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Biomedical subjects

M J Iatropoulos

Publications and source records attributed to M J Iatropoulos.

At least 37 records · Page 2Linked to original sources
PubMed1995

Identity and pathogenesis of stomach tumors in Sprague-Dawley rats associated with the dietary administration of butachlor.

Macroscopic stomach tumors induced in Sprague-Dawley rats during two chronic bioassays with the acetanilide herbicide butachlor at a dietary concentration of 3000 ppm, were evaluated histologically and immunohistochemically in order to determine their identity and pathogenesis. The tumors, which occurred primarily in female rats, were a heterogeneous series, including a few consisting wholly or partly of classic solid or anaplastic epithelium, but with the majority containing diffusely distributed primitive neoplastic cells. The latter had either the general appearance of undifferentiated epithelium or presented a more "mesenchyme-like" pattern where the cells were epithelioid, blastema-like, neuroendocrine-like or sarcoma-like with fascicular disposition. Gastric glandular profiles were also present, usually located near the periphery of the tumors, but in some cases extending into the diffuse tumor tissue. Most of the tumors displayed variable immunohistochemical reactivity for cytokeratin, vimentin and neuron-specific enolase but were negative for muscle-specific actin or desmin except in the stromal tracts. Detailed examination of all available gastric tissue revealed the presence of additional microscopic neoplasms and precursor hyperplastic lesions. All of these were typical gastric neuroendocrine cell lesions (gastric carcinoids) originating in the fundic mucosa but occasionally invading submucosally, and consisting of epithelial cells in organized clusters, rosettes or primitive tubules. The enterochromaffin-like (ECL) nature of these microscopic neoplasms and precursor lesions was substantiated by strong immunohistochemical reactivity for cytokeratin, neuron-specific enolase and chromogranin A, and a negative reaction for vimentin. One microscopic tumor showed a transition from differentiated neuroendocrine type in the fundic mucosa to a dispersed "mesenchyme-like" pattern in the submucosal extension. An additional finding in the butachlor-treated male and female rats was atrophy of the fundic mucosa involving, in particular, reduction in the numbers of parietal cells. This effect was dose-related, being most severe in the high-dose (3000 ppm) females. On the basis of their morphological characteristics, coupled with the continuity evident in the microscopic lesions, it is concluded that the macroscopic stomach tumors associated with the dietary administration of butachlor are poorly differentiated gastric carcinoids, in some cases admixed with a non-neuroendocrine epithelial element. Fundic ECL and stem cells are known to be under the trophic influence of gastrin, which is apparently responsible for the induction of the tumors associated with butachlor administration. Gastric tumor development involving gastrin is recognized as a secondary, hormonal mechanism of carcinogenesis, demonstrating a dose-threshold phenomenon.(ABSTRACT TRUNCATED AT 400 WORDS)

Acetanilides↗
PubMed1995

A study of the mechanism of butachlor-associated gastric neoplasms in Sprague-Dawley rats.

Long term administration of butachlor to Sprague-Dawley rats in a previous bioassay, resulted in the induction of gastric neoplasms which occurred only in the highest dose group (3000 ppm in the diet), primarily in females and specifically in the fundic region. The tumors were a composite of highly undifferentiated enterochromaffin-like (ECL) cells and mucus producing cells with morphologic characteristics unlike those previously described in the rat stomach. Mucosal atrophy of marked intensity was a consistent feature of the gastric mucosa in animals from the highest dose group. An additional long term study was conducted in female Sprague-Dawley rats at dietary levels of 0, 100, 1000 and 3000 ppm to explore the mechanism(s) involved in the formation of these neoplasms. Cell proliferation was evaluated in both fundic and pyloric regions of the stomachs of rats at multiple time periods from 14 days to 26 months. Mucosal thickness was determined in the fundic region at the same time intervals as were used for cell proliferation studies. Gastric pH and gastric acid production were measured after approximately 21 months of exposure. Serum gastrin levels were analyzed at 14, 60, and 120 days and at 6, 18 and 20 months. Cholecystokinin (CCK)/gastrin receptor binding studies were conducted on samples of four tumors and pooled fundic mucosa from five animals in the control group. Cell proliferation was increased in both the neck and base regions of the fundic mucosa at nearly all time points measured from 14 days to 26 months. The magnitude of the changes in the base region were substantially greater than those in the neck region. Fundic mucosal thickness was decreased beginning at the 30-day time point and continued at all intervals, being less than one half that of controls at 20 and 26 months. Gastric pH in rats from the highest dose was elevated to nearly twice control levels at 21 months. Gastric acid secretion was dramatically decreased in animals from the 3000 ppm group and was moderately decreased in the 1000 ppm group at 21 months. Hypergastrinemia was observed at the 3000 ppm level only, beginning at 120 days with progression to extremely high levels by 18 months. CCK/gastrin receptor binding was demonstrated in all tumors studied, at levels comparable to or higher than that of the pooled control sample. All changes involved only the fundic region, the site of tumor formation. Tumors occurred only in animals from the 3000 ppm level, the only level at which hypergastrinemia occurred.(ABSTRACT TRUNCATED AT 400 WORDS)

Acetanilides↗
PubMed1994

Dose response of promotion by butylated hydroxyanisole in chemically initiated tumours of the rat forestomach.

The antioxidant food preservative butylated hydroxyanisole (BHA) was tested in an initiation-promotion protocol in which male F344 rats (6 wk old), 27 per group, were gavaged with a single dose of 200 mg N-methyl-N'-nitro-N-nitrosoguanidine (MNNG)/kg. After 3 wk on control diet, test diets containing 0, 60, 300, 1000, 3000, 6000 or 12,000 ppm BHA were fed until termination of the experiment at approximately 110 wk, at which time most animals had died with stomach tumours. MNNG caused a high incidence of tumours in the glandular stomach and forestomach of all groups. Administration of 12,000 and 6000 ppm BHA, but not 3000 ppm or lower doses, caused statistically significant increases in the time-related incidence of MNNG-induced forestomach tumours as analyzed by life table analysis. BHA had no effect on the incidence of tumours in the glandular stomach or oesophagus. Tumour incidences in other organs were not related to BHA dose. No increase in hyperplasia in the oesophagus was evident in the high-dose BHA-treated animals compared with the MNNG-only group. This study provides corroboration that BHA affects only forestomach tumorigenesis and that the dose for enhancement of tumorigenesis is at least 1500-fold greater than human exposure.

Animals↗
PubMed1994

Urinary bladder hyperplasia in the rat: non-specific pathogenetic considerations using a beta-lactam antibiotic.

Eight of the known chemical substances associated with neoplasia in man are known to target the urinary bladder urothelium. Preneoplastic changes have been identified following exposure to each of these chemicals, and they have also been seen to occur in many species of lab animals. The most important such change is preneoplastic hyperplasia. Adaptive hyperplasia is the first form of hyperplasia to appear. It can be seen both in untreated controls and dosed animals. The distinguishing features are that in treated groups it does not progress with dose or time, and the process is reversible. Reparative hyperplasia involves disruption of homeostasis. Its severity increases with dose and time. It is not seen in controls but it is still reversible during the recovery segment after exposure to a toxic substance. When reparative hyperplasia continues beyond a certain threshold of time and dose, it progresses to preneoplastic hyperplasia, which further progresses with continued stimulation to frank neoplasia. The synthetic beta-lactam penem antibiotic FCE 22891 and its metabolite FCE 22101 caused adaptive urothelial hyperplasia of the urinary bladder only in rats and in no other species. Based on the pharmacokinetic profile of FCE 22891 and FCE 22101, it can be deduced that the morphologic finding of adaptive urothelial hyperplasia is caused by reduction of intravesicular urine pH. This effect has no relevance to therapeutic use in humans. Further, it is important to distinguish adaptive and reparative hyperplasia in preclinical toxicity studies.

Animals↗
PubMed1994

Endocrine considerations in toxicologic pathology.

Detection of xenobiotic-induced toxicity on the endocrine system is a very difficult task because of the close relationship that the endocrine system has with the neural and immune systems. This is further complicated when one is asked to extrapolate from lab animals to man. Knowledge across species of hormonal action, solubility, transportation, plasma half life, receptor location, type of mediator, rhythmicity and pattern of secretion, is essential. One hormone can exert various effects in different tissues, or one function can be regulated by several hormones or even many functions of one endocrine target tissue can be regulated by several hormones acting in concert. The endocrine toxic response is determined by the state of differentiation of the target site. Feedback mechanisms both positive and negative, should also be taken into consideration initially. Because the effects of hormones have wide-ranged ramifications, the toxic responses likewise encompass broad areas such as the regulation of energy availability, maintenance of the internal environmental, development, growth and reproduction. The initial step involves the ascertaining of interference with the general trophic and target gland function and the characterization of the primary toxic effect. Equally important is to calculate the dose which elicited this primary effect, taking into consideration the area under the curve of the target endocrine site. Adapting this step-by-step approach, the causality between a specific toxic dose and a specific toxic effect can be readily and reliably established across all lab animal species and man.

Animals↗
PubMed1993

Major difference in the hepatocarcinogenicity and DNA adduct forming ability between toremifene and tamoxifen in female Crl:CD(BR) rats.

The hepatoproliferative effects of 2 antiestrogens, tamoxifen and toremifene, were compared in a sequential 15-month study in which 2 doses of each compound were administered by daily gavage to female Sprague-Dawley rats for up to 12 months. The doses were 11.3 and 22.6 mg/kg for tamoxifen and 12 and 24 mg/kg for toremifene. There were scheduled sacrifices at 3, 6, 12, and 15 months, the latter including a 3-month recovery period from the 12th through the 14th month. In the chronic toxicity study, tamoxifen at 22.6 mg/kg produced 100% incidence of hepatocellular carcinoma at the 12- and 15-month sacrifice intervals and 67% and 71% incidences at the 11.3-mg/kg dose. Sequential observations showed an increased incidence of glutathione S-transferase-positive foci of hepatocellular alteration by 3 months with tamoxifen in the absence of hepatotoxicity, with the first liver carcinoma appearing by 6 months of treatment. Unscheduled deaths occurring beyond 7.5 months in the tamoxifen treated groups were due in almost all cases to liver cancer. In striking contrast, toremifene did not produce any hepatoproliferative effects at 12- and 24-mg/kg dose levels, nor in a pilot study at 48 mg/kg. The 24-mg/kg dose of toremifene exerted an inhibiting effect on foci of hepatocellular alteration in rat liver detectable by glutathione S-transferase immunohistochemistry at 3 months and by conventional histology at 12 months. An antiproliferative effect was also evident in mammary gland and anterior pituitary where both toremifene and tamoxifen suppressed tumor incidence in comparison to the control group. The ability of these drugs to modify rat liver DNA after p.o. administration was investigated using the 32P-postlabeling assay. Administration of tamoxifen at 45 mg/kg for 7 days produced liver DNA nucleoside modifications represented by 7 spots on the autoradiogram. Unlike tamoxifen, toremifene did not produce any modified bases in rat liver DNA detectable by the 32P-postlabeling technique. The dose levels of tamoxifen that are strongly hepatocarcinogenic in the rat are compared with doses used in humans in various applications. Taking internal drug exposure into account, we conclude that the margin of safety for use of tamoxifen as an endocrine prophylactic agent for healthy, but breast cancer prone, women is questionable.

Adenoma↗
PubMed1993

The triphenylethylene drug tamoxifen is a strong liver carcinogen in the rat.

Tamoxifen (TAM) is used in the treatment of breast cancer and is being given to healthy women to inhibit breast cancer. The present study examines the effects of TAM in female rats exposed for up to one year. Starting at 6 weeks of age, groups of 55-57 female Sprague-Dawley rats were given TAM by gavage daily at 2.8, 11.3 or 45.2 mg/kd body weight/day, for up to 1 year with two recovery segments, 4 weeks of recovery after 6 months of exposure, and 3 months of recovery after 12 months of exposure. Complete necropsies and histopathology were performed. Drug-related mortality was highest in the high TAM group. In the two high dose groups, hepatoproliferative lesions were present in time- and dose-related incidence, severity and multiplicity. In the high dose rats, at 6 months, hepatocellular adenomas and carcinomas were observed in 71 and 29% of rats respectively. With 1 month of recovery, at 7 months the adenomas and carcinomas were increased to 75%. At 12 months the adenomas were present in 50% and carcinomas in 75% of high dose rats. In the mid dose group, liver lesions were not found until 12 months; at this time 50% had adenomas and 10%, carcinomas. After a 3 month recovery period, 45% exhibited adenomas and 45%, carcinomas. Thus, TAM at 45.2 mg/kg/day elicited hepatocellular neoplasia sometime between 3 and 6 months of administration. At 11.3 mg/kg the neoplastic process was evident at 12 months. At 2.8 mg/kg, no hepatoproliferative changes were found. The strong hepatocarcinogenic effect of TAM in rats raises issues bearing on the prophylactic chronic administration to healthy women.

Animals↗
PubMed1992

N-ethyl-N-nitrosourea induced brain tumors in rats monitored by nuclear magnetic resonance imaging, plasma proton nuclear magnetic resonance spectroscopy and microscopy.

Characteristic slow growing brain gliomas were induced in rats by a single subcutaneous injection of N-ethyl-N-nitrosourea (ENU) within 24 h of birth. A parallel control group of rats was injected with saline. Seven treated rats developed gliomas within 2 years. Periodic nuclear magnetic resonance imaging (MRI) of the brain in 3-mm slices at 1.5 Tesla and monthly plasma sampling for proton magnetic resonance spectroscopy (MRS) at 360 MHz were started 6 months after the injection of ENU. In the MRS experiments, the Fossel index, average of the line widths of the methylene and methyl peaks at 360 MHz, was determined from half-line widths of methyl and methylene peaks at 0.8 ppm and 1.3 ppm. In five of the ENU injected animals that developed histologically verified brain tumors, these were also observed by MRI without contrast agents. There was no consistent correlation between the imaged tumors and the Fossel index obtained through MRS during the course of the study where repeated observations were performed on individual animals, nor was there any consistent statistical difference in the Fossel index between ENU-treated and control animals. The results of this study demonstrate that slowly developing carcinogen-induced brain tumors in rats can be successfully and reliably monitored noninvasively by MRI but not by MRS of plasma.

Animals↗
PubMed1991

Butylated hydroxytoluene lacks the activity of phenobarbital in enhancing diethylnitrosamine-induced mouse liver carcinogenesis.

The effect of the food additive butylated hydroxytoluene (BHT) as an enhancer of liver carcinogenesis in mice was investigated. Liver carcinogenesis was initiated by intraperitoneal injection of diethylnitrosamine (DEN) in male B6C3F1 mice at 100 or 200 mumol/kg body weight once a week for 10 weeks (total exposure 1000 or 2000 mumol/kg body weight). After an exposure-free recovery interval of 4 weeks, groups of mice were fed either basal diet or diets containing either 5000 ppm BHT or 500 ppm phenobarbital (PB), as a positive control, for 24 weeks. Exposure to the initiating doses of DEN alone induced no liver foci at 10 weeks or at 14 weeks after the recovery period, but at termination at 38 weeks, foci and adenomas were present in a dose-related incidence. In the groups given BHT after DEN/recovery, the incidence and the multiplicity of liver foci and adenomas were not different from those in mice given only DEN/recovery, whereas, in the groups given PB after DEN, liver lesions were increased by 1.7-3.0-fold. In conclusion, BHT had no promoting or syncarcinogenic effect on DEN-induced mouse liver carcinogenesis, whereas under the same conditions, PB acted as an enhancer.

Animals↗
PubMed1990

Toxicity studies of butylated hydroxyanisole and butylated hydroxytoluene. II. Chronic feeding studies.

The antioxidants butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT) were fed in the diet to male F344 rats in two chronic feeding studies. In one study, feeding BHT for 76 wk at concentrations ranging from 100 to 6000 ppm produced no increase in neoplasms at any site. In a second study, feeding 12,000 ppm BHT for 110 wk had no neoplastic effect at any site, whereas feeding BHA at 12,000 ppm resulted in a small increase in squamous cell papillomas of the non-glandular squamous portion of the stomach.

Animals↗
PubMed1988

Elevated plasma corticosterone levels and histopathology of the adrenals and thymuses in 2,3,7,8-tetrachlorodibenzo-p-dioxin-treated rats.

The relationship between thymic atrophy and plasma corticosterone levels was examined in 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-treated, pair-fed and ad libitum-fed male Sprague-Dawley rats given a usually lethal (125 micrograms/kg) or non-lethal (25 micrograms/kg) dose of TCDD. At both dosages, corticosterone levels in TCDD-treated animals begun to rise as early as day 4 after treatment. At later time points corticosterone levels were 5-7 times higher in rats given the non-lethal dose, and 6-10 times higher in rats administered the lethal dose than the levels observed in ad libitum-fed controls. Corticosterone levels in control rats pair-fed to the lethal dose group (as a result of the severe reduction in feed intake) were similarly elevated as in TCDD-treated rats but this was not the case in pair-fed rats of the non-lethal TCDD dosage (due to an essentially unchanged feed intake). At both dosages, relative thymus weights of TCDD-treated rats started decreasing by day 4 and continued to decline for the most part of the study. Relative thymus weights of rats pair-fed to the non-lethal TCDD dosage were not different from ad libitum-fed rats. However, the decrease in relative thymus weights of rats pair-fed to the lethal TCDD dosage paralleled that of TCDD-treated rats with an apparent 8-day lag period. Morphologically, the thymus as well as the adrenal revealed differential changes in TCDD-treated rats from those observable in pair-fed rats. These results suggest that either TCDD exerts a direct effect on the thymus and the adrenals or it causes an additional stress (e.g., a metabolic stress) over and above the starvation stress, which may be responsible for the differential morphological changes in these glands.

Adrenal Glands↗
PubMed1988

Some endocrine and morphological aspects of the acute toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD).

Hormonal status was evaluated in TCDD-treated rats and in pair-fed and ad libitum-fed controls in order to separate hormonal changes resulting from the toxic insult of TCDD from those arising from progressive feed deprivation as it occurs in pair-fed controls. TCDD-treated rats received either a usually non-lethal (25 micrograms/kg) or a usually lethal (125 micrograms/kg) dose of TCDD whereas pair-fed and ad libitum-fed controls were given vehicle alone. Animals were terminated at predetermined time intervals and several hormones measured in serum or plasma. In addition, the morphology of the thyroid, pancreas, and pituitary was also examined. In both dosage groups, TCDD-treatment had the following effects: decreased TT4, FT4, insulin, and glucagon; mixed effects upon TT3, FT3, TSH, and GH. Pair-feeding to the non-lethal dose of TCDD had no effect on any of the hormones measured. Pair-feeding to the lethal dose of TCDD had the the following effects: slightly decreased TT4, FT4, TT3, TSH, and insulin; no effect on FT3 and glucagon. It is concluded that the endocrine status of TCDD-treated rats was different from that of pair-fed rats suggesting that some hormonal changes represent responses to an insult other than that due to starvation stress alone. A differential response between TCDD-treated and pair-fed rats was also observable morphologically in the corresponding endocrine glands indicating the importance of this additional control for morphologic observations in instances when reduced feed intake and body weight loss are prominent features of toxicity.

Animals↗
PubMed1987

Effect of a sublethal dose of 2,3,7,8-tetrachlorodibenzo-p-dioxin on interscapular brown adipose tissue of rats.

The effect of a sublethal dose (15 micrograms/kg) of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) was studied in selected tissues of male Sprague-Dawley rats by histological techniques 1, 3, 7 and 14 days after TCDD dosage. Histology of the heart, muscle, white adipose tissue, pancreas and the thyroid was unremarkable and that of the liver was found in agreement with previous reports. However, considerable changes were seen in interscapular brown adipose tissue (IBAT) of TCDD-treated rats. Initial accumulation followed by depletion of lipids, appearance of glycogen, cellular, mitochondrial and nuclear transformations were observed. In conjunction with other experiments it is concluded that a sublethal dose of TCDD alters fat and glucose metabolism in IBAT.

Adipose Tissue, Brown↗
PubMed1987

The effect of mitoxantrone treatment in beagle dogs previously treated with minimally cardiotoxic doses of doxorubicin.

Low-grade chronic cardiotoxicity as determined by myocardial biopsy specimens was induced in beagle dogs after four courses of doxorubicin hydrochloride (1.64 mg/kg, 34.0 mg/sq m) given intravenously once every 3 weeks. After this initial treatment, these dogs were separated into three groups. Two groups received six courses of mitoxantrone (0.25 mg/kg, 5 mg/sq m) commencing at 7 weeks or 19 weeks after the final doxorubicin treatment. The third group was treated with six additional courses of doxorubicin after an interval of 7 weeks. Up to seven sequential endomyocardial biopsies were performed to monitor the myocardial changes which were observed after the initial doxorubicin treatment. The low-grade cardiotoxic changes progressed for at least 7-11 weeks without any additional doxorubicin treatment, and stabilized or even partially reversed after 19 weeks of a treatment-free period. Dogs that received additional doxorubicin demonstrated progressive cardiotoxicity, associated with clinical signs, that resulted in death after a total of seven to ten courses of treatment (12-16 mg/kg, 238-340 mg/sq m cumulative dose). In dogs treated with doxorubicin followed by mitoxantrone after a 19-week treatment-free period, myocardial changes were shown to have stabilized and/or partially regressed. This study indicated that in beagle dogs four courses of doxorubicin (7 mg/kg, 136 mg/sq m cumulative dose) are the threshold dose at which non-life-threatening cardiotoxicity occurs. Residual toxic effects of doxorubicin may be erroneously interpreted as adverse findings attributable to other agents given subsequently during the susceptible period, ie, prior to stabilization of the myocardium. Mitoxantrone given after stabilization of doxorubicin-induced low-grade myocardial changes did not show additive or synergistic effects.

Animals↗
PubMed1986

Histopathology of interscapular brown adipose tissue, thyroid, and pancreas in 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-treated rats.

The time course of histological changes was studied in rats lethally intoxicated (150 micrograms/kg) with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). In addition to TCDD-caused tissue damage described by others, the thyroid, pancreas, and interscapular brown adipose tissue (IBAT) were identified as tissues affected by TCDD. Because histological changes in the thyroid and pancreas occurred late (7 days after dosing), these effects are viewed as secondary due to altered hormonal homeostases. Both light and electron microscopic examination of IBAT identified this tissue as a target in TCDD toxicity. Histological changes in IBAT are characterized by three phases: (1) "fatty" IBAT (Days 1 to 3 after dosing); (2) fat depletion accompanied by glycogen accumulation (Days 4 to 7 after dosing); and (3) complete fat and glycogen depletion together with massive cellular damage (Days 8 to 14), particularly affecting the mitochondria. It is concluded that brown adipose tissue is a primary target in TCDD toxicity. It seems that destruction of brown adipose tissue by TCDD leads to an energy imbalance resulting in reduced oxygen consumption which forces animals to contribute a greater proportion of energy to the maintenance of their body temperature by anaerobic pathways. It is suggested that this less efficient energy utilization is the cause of a wasting syndrome.

Adipose Tissue, Brown↗