Effects of GSM-900 microwaves on DMBA-induced mammary gland tumors in female Sprague-Dawley rats

The aim of this investigation was to test the hypothesis that sub-chronic whole-body exposure to GSM-900 microwaves had an effect on tumor promotion and progression. Mammary tumors were induced by ingestion of a single 10-mg dose of 7,12-dimethylbenz(a)anthracene (DMBA) in female Sprague-Dawley rats (Ico:OFA-SD; IOPS Caw). In two independent experiments, DMBA-treated animals were divided into four groups: sham-exposed (16) and exposed (three groups of 16 animals). The specific absorption rates (SARs), averaged over the whole body, were 3.5, 2.2 and 1.4 W/kg in the first experiment (May-July) and 1.4, 0.7 and 0.1 W/kg in the second experiment (September-November). Exposure started 10 days after DMBA treatment and lasted 2 h/day, 5 days/week for 9 weeks. Animals were exposed to plane waves with the electric field parallel to the long axis of the animals. Body weight and the number, location and size of the tumors were recorded at regular intervals. Rats were killed humanely 3 weeks after the end of exposure. The results are negative in terms of latency, multiplicity and tumor volume. With regard to tumor incidence, in the first experiment there was an increase in the rate of incidence at 1.4 W/kg but less at 2.2 W/kg and none at 3.5 W/kg. Overall, these results, which are rather inconsistent, do not bring new evidence of a co-promoting effect of exposure to GSM-900 signals using the DMBA rat model.     

Chemopreventive effect of diclofenac on mammary carcinogenesis in Sprague-Dawley rats

Chemopreventive effect of non-steroidal antiinflammatory drugs (NSAIDs) in mammary carcinogenesis was reported in several studies. In this study, the effect of a nonselective cyclooxygenase inhibitor diclofenac (DICLO) in the prevention of N-methyl-N-nitrosourea (NMU)-induced mammary carcinogenesis in Sprague-Dawley female rats was evaluated. NMU was administered to animals intraperitoneally in two doses of 50 mg kg^?1 b.w. within postnatal days 42-48. In experiment A (short-term administration), DICLO was administrated intramuscularly (5 mg kg^?1 b.w.) every other day, starting 3 days before and for subsequent 25 days after first NMU injection. In experiment B (long-term administration), DICLO was administered in tap water (0.01 mg ml^?1) continually, starting 7 days before and for subsequent 22 weeks after first NMU dose. The study was terminated 22 weeks after the first dose of NMU in both experiments. After DICLO treatment, tumor frequency per group was reduced in both variants of drug administration: in experiment A by 38% and in experiment B by 39.5%. Moreover, DICLO decreased tumor incidence by 11.5% and delayed tumor latency by 14 days in experiment B. In our preventive-curative experiments DICLO decreased some parameters of NMU-induced rat mammary carcinogenesis, mainly the tumor frequency.     

Effects of 900 MHz GSM wireless communication signals on DMBA-induced mammary tumors in rats

The purpose of the study was to investigate whether exposure to 900 MHz GSM wireless communication signals enhances mammary tumor development and growth induced by low-dose DMBA. Five hundred female Sprague-Dawley rats were treated with a single dose of 35 mg/kg DMBA and then divided into five groups in a blinded fashion: one cage control group and four exposure groups, including three microwave exposure groups and one sham exposure with specific absorption rates (SARs) of 4.0, 1.33, 0.44 and 0 W/kg, respectively. Exposure started on the day after DMBA administration and lasted 4 h/day, 5 days/week for 26 weeks. Rats were weighed and palpated weekly for the presence of tumors and were killed humanely at the end of the 26-week exposure period. All mammary glands were examined histologically. There were no statistically significant differences in body weight between sham- and GSM microwave-exposed groups. No significant differences in overall mammary tumor incidence, latency to tumor onset, tumor multiplicity, or tumor size were observed between microwave- and sham-exposed groups. There was a tendency for reduction of mammary adenocarcinoma incidence in the lowest microwave exposure group (0.44 W/ kg) compared with the sham-exposed group (P = 0.058). Additionally, a higher incidence of adenocarcinoma was noticed in the 4.0 W/kg group from the 15th to 26th weeks, especially in the 19th week (P = 0.358 compared to sham). However, neither tendency was statistically significant; thus this study does not provide evidence that GSM microwave exposure promotes mammary tumor development in rats. In the present study there were significant differences between the cage controls and the experimental groups (sham and exposure). Body weight and mammary tumor (malignant plus benign) incidence in the cage control group were significantly higher than in the sham- and GSM microwave-exposed groups. The latency to the mammary tumor onset was significantly shorter in the cage control group than in the other groups.     

Dose-rate effects of mammary tumor development in female Sprague-Dawley rats exposed to X and gamma radiation

Mammary tumour development was followed in two experiments involving a total of 2229 female Sprague-Dawley rats exposed to various doses of X or gamma rays at different dose rates. The data for another 462 rats exposed to tritiated water in one of these experiments were also analyzed. The incidence of adenocarcinomas and fibroadenomas at a given time after exposure increased linearly in proportion to total radiation dose for most groups. However, no significant increase in adenocarcinomas was observed with chronic gamma exposures up to 1.1 Gy, and the increase in fibroadenomas observed with chronic gamma exposures at a dose rate of 0.0076 Gy h-1 up to an accumulated dose of 3.3 Gy was small compared to that observed after acute exposures. The incidence of all mammary tumors increased almost linearly with the log of dose rate in the range 0.0076 to 26.3 Gy h-1 for 3 Gy total dose of gamma rays. The effects of X rays appeared to be less influenced by dose rate than were the effects of gamma rays.     

The effect of dietary zinc - and polyphenols intake on DMBA-induced mammary tumorigenesis in rats

Background

The aim of the study was to investigate the effect of dietary supplementation with zinc and polyphenol compounds, i.e. resveratrol and genistein, on the effectiveness of chemically induced mammary cancer and the changes in the content of selected elements (Zn, Cu, Mg, Fe, Ca) in tumors as compared with normal tissue of the mammary gland.

Methods

Female Sprague-Dawley rats were divided into study groups which, apart from the standard diet and DMBA (7,12-dimethyl-1,2- benz[a]anthracene), were treated with zinc ions (Zn) or zinc ions + resveratrol (Zn + resveratrol) or zinc ions + genistein (Zn + genistein) via gavage for a period from 40 days until 20 weeks of age. The ICP-OES (inductively coupled plasma optical emission spectrometry) technique was used to analyze the following elements: magnesium, iron, zinc and calcium. Copper content in samples was estimated in an atomic absorption spectrophotometer.

Results

Regardless of the diet (standard; Zn; Zn + resveratrol; Zn + genistein), DMBA-induced breast carcinogenesis was not inhibited. On the contrary, in the Zn + resveratrol supplemented group, tumorigenesis developed at a considerably faster rate. On the basis of quantitative analysis of selected elements we found - irrespectively of the diet applied - great accumulation of copper and iron, which are strongly prooxidative, with a simultaneous considerable decrease of the magnesium content in DMBA-induced mammary tumors. The combination of zinc supplementation with resveratrol resulted in particularly large differences in the amount of the investigated elements in tumors as compared with their content in normal tissue.

Conclusions

Diet supplementation with zinc and polyphenol compounds, i.e. resveratrol and genistein had no effect on the decreased copper level in tumor tissue and inhibited mammary carcinogenesis in the rat. Irrespectively of the applied diet, the development of the neoplastic process in rats resulted in changes of the iron and magnesium content in the cancerous tissue in comparison with the healthy mammary tissue. The application of combined diet supplementation with zinc ions and resveratrol considerably promoted the rate of carcinogenesis and increased the number of DMBA-induced mammary tumors.     

Influence of estradiol on mammary tumor collagen solubility in DMBA-induced rat mammary tumors

Estradiol plays a vital role in the growth and development of mammary glands. It is a potent stimulator of metabolic processes in normal and carcinoma breast. A critical factor in determining mammary glandular morphology is the stroma. Collagen is a predominant component of the extracellular matrix and cell-collagen interactions are essential carcinogenesis. The present investigation explored the influence of estradiol on collagen solubility and metabolism in mammary tumors during tumor progression and regression. A single injection of 20 mg of 9,10-dimethyl-1,2-benzanthracene was given to rats at 7 weeks of age. With the appearance of the first palpable mammary tumor, the rats were treated with 0.5 microg estradiol or 50 microg tamoxifen daily for 30 days. The rats were sacrificed 24 h after 30 days of treatment. Estradiol appears to stimulate the synthesis of new collagens and thus contributes to the enlargement of the mammary tumors. This might have created a potential microenvironment by increasing the synthesis of suitable matrix that sustains the growth of the mammary tumors. In short, the present findings emphasize a definite mediatory role for collagen in estradiol promoted mammary tumor growth.     

Reproductive and teratogenic effects of fentanyl in Sprague-Dawley rats

Female Sprague-Dawley rats were administered fentanyl continuously using chronically implanted osmotic minipumps for 2 weeks before breeding and during the entire period of pregnancy. Three different fentanyl dosage regimens were employed, i.e., 10, 100, and 500 micrograms/kg/day. Reproductive indices were determined and the 1,046 offspring delivered at cesarean section were examined for external, visceral, and skeletal abnormalities. There were no major or minor reproductive abnormalities or teratogenic findings in any of the fentanyl-treated groups. We conclude that fentanyl is devoid of adverse reproductive effects in this strain of rats up to dosages of 500 micrograms/kg/day administered by osmotic minipumps. From a methodologic point of view, osmotic minipumps facilitate study of the reproductive effects of narcotics as they allow delivery of dosages that ordinarily would not be tolerated without producing severe respiratory depression.     

Inhibitory effect of combined treatment with the aromatase inhibitor exemestane and tamoxifen on DMBA-induced mammary tumors in rats

The antitumor effect of exemestane (FCE 24304), an irreversible aromatase inhibitor, given alone or in combination with tamoxifen, was investigated in rats with 7, 12-dimethylbenzanthracene (DMBA)-induced mammary tumors. The compounds were given once daily, 6 days a week for 4 weeks. Exemestane, given at the dose of 20 mg/kg/day s.c., induced 26% complete (CR) and 18% partial (PR) tumor regressions, compared to 0% CR and 6% PR observed in controls. Tamoxifen, given at 1 mg/kg/day p.o., induced 16% CR and 13% PR. The combined treatment caused 41% CR and 16% PR, thus resulting in a higher antitumor effect than either single treatment. The apperance of new tumors was reduced by each single treatment and almost totally prevented by the combined treatment. Serum prolactin (PRL) levels, assayed 4 h after the last dose, were unchanged in the group treated with the combination, whereas tamoxifen alone caused a slight increase of serum PRL. These results indicate that estrogen deprivation through aromatase inhibition and estrogen receptor antagonism causes a better inhibition of DMBA-induced mammary tumors than either treatment modality alone.     

Preventive effects of phenoxybenzamine on nitrous oxide-induced reproductive toxicity in Sprague-Dawley rats

In previous studies, we have shown that the reproductive toxicity of N2O in rats is prevented by the co-administration of either halothane or isoflurane, whereas treatment with folinic acid, which should reverse the effects of N2O on DNA production, does not prevent toxicity. These results cast doubt on the commonly held theory that inactivation of methionine synthase is the sole cause of N2O-induced reproductive toxicity, and suggest the need for other hypotheses. One such possibility is that N2O causes adverse reproductive toxicity secondary to its sympathomimetic effects. As a first step to test this theory, we studied the effects of phenoxybenzamine (PX), an alpha-1 adrenergic antagonist, on N2O-induced reproductive toxicity using a well-established in vivo rat model. On day 8 of gestation (plug day = day 0), 130 timed-pregnant Sprague-Dawley rats were injected s.c. with either 0.5 ml of either 0.9% saline (control and N2O alone groups) or PX (0.5, 5, or 50 micrograms/kg) in 0.9% saline, the latter the maximum tolerated PX dose. They were then exposed to either air (control) or 60% N2O for 24 hours (all other groups). On day 20 of gestation, cesarean sections were performed and the fetuses were removed and examined for either visceral of skeletal abnormalities. Compared with control, treatment with N2O alone resulted in increased incidences of fetal resorptions, major and minor visceral abnormalities, and minor skeletal abnormalities.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of estrogen treatment on DMBA-induced mammary tumor growth and biochemistry in intact and diabetic rats (38535).

Sixty percent of DMBA-induced mammary tumors in Sprage-Dawley rats regress after the animals were made diabetic by treatment with streptozotocin. Administration of estradiol valerate, 1 mg/wk/animal, caused regression of 75% of tumors in intact rats but regression of all tumors in diabetic rats. Estrogen treatment appeared to enhance the effects of diabetes, which by itself resulted in decreased activities of glycolytic enzymes. A role of insulin in growth of DMBA-induced mammary tumors may be warranted.     

In utero morphological effects of hydroxyurea on the fetal development in Sprague-Dawley rats

In order to investigate in utero morphological effect of hydroxyurea (HU) in Sprague-Dawley rats, HU was intraperitoneally injected to pregnant Sprague-Dawley rats at a dose of 100 or 200 mg/kg/day during the organogenetic period (days 9-12 of gestation). A dose of 200 mg/kg/day induced growth retardation, high mortality and high incidence of malformations, although a dose of 100 mg/kg/day produced no adverse effects in the next generation. In the HU 200 mg/kg/day group the incidence of malformations in pups at 4 days of age was low as compared with that in fetuses and pups at 21 days of age. Increasing perinatal mortality in fetuses and pups due to severe central nervous system (CNS) malformations and disappearance of some cases of ventricular septal defect after delivery were considered as the possible causes to induce difference in malformation rate in various stage of development. Latent effect on the development of CNS malformations was observed between 4 and 21 days of age. There was no sex difference in teratogenic effect. These findings were compared with those in Wistar rats exposed to HU 200 mg/kg/day. The incidence of perinatal malformations and the stillbirths were significantly higher in the Wistar rats as compared with those in the Sprague-Dawley rats. In addition, such morphological effects of HU as the exencephaly, dilatation of lateral ventricle, anophthalmia, cleft palate and micrognathia are less severe in Sprague-Dawley rat fetuses than in Wistar rat fetuses.     

Long-term metabolic effects of different doses of niacin-bound chromium on Sprague-Dawley rats

We simultaneously assessed benefits and risks of niacin-bound chromium (NBC) intake at varying doses over a prolonged period of time (>1.2 years) in male and female Sprague-Dawley (SD) rats. We performed the study in two phases. First, we followed 60 male and 60 female SD rats, each gender divided into six groups. Through day 150 (phase 1A), all SD rats received a high sucrose diet (30% w/w) with or without different concentrations of NBC. The male/female groups were: 1] control without NBC n = 10, 2] low NBC (2.8 ppm, n = 10), 3] medium NBC (8.7 ppm, n = 20), 4] high NBC (28.0 ppm, n = 20). Based on dosing, we refer to the three treatment groups as 1X, 3X, and 10X. During days 151–312 (phase 1B), NBC was removed from diets of one half of the 3X and 10X groups. These are referred to as 3X satellite and 10X satellite. In phase 2 (days 313–460), males from groups 1X, 3X, 10X, 3X satellite, and 10X satellite received the same 3X dose of NBC (8.7 ppm). The last two groups also ingested different doses of a formulation of natural products in addition to NBC. We examined blood pressure, the renin–angiotensin system (RAS), nitric oxide (NO), and insulin systems and inflammatory parameters. Results in male and female SD rats were comparable. NBC lowered systolic blood pressure (SBP) in a dose-dependent fashion; however, after 200 days, the SBP of the low dose group (1X) began to rise and returned to baseline control. After raising the dose of NBC to 3X, the SBP in the 1X group decreased significantly once more. When half the test rats (3X and 10X) were deprived of NBC, SBP rose gradually to control levels after 2 to 3 months. However, the SBP decreased significantly once more when each satellite group returned to the 3X dose. Special testing suggests that NBC at adequate dosing increases insulin sensitivity, lowers HbA1C, decreases activity of the RAS, at least in part, through ACE inhibition, enhances NO activity, and is without signs of toxicity. The addition of a formula composed of antioxidants and immune modulators to the chromium regimen caused even faster and more profound changes in SBP than with NBC alone. We conclude that NBC at adequate dosing is effective in male and female SD rats on certain metabolic parameters over a prolonged period, effects that disappear over months after NBC is removed. When dosing is returned, the effectiveness of NBC returns. Low doses of NBC may lose their effect over time. No signs of toxicity were observed.     

The effects of spaceflight on mammary metabolism in pregnant rats.

The effects of spaceflight on mammary metabolism of 10 pregnant rats was measured on Day 20 of pregnancy and after parturition. Rats were flown on the space shuttle from Day 11 through Day 20 of pregnancy. After their return to earth, glucose oxidation to carbon dioxide increased 43% (P < 0.05), and incorporation into fatty acids increased 300% (P < 0.005) compared to controls. It is unclear whether the enhanced glucose use is due to spaceflight or a response to landing. Casein mRNA and gross histology were not altered at Day 20 of pregnancy. Six rats gave birth (on Day 22 to 23 of pregnancy) and mammary metabolic activity was measured immediately postpartum. The earlier effects of spaceflight were no longer apparent. There was also no difference in expression of beta-casein mRNA. It is clear from these studies that spaceflight does not impair the normal development of the mammary gland, its ability to use glucose, nor the ability to express mRNA for a major milk protein.     

Orchidectomy attenuates impaired endothelial effects of a high-salt diet in Sprague-Dawley rats

The effect of sex hormones on vascular reactivity is considered one of the underlying factors contributing to gender differences in cardiovascular functions and diseases. Experiments were designed to investigate the role of androgens in salt-induced hypertension by assessing the relaxation response of isolated aortic rings to acetylcholine and sodium nitroprusside in the presence or absence of l-nitroarginine methyl ester in Sprague-Dawley rats. The rats were either orchidectomized or sham-operated, with or without testosterone replacement, and were placed on a normal or high-salt diet for 6?weeks. The results indicate a significant increase (p?< 0.001) in the mean arterial blood pressure of rats on the high-salt diet, when compared with control or orchidectomized rats. Orchidectomy elicited a reduction in mean arterial blood pressure (p?< 0.01), while testosterone replacement normalized mean arterial blood pressure to values seen in intact rats on the high-salt diet. The high-salt diet reduced the relaxation response to acetylcholine both in the presence and absence of inhibition of endothelial nitric oxide synthase with l-nitroarginine methyl ester. Bilateral orchidectomy attenuated the impaired endothelial function induced by the high-salt diet in rats, but this was reversed by concomitant administration of testosterone, suggesting a role for androgens in enhancing long-term vascular smooth muscle tone and hence maintenance of high blood pressure in salt-induced hypertension.     

Metabonomic studies on the physiological effects of acute and chronic psychological stress in Sprague-Dawley rats

The biochemical effects of acute and chronic psychological stress have been investigated in male Sprague-Dawley rats using a combination of 1H NMR spectral analysis of plasma and conventional hematological analyses. Animals were subjected to 35 consecutive days of 6-h sessions of stress, and following a 9 day break, were stressed for a further 6-h period. Plasma samples were collected at 0, 1, 3, and 6 h on days 1, 9, 21, 35, and 44, measured using 600 MHz 1H NMR spectroscopy, and analyzed by Principal Components Analysis. Time-dependent biochemical effects of psychological stress on a range of endogenous metabolites were evident and were correlated with the intensity of the stress response as defined by corticosterone and hematological parameters. Following acute stress, increases in the levels of glucose and ketone bodies, and decreases in the levels of acetate, alanine, isoleucine, lactate, leucine, valine, and lipoproteins, were observed. Chronic stress-induced increases in plasma levels of alanine, lactate (day 9), and leucine, valine, and choline (day 44) and decreases in acetate (day 9) and lipoprotein concentrations were observed. Positive correlations between plasma corticosterone level and glucose and glycerol, and between plasma lipoprotein concentrations and hemoglobin levels, were established using Projection to Latent Structures (PLS) analysis. This study indicates the potential of using NMR-based metabonomic strategies for the characterization of endogenous metabolic perturbations induced by psychological stressors and lifestyle choices.