芍药苷对大鼠低氧性肺动脉高压的防治作用及其抗氧化机制研究

目的 研究芍药苷对低氧诱导的肺动脉高压大鼠模型的作用并初步探讨其作用机制。方法 60只SD大鼠随机分为6组,每组10只,分别为：对照组（等体积生理盐水,ig）、模型组（等体积生理盐水,ig）、阳性对照组（西地那非25 mg/kg,ig）、芍药苷低、中、高剂量组（20、40、80 mg/kg,ig）。对照组大鼠置于正常环境中饲养,其余各组均于给药0.5 h后置于全自动低压低氧舱内（大气压50 kPa,氧浓度10%）,每天8 h,持续21 d。在实验终点时检测各组大鼠平均肺动脉压（mPAP）、平均颈动脉压（mCAP）、右心室肥厚指数（RVHI）及观察肺动脉病理变化;检测血浆内皮素（ET-1）、血清一氧化氮（NO）水平;检测肺组织匀浆超氧化物歧化酶（SOD）、过氧化氢酶（CAT）、谷胱甘肽过氧化物酶（GSH-Px）活性、丙二醛（MDA）含量。结果 与对照组比较,模型组大鼠mPAP、RVHI、血浆ET-1水平、肺组织中MDA含量显著升高（P＜0.01）,血清中NO水平、肺组织中SOD、CAT、GSH-Px活性显著降低（P＜0.01）,HE染色显示大鼠肺小动脉管壁明显增厚,管腔狭窄。与模型组比较,芍药苷中、高剂量组大鼠mPAP、RVHI、血浆ET-1水平、肺组织中MDA含量显著降低（P＜0.05或P＜0.01）,血清中NO水平、肺组织中SOD、CAT、GSH-Px活性显著升高（P＜0.05或P＜0.01）;HE染色显示不同剂量芍药苷干预后,大鼠肺小动脉管壁增厚和管腔狭窄均不同程度减轻。结论 芍药苷可降低低氧诱导的大鼠肺动脉高压与右心室肥厚程度,减轻肺小动脉血管重塑,其机制可能与降低大鼠血浆ET-1水平、升高血清NO水平,改善血管内皮舒缩因子失衡,提高大鼠肺组织匀浆中SOD、CAT、GSH-Px活性、降低MDA含量,减轻大鼠肺组织氧化应激损伤有关。     

Liver and colon DNA oxidative damage and gene expression profiles of rats fed Arabidopsis thaliana mutant seeds containing contrasted flavonoids.

Plant polyphenols, such as flavonoids, comprise many compounds, ranging from simple phenolic molecules (i.e. flavonols, anthocyanins) to polymeric structures with high molecular weight (as proanthocyanidins, PAs). We investigated the effects of flavonoids by feeding Wistar rats Arabidopsis thaliana seeds carrying mutations in key enzymes of the flavonoid biosynthetic pathway (15% w/w seeds for 4 weeks). The seeds used were: Ws-2 wild-type containing flavonols and PAs, tt3-4 mutant containing flavonols only, ban-5 accumulating flavonols and anthocyanins, tt4-8 mutant, deprived of flavonoids. DNA oxidative damage was significantly reduced only in the liver of rats fed tt3-4 mutant seeds. Microarray analysis of the liver revealed down-regulation of genes associated with oxidative stress, Krebs cycle, electron transport and proteasome degradation in all experimental groups compared to the tt4-8-fed reference rats; therefore, these effects were due to the flavonol content and not to high molecular weight compounds. We observed a down-regulation of inflammatory response genes in the colon mucosa in ban-5- fed rats, probably due to anthocyanin content. In conclusion, flavonols exhibited antioxidant effects at systemic level, whereas high molecular weight flavonoids affected only the colon, probably due to their limited absorption.     

Nitrogen Deficits in Aroclor 1254-Treated Rats

Nitrogen Deficits in Aroclor 1254-Treated Rats. EBNER, K. V.,BERGEN, W. G., and BRASELTON, W. E., Jr. (1987). Fundam. Appl.Toxicol. 8, 89–96. Nitrogen balance and the efficiencyof retaining assimilated dietary nitrogen (biological value)were evaluated in Aroclor 1254-treated (ARO) rats and in vehicle-treated,pair-fed (PF) and ad libitum-fed (AF) rats (150–190 g).ARO-treated rats (300 mg/kg/day, po on 4 consecutive days) lostweight and consumed less chow than the AF group while the weightof the PF rats was not different from those of either the AROor AF groups. The nitrogen balance and the biological valuefor the ARO rats were also significantly less than those ofthe AF rats whereas the PF controls were not different. Theingested calories (expressed in kcal/(kg body wt)^0.73) by theARO and PF rats were equal, but were less than those of theAF group. The ARO and PF groups excreted the same amounts offecal nitrogen which were less than the fecal nitrogen excretionby the AF rats. The absorbed fraction of the ingested nitrogenwas the same among all groups, which indicated that the digestibilityand absorption of the dietary nitrogen were not changed. Bycontrast, the ARO group excreted the same amount of urinarynitrogen and urea as AF rats while the PF group excreted significantlyless urinary nitrogen than the latter controls. Thus, the lossof nitrogen by the ARO group was attributed to increased excretionof urinary nitrogen, most likely as urea, in relation to thenitrogen intake. The nitrogen retention and balance in ratswith ARO exposure are similar to the response in rats fed adiet of low biological value except that the influence of AROon nitrogen metabolism occurred during the postabsorption phase.     

Flax and Pumpkin seeds mixture ameliorates diabetic nephropathy in rats

This study investigated the hypoglycemic and antioxidant effects of Flax and Pumpkin seeds mixture on the kidney of alloxan-induced diabetic rats. Animals were allocated into three groups of six rats each: a control group (CD), a diabetic group (DD) and diabetic rats fed with Flax and Pumpkin seeds mixture (DMS) group. The DD rats showed a significant increase of glycemia and lipid parameters such as total lipid, total cholesterol and triglycerides levels compared to those of the control group (CD). In addition, plasma and kidney malonaldialdehyde levels (MDA) were significantly increased compared to (CD) group. Antioxidant enzyme activities such as catalase (CAT), superoxide dismutase (SOD) and non-enzymatic levels of reduced glutathione (GSH) significantly decreased in the plasma and kidney of diabetic rats compared to those of controls. Diet supplemented with Flax and Pumpkin seeds mixture ameliorated the antioxidant enzymes activities observed in diabetic rats and significantly decreased MDA levels. Kidney histological sections, showed glomerular hypertrophy and tubular dilatation. In DMS rats, these histopathological changes were less prominent. Our results suggest that Flax and Pumpkin seeds mixture supplemented in diet of diabetic rats may be helpful to prevent diabetes and its complications.     

Modulation by dietary factors of BHA-induced alterations in cell kinetics of gastro-intestinal tract tissues in rats.

To determine the effects of dietary ethanol or fibre on 2(3)-tert-butyl-4-hydroxyanisole (BHA)-induced alterations in cell kinetics in gastro-intestinal tract tissues, groups of six male Wistar rats were fed diets containing 0% (control) or 1.5% BHA for 2 wk. One group fed 1.5% BHA and one pair-fed control group received 10% ethanol in the drinking-water; two similarly fed groups received drinking-water only. Another group fed 1.5% BHA and a pair-fed control group received a diet supplemented with 20% cellulose; two similar groups received no fibre supplementation. Cell kinetics in the forestomach, glandular stomach and oesophageal tissue were determined, after 14 days, by bivariate 5-bromo-deoxyuridine/DNA analysis using immunocytochemistry and flow cytometry. In the fibre experiment, colorectal tissue was also examined. In both experiments the labelling indices in all the gastro-intestinal tract tissues were significantly altered in the BHA-fed groups compared with the corresponding control groups. In the ethanol experiment no statistically significant difference in the labelling indices was observed in the forestomach or glandular stomach between the two control groups or between the two BHA-fed groups. However, intake of ethanol-supplemented drinking-water induced increases in oesophageal labelling indices in rats fed a BHA-free diet. Thus 14 days of simultaneous ethanol administration has no effect on BHA-induced alterations in cell kinetics in the oesophagus, glandular stomach or forestomach of rats. In the forestomach and colorectal tissue, a high-cellulose diet resulted in a significant decrease in the BHA-induced elevation of labelling indices. Thus dietary cellulose provides a partial protection against the proliferation-enhancing effects of BHA in the rat gastro-intestinal tract.     

The effect of dietary administration of Disperse Blue 1 on the urinary system of the Fischer 344 rat

Disperse Blue 1 (containing 50% lignosulphonate dispersants) was fed to Fischer 344 rats at dietary levels of 0.01 and 0.1% for 19 months and at 1.0% for 6 months. Fischer 344 rats were also given the dye by gavage at 1 g/kg for 1-3 days or in the diet at 0.5 or 1% for 4 days, and corresponding dietary levels of the colouring without dispersant were also fed for 4 days. Bladders and kidneys were examined after the 1-4 day treatments, in animals dying or killed from month 6 to termination (19 months) in the chronic study and in those killed at wk 5, 9 and 17. At the latter three times, autoradiography following injection of tritiated thymidine showed increased DNA synthesis in the urothelium of high-dose rats, but no other increased labelling in any group. Bladder lesions were seen only at the 1.0% level, epithelial erosion with adhering dye particles being seen by day 4, calculi and hyperplasia by wk 5 and squamous metaplasia by wk 9. The calculi contained more dye in males than in females and more calcium in females. By month 6, dye particles were embedded in the bladder wall, with some evidence of histiocyte accumulation in their vicinity. Two papillomas and one carcinoma, but no leiomyosarcomas, were diagnosed. The earliest tumours, two papillomas, were detected at wk 17. Tumour incidence following surgical removal of calculus was about double that in rats not subjected to surgery and the incidence of normal bladders at month 19 was higher in the latter group. Compound-related effects in the kidneys--inflammation, pelvic epithelial hyperplasia and tubular degeneration and regeneration with interstitial fibrosis--were seen only in the high-dose group. Dye present in the tubules and renal pelvis persisted in many rats for a year after cessation of treatment.     

Effect of food restriction on hepatotoxicity of carbon tetrachloride in rats

Five-week-old Sprague-Dawley rats of both sexes were assigned to two types of feeding condition. One was fed ad libitum (AL) on commercial chow and another was fed a restricted amount of the chow (FR), approximately 75% of that fed in the AL condition. In each feeding condition, animals were orally administered carbon tetrachloride (CCl4) at levels of 0 (control), 0.1 or 0.2 ml/kg 6 days a week for 8 weeks. Lesions of the liver (hepatic cellular degeneration and fibrosis) and of the kidney (proximal tubular vacuolation and glomerular sclerosis) induced by CCl4 were aggravated in the FR group. The FR-control showed a higher metabolic activity of aniline in the liver than the AL-control group. Plasma lipid-peroxide (LPO) level was higher in the AL-control group than in the FR-control group. With CCl4 0.2 ml/kg treatment, however, the plasma LPO level was reversed between the AL and the FR groups. Taking together these somewhat unexpected results, it was concluded that (1) 25% food restriction increases toxicity of repeatedly administered CCl4 in rats, and (2) aggravation of CCl4 toxicity may be partly due to enhanced metabolic activation of CCl4 resulting from food restriction.     

地黄寡糖对二型糖尿病大鼠糖脂代谢及肝脏超微结构的影响

目的 观察地黄寡糖对2型糖尿病大鼠糖脂代谢的影响及肝脏的保护作用。方法 取♂SD大鼠用高脂高糖饲料喂养8周后,腹腔注射链脲佐菌素25 mg·kg^-1制备糖尿病大鼠模型,造模成功后随机分组为：糖尿病模型组、地黄寡糖高剂量组、地黄寡糖中剂量组、地黄寡糖低剂量组、二甲双胍组,每组10只;另取8只用普通大鼠饲料喂养8周后,腹腔注射等体积柠檬酸-柠檬酸钠缓冲液,作正常对照组。在第0,2,4,8周末各测定一次空腹血糖(FBG);第8周末测定血清甘油三酯(TG)、总胆固醇(TC)、低密度脂蛋白(LDL-C)、高密度脂蛋白(HDL-C)、和空腹血清胰岛素(FINS);实验结束处死大鼠,取肝组织检测谷胱甘肽过氧化物酶(GSH-Px)、超氧化物歧化酶(SOD)活性和丙二醛(MDA)水平;HE染色后光镜观察肝脏病理变化;透射电镜观察肝脏超微结构的改变。结果 与糖尿病模型组比较,地黄寡糖中、高剂量组FBG、TG、TC、LDL-C、FINS水平均明显降低,HDL-C升高(P<0.05);糖尿病大鼠肝组织氧化应激水平增高,地黄寡糖中、高剂量组糖尿病大鼠SOD、GSH-Px活性均显著增加,MDA水平显著下降;HE染色显示,各地黄寡糖治疗组大鼠肝细胞脂肪变性明显减少,肝细胞排列基本规则。透射电镜结果显示,地黄寡糖高剂量组大部分线粒体结构清晰内质网完整。结论 地黄寡糖可降低糖尿病大鼠血糖、血脂,减轻肝细胞脂肪变性,从而达到保护肝脏的作用,其作用机制可能与其增强肝组织抗氧化作用,减缓糖尿病对肝组织的损伤有关。     

Biological effects of short-term feeding to rats of repeatedly used deep-frying fats in relation to fat mutagen content

The effects of short-term feeding of mutagen containing, heated deep-frying oils on urinary and faecal mutagenicity, plasma clinical biochemical parameters, peroxidative effects and cell proliferative indices in the gastro-intestinal tract were determined in rats. Repeatedly used frying oils [a saturated fatty acid-rich coconut oil (CO) and a polyunsaturated fatty acid (PUFA)-rich (greater than 60% PUFA) vegetable frying oil (PO)] were administered to groups of seven rats at a level of 10% (by weight) in the diet for 4 wk; control groups were fed equal amounts of the unheated oils. Both heated oils showed direct-acting mutagenicity to Salmonella tester strain TA97; heated PO was also mutagenic to strain TA100. Both heated CO and heated PO contained detectable amounts of thiobarbituric acid-reactive substances (TBA-RS). In heated PO, hydroperoxides of linoleic acid were also present. In groups fed heated oils the mutagenicity of urine and faeces to strain TA97 was not found to be increased in comparison with the control groups. Faecal mutagenicity to strain TA100 was also unaffected by consumption of heated oils. Urinary excretion of TA100 mutagens was significantly increased in rats fed heated PO. Plasma alkaline phosphatase activity was clearly raised in rats fed heated PO, in comparison with rats fed unheated oils or heated CO. In addition, other clinical biochemical plasma parameters showed a tendency to be increased in rats fed heated PO, indicating hepatic and renal cellular toxicity. Urinary and faecal excretion of thiobarbituric acid-reactive substances (TBA-RS) were also slightly, but not significantly, increased in rats fed heated PO. Feeding heated CO to rats did not result in increased plasma enzyme activities and excretion of TBA-RS, nor in increased cell proliferation in gastro-intestinal tissues. Cell proliferation of the oesophageal tissues were slightly, but significantly, increased in rats fed heated PO, in comparison with the group fed unheated PO. Tissues of the glandular stomach and colon/rectum did not show significantly enhanced cell proliferation in the group fed heated PO. The results obtained in this study indicated that consumption of heated oils containing TA100 mutagens and oxidation products of linoleic acid produced indications of cellular damage to liver and kidneys, and increased urine mutagenicity, as well as enhanced cell proliferation in the oesophagus.     

Hypolipidemic and hepatoprotective effects of flax and pumpkin seed mixture rich in ω-3 and ω-6 fatty acids in hypercholesterolemic rats

Flax and pumpkin seeds are a rich source of unsaturated fatty acids, antioxidants and fibers, known to have anti-atherogenic and hepatoprotective activities. These effects were evaluated in Wistar rats fed with 1% cholesterol diet. The study was performed on 30 male rats divided into three groups: a control group (CD), CD-chol group fed diet with 1% cholesterol and MS-chol group fed diet enriched with flax and pumpkin seed mixture. In CD-chol group, total cholesterol TC, triacylglycerol TG in plasma and liver, plasma LDL-C, atherogenic index AI and LDL/HDL ratio significantly increased. In MS-chol group lipid parameters decreased significantly, plasma and liver fatty acid composition showed an increase of PUFAs (ALA and LA), and MUFAs (oleic and eicosaenoic acid) and a decrease of SFA (palmitic and stearic acid). In plasma and liver of MS-chol group, malondialdehyde levels decreased and the efficiency of antioxidant defense system was improved compared to CD-chol group. Liver histological sections showed lipid storage in hepatocytes of CD-chol group and an improvement was noted in MS-chol group. Our results suggested that flax and pumpkin seed mixture had anti-atherogenic and hepatoprotective effects which were probably mediated by unsaturated fatty acids present in seed mixture.     

Influence of corn oil and diet on reproduction and the kidney in female Sprague-Dawley rats.

The purpose of this study was to investigate the influence of corn oil administration on gestation, parturition, and lactation in rats, in conjunction with diets differing in composition of nutrients. Rats were divided into two groups, each fed different commercial pellets for rodents, CA-1 or CE-2, different from each other mainly in the source of protein. Female Sprague-Dawley rats in both diet groups were administered 0 (untreated control), 2, or 10 ml corn oil/kg body weight by gavage during the premating period (2 weeks), the mating period, the gestation period, and the lactation period (until day 3 of lactation). Food consumption of both the 10 ml/kg corn oil groups was significantly reduced throughout the study. Body weight gain in the 10 ml/kg corn oil group fed the CA-1 diet was significantly reduced on days 0 through 4 of lactation. Neither mating nor fertility indices were affected, and no clinical signs were observed during the gestation period in any groups. Several dams in the 10 ml/kg corn oil group fed the CA-1 diet, however, showed abnormal conditions after parturition, and three dams became moribund. Pup viability was also reduced in this group. Histopathologic examination of the kidneys of dams in the 10 ml/kg corn oil group fed the CA-1 diet revealed severe lesions in the proximal tubular epithelium, i.e., necrosis and fatty degeneration. Females in any group fed the CE-2 diet showed neither abnormal condition after parturition nor any severe lesions in the kidney. These data show that the combination of corn oil and diet with a particular constitution may cause adverse effects on the renal tubules in pregnant and/or lactating rats, suggesting that corn oil gavage as a vehicle can be a confounding factor in the reproductive toxicity studies, depending on the diet.     

Promotion of thyroid carcinogenesis by para-aminobenzoic acid in rats initiated with N-bis(2-hydroxypropyl)nitrosamine.

Sulfonamide analogues of para-aminobenzoic acid (PABA), a precursor of folate synthesis, have beneficial effects as antifolate, but thyroid peroxidase inhibition has been reported as a side effect that results in promotion of rat thyroid carcinogenesis. In the present study, effects of PABA itself on F344 rat thyroid carcinogenesis after initiation with N-bis(2-hydroxypropyl)nitrosamine (DHPN) were evaluated. In experiment 1, rats in groups 1-4 received a single subcutaneous injection of DHPN at 2800 mg/kg, and groups 5 and 6 received vehicle saline alone. From 1 week after DHPN initiation, rats in groups 2, 3, 4, and 6 were fed basal diet containing 0.25%, 0.5%, 1.0%, and 1.0% PABA, respectively, for 40 weeks. Rats in groups 1 and 5 received basal diet alone throughout the experiment. The final incidence of thyroid follicular cell adenomas and adenocarcinomas was significantly (p < 0.05 or 0.01) increased in groups 3 and 4 as compared to group 1. No thyroid tumors were found in groups 5 and 6. In experiment 2, animals in group 1 were fed basal diet alone, while groups 2 and 3 were given 0.5% and 1.0% PABA in the diet, respectively, for 2 weeks. Thyroid weights in group 3, and serum thyroid stimulating hormone level and proliferative activity of follicular cells in groups 2 and 3 were significantly (p < 0.05 or 0.01) elevated. In addition, the serum thyroxine level in group 3 was significantly (p < 0.05) depressed. These results clearly indicate that PABA exerts promotion/progression effects on rat thyroid carcinogenesis as a result of hypothyroidism followed by negative-feedback via the thyroid-pituitary axis.     

Reward reductions found more aversive by rats fed environmentally contaminated salmon

Pacific salmon stocked in Lake Ontario concentrate persistent toxic chemicals such as PCBs, DDT, DDE, mercury and dioxin. The present experiments support earlier findings that consumption of these salmon by laboratory rats increases their behavioral reactions to negative events. For 20 days rats were fed a diet consisting of 30% Lake Ontario salmon or a control diet of Pacific Ocean salmon or no salmon. They were then trained to run down an alley to receive a large 15-pellet or small 1-pellet food reward (6 trials/day). Following 72 trials the 15-pellet groups were shifted to 1 pellet for 90 trials, and showed a contrast (depression) effect: they ran more slowly than the groups always given 1 pellet. Rats previously fed Lake Ontario salmon showed a much larger contrast effect than the two control groups. These results were replicated in a second experiment, and a group fed a 10% diet of Lake Ontario salmon for 60 days showed the same size contrast effect as the group fed a 30% diet for 20 days.     

Pathological-anatomical results on the effect of coumarin in animal experiments (author's transl)

Pathological-anatomical results on the effect of coumarin in animal experiments5 groups of rats were fed in chronic feeding studies extending over a period of up to 2 years a diet to which coumarin (1,2-benzopyrone) had been added in concentrations of 0.1% (group 1), 0.25% (group 3), 0.5% (group 2) or 0.6% (groups 4 and 5). The groups consisted of 20 male and 20 female rats of each of the groups 1 and 2, 25 male and 25 female rats of each of the groups 3 and 4 or 32 male rats of the group 5. Control rats: 40 rats to groups 1 and 2, 50 rats to group 3, 4 and 5. 14 rats from the group 2 which had received 0.5% coumarin in their diet and 25 rats from the two groups 4 and 5 that had been fed 0.6% coumarin survived until the end of the experimental period. In the group that had been fed 0.5% coumarin, 12 of the 14 surviving animals developed liver carcinomas; in the two groups that had received 0.6% coumarin, but with a reduced uptake of food, 5 of the 25 survivors had carcinomas. The rats in the groups fed 0.1% or 0.25% coumarin in their diet exhibited only some benign adenomas or proliferations of the bile ducts.Gross autopsy revealed a number of small to massive greyish-white tumours with a nodular and uneven surface in different areas of the liver. Microscopically, all carcinomas corresponded to an identical type — that of bile duct carcinoma. The histological findings are described in detail.     

The Effects of Puerariae Flos on Stress-induced Deficits of Learning and Memory in Ovariectomized Female Rats

Puerariae flos (PF) is a traditional oriental medicinal plant and has clinically been prescribed for a long time. The purpose of the present study was to examine the effect of PF on repeated stress-induced alterations of learning and memory on a Morris water maze (MWM) test in ovariectomized (OVX) female rats. The changes in the reactivity of the cholinergic system were assessed by measuring the immunoreactive neurons of choline acetyltransferase (ChAT) in the hippocampus after behavioral testing. The female rats were randomly divided into four groups: the nonoperated and nonstressed group (normal), the sham-operated and stressed group (control), the ovariectomized and stressed group (OS), and the ovariectomized, stressed and PF treated group (OSF). Rats were exposed to immobilization stress (IMO) for 14 d (2 h/d), and PF (400 mg/kg, p.o.) was administered 30 min before IMO stress. Results showed that treatments with PF caused significant reversals of the stress-induced deficits in learning and memory on a spatial memory task, and also increased the ChAT immunoreactivities. In conclusion, administration of PF improved spatial learning and memory in OVX rats, and PF may be useful for the treatment of postmenopausal-related dementia.     

Effects of continuous administration of dietary theobromine on rat testicular weight and morphology

Previous studies have shown that high dietary theobromine levels fed to rats results in testicular atrophy with changes in testicular cytology. An experiment was performed to determine whether these changes in rat testes are reversible. Proven breeder male rats were fed Purina lab chow containing 0, 0.2, 0.6, or 0.8% theobromine for 49 days. At that time, unilateral orchiectomy was performed on all rats. Testicular weights in the rats fed 0.6 and 0.8% theobromine-containing diets were significantly less than those from control rats and from rats fed 0.2% dietary theobromine (p < 0.01). The seminiferous tubules from rats fed the 0.6 or 0.8% theobromine diets showed extensive severe cellular degeneration and necrosis and contained many multinucleated cells. The interstitial tissue was edematous and there was evidence of apparent proliferation of arterioles. The rats were allowed to recover and were fed the diet without theobromine for an additional 49 days. Testicular weights of the rats given 0.6 and 0.8% dietary theobromine in the first 49-day period remained significantly below those of control rats and of rats fed 0.2% dietary theobromine (p < 0.01). Histologically, 70 to 90% of the seminiferous tubules from the rats given the two highest dietary levels of theobromine appeared almost deplete of well-formed spermatozoa. These results indicate that the theobromine-induced testicular injury appears to be irreversible over time in the affected seminiferous tubules.     

The effect of saccharin ingestion on the excretion of microbial amino acid metabolites in rat and man

Low dietary levels of sodium saccharin (0-2%) fed to male rats for 6 weeks produced a dose-related increase in the urinary excretion of p-cresol, a major microbial metabolite of tyrosine. Some animals fed higher levels of saccharin (5-7.5%) for 6 weeks excreted increased amounts of p-cresol, but many excreted negligible amounts so that the overall dose-response relationship was bell shaped. After 20 weeks of exposure, all rats in the higher dose groups showed increased p-cresol excretion and by 26 weeks the 7.5% saccharin group showed a 36-fold increase over animals fed the 0% saccharin diet. The urinary excretion of phenol, another microbial amino acid metabolite, was constant in animals fed dietary levels of saccharin below 2% for 6 weeks, but was virtually abolished at higher levels. The excretion of indican (formed from indole, a microbial metabolite of tryptophan) was increased by saccharin in a dose-related fashion at all time points, but showed only a 3-fold increase at 7.5% compared with the 0% group. p-Cresol may therefore prove more sensitive than indican as an indicator of altered microbial metabolism due to saccharin. In a separate study the effect of 7.5% saccharin on p-cresol and indican excretion was shown to be largely reversible and the excretion of phenol increased rapidly when saccharin was withdrawn from the diet. Chronic saccharin administration to man at high doses (1 g/day for 4 weeks) had no perceptible effect on the excretion of these three metabolites.     

Comparative toxicities of dietary caffeine and theobromine in the rat

Caffeine, incorporated into pulverized Purina Rat Chow at a concentration of 0.5%, was fed to male Sprague-Dawley rats for 7 or 8 wk and the effects were compared with those of 0.8% dietary theobromine, fed to male rats for 7 wk. Both dietary methylated xanthines produced significant decreases in food consumption and body-weight gain when compared to their respective control groups. Food consumption of caffeine-fed rats was 57.2% of controls and for theobromine-fed rats it was 77.9% of the respective controls. Theobromine produced significant decreases in thymus weights, with caffeine producing smaller decreases. The theobromine-fed rats showed severe testicular atrophy with extensive spermatogenic cell degeneration and necrosis, while the testes of rats fed caffeine for 7 or 8 wk showed only scattered vacuolar degeneration of spermatogenic cells. Caffeine appears to be more potent than theobromine as an anorexic agent in rats, but to be equivalent to theobromine in its potential for inducing thymic atrophy and spermatogenic cell destruction with testicular atrophy.     

The toxicity of Burttia prunoides in rats and goats

Studies of the toxicity of the leaves and seeds of the plant Burttia prunoides from Singida district of Tanzania were conducted in rats and goats. One group of rats was drenched with a decoction of powdered seeds or leaves while the other group was fed rations containing different proportions of powdered seeds or leaves. The goats were drenched with aqueous suspensions of powdered seeds or leaves. All animals were observed for behavioral changes and clinical signs. Leaves were not toxic to the rats or the goats. In rats the seeds induced a severe acute central nervous system (CNS) disorder and death and also a subacute syndrome characterized by emaciation and milder CNS signs. In goats the seeds induced a severe CNS disorder where unlike the rats the animals did recover. Postmortem findings in the rats included hemorrhage and inflammation of the glandular stomach and edema and congestion of the lungs, brain and mucosa of the gastrointestinal tract. The kidneys were congested and showed complete nephrosis of the proximal tubular epithelium. Livers were congested and had focal areas of necrosis. The findings in this study resemble those obtained in calves and sheep using the same plant.     

Toxicologic changes in rats fed graded dietary levels of ochratoxin A

In a short-term study, groups of weanling male rats were fed a semipurified diet containing 0, 2.4, 4.8, 9.6 or 24 ppm of ochratoxin A for a period of 2 weeks. Growth retardation and reduced food consumption were observed in rats fed 9.6 or 24 ppm but not in those fed 2.4 or 4.8 ppm of the compound. Rats fed 24 ppm of ochratoxin A had elevated serum blood urea nitrogen (BUN) values and significantly increased kidney weights accompanied by marked degenerative changes involving the entire tubular system. Similar, but less extensive, changes were noted in the 4.8 and 9.6 ppm groups. In a subacute study groups of 15 weanling male and female rats were fed a semipurified diet for 90 days containing 0, 0.2, 1.0 or 5.0 ppm of ochratoxin A. Body weight was significantly reduced in the 5.0 ppm group. In contrast to the short-term study, relative kidney weights were reduced in the 1.0 and 5.0 ppm groups, and the latter group had elevated BUN values. Dose-related pathologic changes were noted in the kidneys of all treated rats. In the 0.2 ppm group a few scattered cells in the proximal convoluted tubules underwent granular eosinophilic degeneration, and a few cells developed bizarre giant nuclei. At the higher doses, similar, but more extensive changes were observed.