileum were much less affected than were duodenum, cecum, or colon. In contrast, 5-fluorouracil and nitrogen mustard, agents that can inhibit proliferating cells but are not known to be intestinal carcinogens, affected all of the segments equally. The results indicate that a correlation exists between those segments of intestine acutely affected by methylazoxymethanol acetate and the sites of eventual tumor development. The level of deacetylase activity in the various intestinal segments did not correlate with sensitivity to methylazoxymethanol acetate-induced inhibition of DNA synthesis. We also found that methylazoxy-methanol acetate inhibited DNA synthesis in the duodenum and colon in rats with cannulated bile ducts. These data indicate that the carcinogen does not require biliary transport to the intestinal lumen to exert its biological effects. Mechanisms that might account for the observed selectivity in action of methylazoxymethanol acetate in the various rat intestinal segments are discussed.

Acetylation↗
PubMed1979

Mechanism of inhibition of hepatic protein synthesis in rats by the carcinogen, methylazoxymethanol acetate.

Treatment of rats with the carcinogen, methylazoxymethanol acetate, results in a rapid, marked inhibition of hepatic protein synthesis and disaggregation of polysomes. Studies were undertaken to learn the mechanism by which this carcinogen induces these effects in rat liver. The data show that the inhibition of endogenous protein synthesis is not due to an effect on the high speed supernatant 'factors' but rather at the level of the polysome, and that both free and membrane-bound polysomes are affected. Poly(U)-directed polyphenylalanine synthesis by native ribosomal subunits is greater in preparations isolated from rats treated with carcinogen than it is in controls. Moreover, the native ribosomal subunit fraction from treated livers in response to added rabbit globin mRNA is able to synthesize a protein similar in molecular weight to globin. These studies show that methylazoxymethanol acetate does not induce significant alterations of ribosomal subunits or of initiation factors and suggest that the inhibition of protein synthesis and disaggregation of polysomes may be the results of an alteration of cytoplasmic mRNA, or its association with ribosomes.

Animals↗
PubMed1988

Depletion of cholinergic habenulo-interpeduncular neurons by selectively timed methylazoxymethanol acetate (MAM) treatment during pregnancy.

Methylazoxymethanol acetate (MAM) was injected to female rats at the beginning of the 17th day of gestation. Resulting offspring showed a remarkable decrease in the size of the medial habenula while the interpeduncular nucleus, whose neurons are generated before the time of MAM treatment, appeared anatomically unaffected. Choline acetyltransferase was significantly reduced in the habenulae and in the interpeduncular nucleus suggesting that MAM treatment had depleted a portion of the cholinergic neurons of the medial habenula which project to the interpeduncular nucleus. Aromatic amino acid decarboxylase significantly increased in the interpeduncular nucleus, a likely effect of monoaminergic hyperinnervation in response to partial cholinergic deprivation. MAM strategy can be usefully adopted for the study of general aspects of brain development when connected nuclei showing no overlapping in neuronal generation times are involved.

Acetylcholinesterase↗
PubMed1983

Effect of methylazoxymethanol acetate on rat liver nuclear and nucleolar RNA synthesis.

The effect of methylazoxymethanol acetate on rat liver nuclear and nucleolar RNA synthesis is investigated at various doses (5 to 50 mg/100 g body weight) and for various lengths of time (1 to 24 hr). The results show that this carcinogen is a potent inhibitor of both nuclear and nucleolar RNA synthesis. Like other carcinogens studied previously in this laboratory, e.g., N-hydroxy-2-acetylaminofluorene, aflatoxin B1, and actinomycin D, methylazoxymethanol acetate inhibits RNA synthesis at multiple sites. It impairs chromatin template function and selectively inhibits the activity of RNA polymerase II. Experimental evidence suggests the mechanism of inhibition of RNA polymerase II activity is due to a decrease in catalytic efficiency rather than in the total number of the enzyme. In addition, it is found that methylazoxymethanol acetate induces a dramatic condensation of nucleoplasmic chromatin.

Animals↗
PubMed1977

Methylation of intestinal and hepatic DNA in rats treated with methylazoxymethanol acetate.

Descending colon is the most sensitive segment of rat intestine and is at least as sensitive as liver to the carcinogenic effects of methylazoxymethanol acetate. To determine whether a relationship exists between tumor induction and level of DNA methylation, we measured the levels of 7-methylguanine in the DNA isolated from duodenum, descending colon, and liver of rats treated with this carcinogen. Because radiolabeled methylazoxymethanol acetate is not available, we utilized high pressure liquid chromatography whereby methylated purines could be detected in amounts as little as 100-300 pmoles. DNA isolated from liver of carcinogen-treated rats had significant amounts of 7-methylguanine. On the contrary, DNA isolated from descending colon of rats treated with methylazoxymethanol acetate had minimal amounts of 7-methylguanine; these data suggest that the level of 7-methylguanine does not correlate with sensitivity to tumor induction by methylazoxymethanol acetate.

Animals↗
PubMed1992

Changes in secondary structure of DNA of rat embryos following treatment with diethylnitrosamine and methylazoxymethanol acetate in vivo.

Diethylnitrosamine (DEN) and methylazoxymethanol acetate (MAM) are not transplacental carcinogenic but embryotoxic to Wistar rats when administered by i.p. injection on day 12 of gestation. MAM, a weak teratogen to rats during this period, induced a dose dependent increase in the number of resorptions to 15% and 40% of the litters following doses of 15 and 25 mg/kg bw, respectively. Rats similarly treated with 70, 150, and 180 mg DEN/kg bw resulted in increases in total DNA mass of day 13 embryos by 31%, 45% and 52%, respectively, compared to the saline treated controls. Twenty percent reduction in total DNA amount was detected following 25 mg MAM/kg bw. Benzoylated DEAE-cellulose (BD-cellulose) chromatography fractionates DNA on the basis of secondary structure by stepwise elution of double-stranded DNA with 1.0M NaCl solution (SE-DNA) followed by elution of DNA containing single-stranded regions with caffeine solution (CE-DNA). Day 13 embryonic DNA was monitored by in vivo labelling with [methyl-3H]-thymidine (3H-TdR) on days 6 and 7 of gestation. Significant increases in percentages of caffeine-eluted DNA (%CE-DNA) compared to control values were detected 24 h after treatment of day 12 embryos with 70, 150, and 180 mg DEN/kg bw. Such increases were not observed after MAM. Incorporation of [methyl-14C]-thymidine (14C-TdR) into embryonic DNA demonstrated the effects of treatment with these compounds on DNA synthesis in vivo. When compared to saline controls, DEN induced significant increases in 14C-TdR incorporation into embryo DNA, 1 h prior to analysis, but the increases were not proportional to the doses administered. Similar analysis of MAM treated samples showed no significant changes to %CE-DNA values. The relative %CE-DNA is expressed as the ratio of the percentage of caffeine-eluted 14C-labelled DNA to %CE-DNA (i.e., %CE-14C-DNA:%CE-3H-DNA). In the majority of control embryos the 14C-specific activity of CE-DNA was higher than the 14C-specific activity of SE-DNA. No significant change to relative %CE-DNA values of embryos to those of the controls was observed 24 h after treatment of day 12 gestation rats with single doses of DEN and MAM. The results of this study support the hypothesis that initiation mechanisms of teratogenesis and transplacental carcinogenesis are different. The pertinence of %CE-DNA and relative %CE-DNA values to teratogenesis and transplacental carcinogenesis is also discussed.

Analysis of Variance↗
PubMed2005

Effects of prenatal methylazoxymethanol acetate (MAM) treatment in rats on water maze performance.

Prenatal methylazoxymethanol acetate (MAM) treatment has been shown to induce morphological abnormalities in cortical areas of the offspring. Based on the neuroanatomical and behavioural abnormalities, this treatment has been suggested as a useful animal model for schizophrenia. In a previous study (Jongen-Relo AL, Leng A, Luber M, Pothuizen HHJ, Weber L, Feldon J. The prenatal methylazoxymethanol acetate treatment: a neurodevelopmental animal model for schizophrenia? Behav Brain Res 2004;149:159-81) we have studied MAM-treated animals in a series of behavioural tests related to schizophrenia, such as latent inhibition and pre-pulse inhibition of the acoustic startle response to establish the validity of prenatal MAM treatment (20mg/kg i.p. on gestational days 9-15; MAM 9-MAM 15). We found that, apart from a marginal effect of increased activity in the open field, the MAM treatment on gestational day 15 was behaviourally ineffective. Here, we extended our previous study to a water maze experiment conducted in the same batch of animals as presented previously (MAM 12-MAM 15). MAM-treated animals showed similar water maze performance compared with control animals during the acquisition phase and the probe tests. However, during the reversal phase, MAM 15 animals showed impaired acquisition of the new platform location. This might indicate some cognitive deficits in MAM 15 animals in terms of working memory or behavioural flexibility. However, in combination with the lack of behavioural abnormalities of MAM 12-MAM 15 animals in several other tests related to schizophrenia in the previously reported study, the use of MAM treatment (MAM 12-MAM 15) as a valid model for schizophrenia still remains debatable.

Analysis of Variance↗
PubMed1995

Seizure susceptibility in immature rats with micrencephaly induced by prenatal exposure to methylazoxymethanol acetate.

The administration of the alkylating neurotoxin methylazoxymethanol acetate (MAM) to pregnant rats on day 15 of gestation induces, in the offspring, a marked micrencephaly, characterized by an impaired formation of interneurons at cortical, hippocampal and striatal levels. Since in man developmental CNS malformations are often associated with severe epileptogenic encephalopathies with seizures appearing in the first months or years of life, we have studied the development of kainic-acid- and bicuculline-induced seizures in 15- and 30-day-old rats, prenatally exposed to MAM. Compared to controls, a higher susceptibility to seizures has been found in micrencephalic rats aged 15 days, while no significant differences have been observed in those aged 30 days. It is hypothesized that the cerebral global anatomical dysgenesis caused by MAM underlies the higher seizure susceptibility shown by animals during the first periods of life. Successively, the processes of adjustment occurring between the cerebral regions affected by the neurotoxic action of MAM and the afferent and efferent pathways spared by the substance may re-establish adequate interneuronal relationships and, therefore, a normal convulsive susceptibility.

Age Factors↗
PubMed1988

Perinatal methylazoxymethanol acetate uncouples coincidence of orientation of cerebellar folia and parallel fibers.

Perinatal administration of methylazoxymethanol acetate in the rat, as a one time injection on gestational day 21, postnatal days 0, 1 or 2, altered the parallel orientation of cerebellar folia. The effect persisted into adulthood. In animals injected on one of the postnatal days 3, 4 or 5, the folial pattern was not altered. Even when the injection was repeated for three days on postnatal days 3, 4 and 5, changes in the cerebellar surface were not found. However, in animals receiving a low protein diet during the last five days of gestation, the three injection regimen produced a distortion of the folial pattern. The surface of cerebella of animals injected on gestational day 21 through postnatal day 2 was covered with small blebs resembling the surface of a cauliflower head. In sagittal sections, islands of cortical laminae appeared to be isolated from the arbor vitae. However, serial reconstruction of the granular layer from sections revealed that these pieces were continuous with the arbor vitae. Surprisingly, cerebella having malaligned folia also had varying degrees of Purkinje cell somas distributed throughout the granule cell layer rather than in a single layer. This occurred even when the granule cell layer approached normal thickness. Analysis of cerebellar weight from the group injected on the day of birth revealed three levels of weight reduction: severe (greater than 40%), moderate (20-40%) and mild (less than 20%). The granule cell deficit was directly related to the weight reduction of the cerebella. In the severely-affected cerebella, areas of the cortex were virtually devoid of granule cells. The moderately-affected cerebella had a continuous granular layer which was thick and thin. In the mild type, the layer was relatively normal in thickness but, nevertheless, the cerebellar surface was highly distorted. In all animals treated with methylazoxymethanol acetate on days G21 through P5, parallel fibers were disoriented. This occurred even though the folia appeared normal in the G20, P3, P4, P5 and P3-5 injected groups. Bundles of parallel fibers crisscrossed in the plane of the cerebellar surface in all areas where a molecular layer was found.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1975

Megalocytosis and other abnormalities expressed during proliferation in regenerating liver of rats treated with methylazoxymethanol acetate prior to partial hepatectomy.

Rats were partially hepactectomized at various intervals after receiving a single injection of the carcinogen, methylazoxymethanol acetate. In treated rats, there was a delay and a reduction in the peak response of hepatic DNA synthesis. At 48 hr after partial hepatectomy, following completion of the first mitoses, almost all hepatocytes were enlarged (megalocytes) and many contained enlarged nuclei. Although at 7 days after the hepatectomy many megalocytes could still be found in centrilobular zones, the majority of the hepatocytes were of normal size or smaller. Abnormal anaphase and telophase figures containing chromosomal bridges and acentric fragments were found during the period of regeneration. In addition, discrete nests of small cells with increased cytoplasmic basophilia were evident. Megalocytes also appeared when rats were partially hepatectomized as late as 26 weeks after injection of the carcinogen. These results show that a single dose of methylazoxymethanol acetate can affect almost all hepatocytes and that latent effects persist for long periods of time.

Age Factors↗
PubMed1976

Carcinomas of the colon in Buffalo strain rats given intraperitoneal injections of methylazoxymethanol acetate.

Buffalo strain male and female rats were given methylazoxymethanol acetate (20% solution) intraperitoneally 20 mg/kg body weight weekly for 9 weeks, and killed 27 weeks later. Carcinomas of the large intestine, predominantly in the descending colon, developed in some of the rats. The incidence was higher in male than in female rats. Polypoid carcinomas were observed more often in male rats and sessile carcinomas with metastases in the female rats. Carcinomas were not observed in organs other than the large intestine.

Adenocarcinoma↗
PubMed1982

Neurotransmitter chemistry of lissencephalic cortex induced in ferrets by fetal treatment with methylazoxymethanol acetate.

Treatment of pregnant ferrets with 15 mg/kg of methylazoxymethanol acetate (MAM) at 33 days of fetal gestation results in offspring with cortical hypoplasia and lissencephally. Neurochemical analysis of 5 areas of cortex from 8-week-old offspring of MAM- or vehicle-treated jills indicated an overall enrichment in markers for catecholaminergic (tyrosine hydroxylase, norepinephrine) and cholinergic (choline acetyltransferase, acetylcholine) terminals but minimal change in the concentration of GABAergic markers (glutamate decarboxylase, gamma-aminobutyric acid); however, there did not appear to be a direct, inverse relationship between the concentration of catecholaminergic and cholinergic markers and the degree of hypoplasia in cortical subareas unlike what has been found previously in the rat.

Animals↗
PubMed1978

Effect of colostomy on intestinal carcinogenesis by methylazoxymethanol acetate in rats.

The effect of the fecal stream on the induction of intestinal tumors was studied in 3 groups of SD rats. Rats in group 1 were subjected to single-barreled colostomies for the complete exclusion of the fecal stream at the proximal one-third level of the colons and were given consecutive iv injections of methylazoxymethanol acetate. Rats in group 2 were given methylazoxymethanol acetate alone. Rats in group 3 were not treated and served as controls. Tumors were noted in the small and large intestines of almost all rats in both groups 1 and 2. Even animals with single-barreled colostomies frequently developed tumors in the colon distal to the colostomy where the mucosa did not have contact with the fecal stream. These results indicated that carcinogens could probably reach the intestinal mucosa via the vascular system as well as by biliary transport.

Animals↗
PubMed1994

The insular claustrum in the methylazoxymethanol acetate (MAM) treated rats shows two different populations of neurons.

Methylazoxymethanol acetate (MAM) is a substance that inhibits migration of neurons in the embryonic brain. After intraperitoneal injection of two different doses of MAM to pregnant rats, microcephaly with or without complete development of the cerebral cortex was observed in every litter. High MAM doses (30 mg/kg) resulted in the lack of superficial layers (II-IV) of the cerebral cortex when the deep layers (V, VI) were seen. The claustrum was present but composed of loosely packed, medium-size, triangular or fusiform neurons with anarchic oriented long axes. After administration of low MAM doses (14 mg/kg) two different parts (medial and lateral) of the insular claustrum were observed. Our results suggest that neurons of the insular claustrum create two different subpopulations of cells, which were similar to that observed in primitive insectivore (e.g., hedgehog), but fuse in development.

Animals↗