Urothelial hyperplasia of the renal papillae in female Sprague-Dawley rats induced by long term feeding of phenacetin

Twenty-one of 40 rats fed phenacetin in the diet for up to 86 weeks developed urothelial hyperplasia of the renal papillae. Two of 30 rats in the control group had similar changes associated with chronic pyelitis. The difference is statistically significant (p less than 0.01).     

Tumorigenicity of sodium ascorbate in male rats

Sodium ascorbate, like other sodium salts such as saccharin, glutamate, and bicarbonate, produces urinary alterations when fed at high doses to rats, which results in mild superficial urothelial cytotoxicity and regeneration but not tumors in a standard 2-year bioassay. Sodium saccharin was shown to produce a low incidence of bladder tumors in rats if administered in a two-generation bioassay. In the present study, we evaluated sodium ascorbate in a two-generation bioassay that involved feeding to the male and female parental F344 rats for 4 weeks before mating, feeding the dams during gestation and lactation, and then feeding the weaned (at 28 days of age) male F1 generation rats for the remainder of their lifetime (up to 128 weeks of the experiment). Dietary levels of 1.0, 5.0, and 7.0% sodium ascorbate were tested. At 5.0 and 7.0% sodium ascorbate, there was an increase in urinary bladder urothelial papillary and nodular hyperplasia and the induction of a few papillomas and carcinomas. There was a dose-responsive increase in renal pelvic calcification and hyperplasia and inhibition of the aging nephropathy of rats even at the level of 1% sodium ascorbate. Because the short-term urothelial effects of sodium ascorbate in rats are inhibited by treatments producing urinary acidification to pH < 6.0, we coadministered high doses of long-term NH4Cl to groups of rats with 5.0 or 7.0% sodium ascorbate to evaluate the long-term effects. The combination of 7.0% sodium ascorbate plus 2.78% NH4Cl in the diet was toxic, and the group was terminated early during the course of the experiment. The group fed 5.0% sodium ascorbate plus 2.04% NH4Cl showed complete inhibition of the urothelial effects of sodium ascorbate and significant inhibition of its renal effects. We also demonstrated the presence of a calcium phosphate-containing urinary precipitate in rats fed sodium ascorbate at all doses, in a dose-responsive manner. The formation of the precipitate was inhibited by coadministration with NH4Cl. The proliferative effects of sodium ascorbate on the male rat urinary tract in this study are similar to those seen with sodium saccharin when administered in a two-generation bioassay. Mechanistic information suggests that this is a high-dose, rat-specific phenomenon.     

Human herpesvirus-8 glycoprotein B interacts with Epstein-Barr virus (EBV) glycoprotein 110 but fails to complement the infectivity of EBV mutants

ortho-Phenylphenol (OPP), a fungicide and antibacterial agent with food residues, is carcinogenic to rat bladder. The present studies provide information on changes in urinary composition and urinary metabolites, urothelial cytotoxicity and regenerative hyperplasia, and DNA adducts in male F344 rats fed OPP. An initial experiment evaluated dietary doses of 0, 1,000, 4,000, and 12,500 ppm OPP fed for 13 weeks. There was no evidence of urinary calculi, microcrystalluria, or calcium phosphate-containing precipitate, but urothelial cytotoxicity and hyperplasia occurred at the highest dose only. In a second experiment, rats were fed dietary OPP levels of 0, 800, 4,000, 8,000, and 12,500 ppm. Urinary pH was > 7 in all groups. Urinary volume was increased at the 2 highest doses with consequent decreases in osmolality, creatinine, and other solutes. Total urinary OPP metabolite excretions were increased, mostly excreted as conjugates of OPP and of phenylhydroquinone. Free OPP or free metabolites accounted for less than 2% excreted in the urine without a dose response. Urothelial toxicity and hyperplasia occurred only at doses of 8,000 and 12,500 ppm. OPP-DNA adducts were not detected in the urothelium at any dose. In summary, OPP produces cytotoxicity and proliferation of the urothelium at dietary doses > or = 8,000 ppm without formation of urinary solids. The paucity of unconjugated metabolites and the lack of OPP-DNA adducts suggests that OPP is acting as a bladder carcinogen in male rats by inducing cytotoxicity and hyperplasia without it or its metabolites directly binding to DNA.     

Bladder tumor associated with phenacetin abuse

The association between phenacetin abuse and renal papillary necrosis is widely known. Recently, reports in the European literature indicated a possible correlation between phenacetin abuse and the development of transitional cell carcinoma of the renal pelvis and bladder. A case of transitional cell carcinoma associated with phenacetin abuse is presented. The pharmacology of phenacetin metabolites is discussed, and the world literature is reviewed. The data available warrant careful reappraisal of the ready availability of phenacetin.     

A risk characterization for atrazine: oncogenicity profile

An extensive safety database has been developed for the chlorotriazine herbicide, atrazine. The results from five oncogenicity studies conducted in the Sprague-Dawley rat, two studies in the Fischer 344 rat, and two studies in the CD-1 mouse were reviewed. No increase in the incidence of tumors of any type was observed in male or female Fischer 344 rats, male or female CD-1 mice, or male Sprague-Dawley rats fed atrazine at a maximum tolerated level in their diet for 24 mo. Female Sprague-Dawley rats fed atrazine at levels of 400, 500, and 1000 ppm developed mammary tumors earlier than did the control group. The incidence of female Sprague-Dawley rats with mammary tumors after 24 mo of treatment was statistically increased at feeding levels of > or = 70 ppm in 1 study and at 400 ppm in a second study, whereas there were no significant differences between the treated and the control group in 3 other studies. No increase in tumors of any type was observed in ovariectomized female Sprague-Dawley rats after 24 mo of atrazine treatment at the highest level tested, 400 ppm. Therefore, the mammary tumor response in female Sprague-Dawley rats following the administration of high levels of atrazine appears to be due to an acceleration of the normal reproductive aging process resulting in increased exposure to endogenous estrogen and prolactin. The Sprague-Dawley rat differs from the Fischer 344 rat, the CD-1 mouse, and humans in the endocrine control mechanisms affecting reproductive senescence and the development of the mammary tumors during aging. These data indicate that the carcinogenic effect of high doses of atrazine observed in the female Sprague-Dawley is a strain-, sex-, and tissue-specific response that does not have biological relevance to humans.     

The effect of dietary flaxseed supplementation on organic anion and osmolyte content and excretion in rat polycystic kidney disease

Progression of chronic renal failure in the Han:SPRD-cy rat polycystic kidney disease is associated with renal depletion of citric acid cycle metabolites and betaine. Amelioration of this disease by a soy protein diet is associated with retention of citric acid cycle anions, despite increased excretion, and preservation of tissue levels of betaine. As we have recently found that modest dietary supplementation with flaxseed preserves renal function and reduces histologic injury in the Han:SPRD-cy rat, we undertook a high-resolution 1H NMR spectroscopic study of urine and renal tissue extracts from Han:SPRD-cy rats to explore the renal biochemical consequences of a flaxseed diet. There was no significant dietary effect upon organic anion, methylamine, or osmolyte excretion in healthy animals. There was increased citrate excretion in Han:SPRD-cy rats fed flaxseed. Urinary ammonium excretion did not differ, suggesting that the observed increase in citrate excretion was not due to an alkaline effect of diet. Tissue extract studies revealed that disease amelioration was associated with tissue retention of succinate and betaine. Amelioration of Han:SPRD-cy rat polycystic kidney disease by diet is associated with alteration in the handling of citric acid cycle metabolites. Betaine may have a metabolic role in the reduction of chronic renal injury.     

Three-dimensional triple-quantum-filtered 23Na imaging of the dog head in vivo

Uninephrectomized rats with diet-induced hypercholesterolemia develop interstitial inflammation and fibrosis after 8 to 12 weeks. Fibrosis has been associated with the accumulation of lipid peroxidation products within the tubulointerstitium, along with increased renal mRNA levels for transforming growth factor beta-1 (TCF-beta 1), some matrix proteins, and the tissue inhibitor of metalloproteinases (TIMP-1). However, mRNA levels for urokinase-type plasminogen activator (uPA) have been found to be decreased. The purpose of the present study was to determine whether antioxidant therapy could attenuate interstitial fibrosis in hypercholesterolemic rats and to determine changes in the pattern of renal gene expression induced by antioxidant therapy. Three groups of uninephrectomized rats were studied after 12 weeks of feeding standard rat chow, an atherogenic diet (standard chow plus 4% cholesterol/1% cholic acid), or an atherogenic diet supplemented with high doses of the antioxidants probucol and vitamin E. Rats fed the atherogenic diet developed hypercholesterolemia and a 56% increase in total kidney collagen compared with rats fed standard chow. In comparison, the hypercholesterolemic rats treated with antioxidants had normal levels of renal lipid peroxidation products and a normal kidney collagen content. In contrast, there were no significant differences in urinary albumin excretion rates or the number of interstitial macrophages between the two hypercholesterolemic groups. Compared with the untreated hypercholesterolemic group, antioxidant therapy induced significant reductions in renal mRNA levels for procollagen III (to 60% of untreated levels), collagen IV (60%), and TIMP-1 (20%), while uPA levels were significantly increased (to 210%). Paradoxically, antioxidant therapy was associated with a significant increase in renal TGF-beta 1 mRNA levels (to 150%), although TGF-beta 1 protein expression shifted from interstitial to tubular epithelial cells in predominance. The results of the present study demonstrate the efficiency of antioxidant therapy in preventing renal interstitial fibrosis in hypercholesterolemic rats with a single kidney. Based on changes in renal gene expression at the mRNA level, impaired matrix protein synthesis and increased intrarenal activity of the metalloproteinases and uPA/plasmin may play a role in the attenuation of fibrosis.     

Long-term regulation of renal urea transporter protein expression in rat

To test the hypothesis that the abundance of the apical urea transporter of the inner medullary collecting duct (IMCD) is regulated in vivo by factors associated with altered water balance, immunoblots of rat inner medullary membrane fractions were probed with rabbit polyclonal antibodies against the renal urea transporter (RUT) gene product. In inner medullas of Brattleboro rats, which manifest severe chronic water diuresis, a 117-kD band was seen, in addition to the previously described 97-kD band. These two bands were detectable by antibodies directed against two different regions of the RUT sequence. When Brattleboro rats were treated with a 5-d infusion of arginine vasopressin (AVP) by osmotic minipump, the 117-kD band was markedly diminished, whereas the 97-kD band was unchanged. Simultaneous infusion of the diuretic agent furosemide prevented the AVP-induced decrease in the 117-kD band. In AVP-infused Sprague Dawley rats, the 117-kD band was barely perceptible. However, when AVP-treated rats were infused with furosemide for 5 d, the 117-kD band was markedly accentuated, whereas the 97-kD band was unchanged. The abundance of the 117-kD RUT protein in the renal papilla was inversely correlated with dietary protein intake. Further immunoblotting studies revealed that the 117-kD protein is heavily expressed in IMCD cells and not in non-collecting duct components of the inner medulla, and is present in low-density microsome fractions from inner medulla. From this study, the following conclusions can be made: (1) The collecting duct urea transporter is present in at least two forms (97 and 117 kD) in the IMCD. (2) The expression level of the 117-kD urea transporter protein is regulated and is inversely correlated with medullary osmolality and urea concentration, but does not correlate with circulating AVP level. (3) Although AVP regulates RUT function on a short-term basis, long-term changes in AVP levels do not increase RUT abundance.     

90-day feeding and one-generation reproduction study in Crl:CD BR rats with 17 beta-estradiol

Over the past several years, there has been increasing concern that chemicals and pesticides found in the environment may mimic endogenous estrogens, potentially producing adverse effects in wildlife and human populations. Because estrogenicity is one of the primary concerns, a 90-day/one-generation reproduction study with 17 beta-estradiol was designed to set dose levels for future multigenerational reproduction and combined chronic toxicity/oncogenicity studies. The purpose of these studies is to evaluate the significance of a range of responses as well as to provide benchmark data for a risk assessment for chemicals with estrogen-like activities. This 90-day/one-generation reproduction study was conducted in male and female Crl:CD BR rats using dietary concentrations of 0, 0.05, 2.5, 10, and 50 ppm 17 beta-estradiol. Endpoints were chosen in order to evaluate both subchronic and reproductive toxicity. In addition, several mechanistic/biochemical endpoints were evaluated for their usefulness in follow-up studies. In the P1 generation, dietary administration of 2.5, 10, and 50 ppm 17 beta-estradiol produced dose-dependent decreases in body weight, body weight gain, food consumption, and food efficiency. At 10 and 50 ppm 17 beta-estradiol, minimal to mild nonregenerative anemia, lymphopenia, decreased serum cholesterol (50 ppm only), and altered splenic lymphocyte subtypes were also observed in the P1 generation. Additionally, at these concentrations, there were changes in the weights of several organs. Evidence of ovarian malfunction, characterized by reduced numbers of corpora lutea and large antral follicles, was observed at 2.5 ppm 17 beta-estradiol and above. Other pathologic changes in males and females fed 10 and 50 ppm 17 beta-estradiol included centrilobular hepatocellular hypertrophy; diffuse hyperplasia of the pituitary gland; feminization of the male mammary glands; mammary gland hyperplasia in females; increased number of cystic follicles in the ovary; hypertrophy of the endometrium and endometrial glands in the uterus; degeneration of seminiferous epithelium; and atrophy of the testes and the accessory sex glands. In the reproduction portion of this study, rats fed 10 or 50 ppm 17 beta-estradiol did not produce litters. While there was no evidence that the 50 ppm treated rats mated, 33.3% of the rats fed 10 ppm mated but did not produce litters. No effects on mating and fertility indices were observed in rats fed 0.05 and 2.5 ppm 17 beta-estradiol. Pup weights at birth were statistically decreased relative to control in the groups fed 0.05 and 2.5 ppm 17 beta-estradiol. Weights of the rats in the 0.05 ppm group recovered by postnatal day 4 and remained similar to control throughout the remainder of the study. The mean gestation length of the 0.05 ppm group was slightly, albeit not statistically significantly, shorter (0.5 days) than that of the control group, which may have contributed to the decrease in birth weight of the 0.05 ppm group. In contrast, the weights of the F1 generation rats fed 2.5 ppm 17 beta-estradiol remained decreased relative to the control group throughout the study. Parental administration of 17 beta-estradiol did not alter anogenital distance in male or female pups. The onset of sexual maturation, as measured by day of preputial separation in males and day of vaginal opening in females, was delayed in male rats fed 2.5 ppm (by 8.2 days) and was hastened in female rats fed 0.05 and 2.5 ppm (by 1.6 and 8.8 days, respectively). The age at vaginal opening ranged from 26 to 37, 26 to 35, and 21 to 25 days for rats fed 0, 0.05, and 2.5 ppm 17 beta-estradiol, respectively. Hence, the range of age at vaginal opening was similar between the control and 0.05 ppm group. The organ weight and pathologic alterations observed in the adult F1 generation rats were similar to those observed in the P1 generation rats. (ABSTRACT TRUNCATED)     

Chemoprevention of radiation-induced mammary tumors in rats by bezafibrate administered together with diethylstilbestrol as a promoter

Pregnant Wistar-MS strain rats were irradiated with 2.6 Gy of gamma-rays at day 20 of pregnancy. Rats in the control group (n = 48) were then implanted with a diethylstilbestrol (DES) pellet at 35 days after weaning, while being fed a control (MB-1) diet. The incidence of mammary tumors was 89.6% within 1 year. In the experimental group (n = 22), a bezafibrate (0.15%) diet was initiated immediately after weaning, and 35 days after weaning a DES pellet was implanted. Administration of dietary bezafibrate together with DES-implantation continued for a period of 1 year, at which time the experiment was terminated. The incidence (27.3%) of the mammary tumors in the bezafibrate-fed rats was less than one-third of that in the control rats. Compared with the control group, the number of mammary tumors per tumor-bearing rat in the bezafibrate-treated group was reduced. For clarification of the mechanism of the chemopreventive effects of bezafibrate, lipid and hormone concentrations in serum were measured. Bezafibrate-fed rats showed a significant decrease in serum prolactin (56%) and triglyceride (63%) concentrations, and a significant increase in serum estradiol-17beta (3.8-fold), cholesterol ester (2.0-fold) and TSH (2.0-fold) concentrations in comparison with the control rats. The bezafibrate diet inhibited the formation of DES-induced pituitary tumors. However, the development of mammary glands in the bezafibrate-fed rats was stimulated more than that in the control rats treated with DES alone. The present results demonstrate that bezafibrate is effective in preventing mammary tumors induced by radiation together with DES, possibly by reducing prolactin and triglyceride concentrations.     

A rice protein isolate alters 7,12-dimethylbenz[alpha]anthracene-induced mammary tumor development in female rats

The effects of a rice protein isolate (RPI) on 7,12-dimethylbenz[alpha]anthracene (DMBA)-induced mammary tumor progression were investigated in female Sprague-Dawley rats. At 6 weeks of age, rats were fed a casein, RPI or soybean protein isolate (SPI) diet, respectively. After 1 week, DMBA was administered orally at the dose of 30 mg/kg body weight. The mean tumor number per tumor-bearing rat at autopsy was significantly lower only in rats fed RPI than in those fed casein. Palpable tumors at the mid point of the experiment were significantly lower in rats fed RPI and SPI than in those fed casein. Serum estradiol-17 beta concentrations were lower in rats fed the SPI (but not in those fed RPI) than in those fed casein. In a further experiment, no differences were found in hepatic microsomal DMBA-arylhydrocarbon hydroxylase activity after 7 days of feeding the respective diets. These results suggest that RPI exerts its inhibitory effect on DMBA-induced mammary tumorigenesis irrespective of changes in circulating estrogens or modulation of hepatic DMBA metabolism.     

Black tea and mammary gland carcinogenesis by 7,12-dimethylbenz[a]anthracene in rats fed control or high fat diets

Epidemiological studies suggest that tea may reduce cancer risk, and in laboratory rodents, chemopreventive effects of tea or purified extracts of tea have been demonstrated in lung, gastrointestinal tract and skin. There is some evidence of chemoprevention by tea in the mammary gland, but the data are not conclusive. In order to evaluate more fully the possible influence of black tea on 7,12-dimethylbenz[a]anthracene (DMBA)-induced mammary gland tumors in the female S-D (Sprague-Dawley) rat, three large studies were performed: experiment 1, tumorigenesis in rats fed AIN-76A diet and given 25 mg/kg DMBA and 1.25 or 2.5% whole tea extract or water to drink; experiment 2, tumorigenesis in rats given 15 mg/kg DMBA and the same diet and fluids as in experiment 1; experiment 3, tumorigenesis in rats fed control or HF (high fat, corn oil) diet and given 15 mg/kg DMBA and 2% tea or water to drink. Tea was given throughout the experiment; DMBA was given by gastric gavage at 8 weeks of age. There was no consistent effect of tea on tumorigenesis in rats fed AIN-76A diet; there was, however, evidence in experiment 3 of a reduction of tumorigenesis by tea in rats fed the HF diet. In experiment 3, rats fed the HF diet and given water showed the expected increase in tumor burden (number and weight) compared with rats fed control diet. However, rats fed the HF diet and given 2% tea showed no increase in tumor burden; their tumor burden was significantly lower than in rats fed the HF diet and given water (P < 0.01) and was not different from rats fed control diet and given water or tea. In addition, in experiment 3, the number of malignant tumors per tumor-bearing rat was increased by the HF diet in water-drinking rats (P < 0.01) but not in tea-drinking rats. Therefore, it appears that tea partially blocked the promotion of DMBA-induced mammary tumorigenesis by the HF diet.     

Chemoprevention of mammary carcinoma by LGD1069 (Targretin): an RXR-selective ligand

Recently, 9-cis retinoic acid, a high affinity ligand for retinoic acid receptors and retinoid X-receptors (RXRs), was shown to have efficacy superior to all-trans retinoic acid as a chemopreventive agent in the N-nitroso-N-methylurea-induced rat mammary carcinoma model. To further explore the specific contribution RXR activation may play in suppression of carcinogenesis, the efficacy of LGD1069 (Targretin), an RXR-selective ligand, in the N-nitroso-N-methylurea-induced rat mammary tumor model was studied. LGD1069-treated animals showed a 90% reduction in tumor burden and tumor incidence compared with vehicle-treated rats with an efficacy similar to that achieved with tamoxifen. LGD1069 was very well tolerated during 13 weeks of chronic therapy with no classic signs of "retinoid-associated" toxicities. These data demonstrate that LGD1069, an RXR-selective ligand, can act as a highly effective and benign chemopreventive agent for mammary carcinoma.     

Liver carcinogenesis associated with feeding of ethionine in a choline-free diet: evidence against a role of oval cells in the emergence of hepatocellular carcinoma

In an attempt to clarify the role of oval cells in the emergence of hepatocellular carcinoma, we fed rats a choline-free diet containing 0%, 0.05% or 0.1% ethionine. The incidence and nature of premalignant and malignant hepatic lesions were then related to the degree of oval cell proliferation. Intake of choline-free diet alone for up to 12 mo was associated with minimal oval cell proliferation; cholangiofibrosis, hepatocellular nodules and hepatocellular carcinoma were observed in 55%, 23% and 14% of the animals, respectively. When rats were given the choline-free diet with 0.05% ethionine, proliferation of oval cells was more pronounced; after a 6- to 12 mo feeding period, cholangiofibrosis (57%) was again observed. However, hepatocellular nodules (91%) and hepatocellular carcinoma (74%) were the most common lesions seen with this feeding regimen. Finally, rats fed the choline-free diet with 0.1% ethionine had massive oval cell proliferation and progressive loss of parenchymal liver tissue. Most of these animals died before they had consumed the choline-free diet with 0.1% ethionine for 12 mo. Rats in this group (96%) exhibited large and numerous cholangiofibrotic lesions, but hepatocellular nodules and carcinoma were not detected. In all animals of each experimental group, hyperplastic bile duct cells in areas of cholangiofibrosis and oval cells were positive for cytokeratin 19, an intermediate filament protein present only in bile duct cells in normal liver. Hepatocellular nodules and hepatocellular carcinoma were invariably negative for cytokeratin 19. We interpret these findings to suggest that oval cells are not involved in the histogenesis of hepatocellular carcinoma.(ABSTRACT TRUNCATED AT 250 WORDS)     

Inhibition of human breast cancer cell proliferation and delay of mammary tumorigenesis by flavonoids and citrus juices

Two citrus flavonoids, hesperetin and naringenin, found in oranges and grapefruit, respectively, and four noncitrus flavonoids, baicalein, galangin, genistein, and quercetin, were tested singly and in one-to-one combinations for their effects on proliferation and growth of a human breast carcinoma cell line, MDA-MB-435. The concentration at which cell proliferation was inhibited by 50% (IC50), based on incorporation of [3H]thymidine, varied from 5.9 to 140 micrograms/ml for the single flavonoids, with the most potent being baicalein. IC50 values for the one-to-one combinations ranged from 4.7 micrograms/ml (quercetin + hesperetin, quercetin + naringenin) to 22.5 micrograms/ml (naringenin + hesperetin). All the flavonoids showed low cytotoxicity (> 500 micrograms/ml for 50% cell death). Naringenin is present in grapefruit mainly as its glycosylated form, naringin. These compounds, as well as grapefruit and orange juice concentrates, were tested for their ability to inhibit development of mammary tumors induced by 7,12-dimethylbenz[a]anthracene (DMBA) in female Sprague-Dawley rats. Two experiments were conducted in which groups of 21 rats were fed a semipurified diet containing 5% corn oil and were given a 5-mg dose of DMBA intragastrically at approximately 50 days of age while in diestrus. One week later, individual groups were given double-strength grapefruit juice or orange juice or fed naringin or naringenin at levels comparable to that provided by the grapefruit juice; in the second experiment, the rats were fed a semipurified diet containing 20% corn oil at that time. As expected, rats fed the high-fat diet developed more tumors than rats fed the low-fat diet, but in both experiments tumor development was delayed in the groups given orange juice or fed the naringin-supplemented diet compared with the other three groups. Although tumor incidence and tumor burden (grams of tumor/rat) were somewhat variable in the different groups, rats given orange juice had a smaller tumor burden than controls, although they grew better than any of the other groups. These experiments provide evidence of anticancer properties of orange juice and indicate that citrus flavonoids are effective inhibitors of human breast cancer cell proliferation in vitro, especially when paired with quercetin, which is widely distributed in other foods.     

Estrogen treatment enhances hereditary renal tumor development in Eker rats

Hormonal influences are known to affect the development of renal cell carcinoma in man and laboratory animal models. We tested the hypothesis that estrogen treatment or ovariectomy of rats modulates renal tumor development using tuberous sclerosis 2 (Tsc2) heterozygous mutant (Eker) rats in which a germline mutation predisposes the animals to renal cell tumor development. Two-month-old female wild-type and Eker rats were ovariectomized or sham-operated and treated with placebo or 5 mg 17beta-estradiol in s.c. pellets for 6 or 10 months. Rats were examined at 8 or 12 months of age, at which time the numbers of renal tumors and preneoplastic foci were quantitated and the severity of nephropathy was assessed. In contrast to what may have been expected, prolonged estrogen treatment enhanced the development of hereditary renal cell tumors, with a 2-fold greater number of preneoplastic and neoplastic renal lesions compared with untreated Eker rats. Ovariectomized Eker rats had 33% fewer renal lesions than the unmanipulated control group. No tumors or preneoplastic lesions were present in wild-type rats at either time point. Estrogen treatment increased the severity of nephropathy in both wild-type and Eker rats, whereas ovariectomy was protective against nephropathic changes. Although estrogen is not a rat renal carcinogen, it enhanced the development of hereditary renal cell tumors when administered to Eker rats. Eker rats heterozygous for a mutation in the Tsc2 locus provide a good model in which to study how genetic and hormonal factors contribute to the development of renal cell tumors and to understand the influence genetic susceptibility has on the development of renal cell carcinoma.     

Effect of dietary soy protein isolate, genistein, and 1,4-phenylenebis(methylene)selenocyanate on DNA binding of 7,12-dimethylbenz[a]anthracene in mammary glands of CD rats

We examined whether a soy protein isolate or one of its major components (genistein) influences the initiation stage of carcinogenesis via DNA binding studies of 7,12-dimethylbenz[a]anthracene (DMBA) in liver and mammary tissue of female CD rats. A semipurified high-fat diet (23.5% corn oil) containing the soy protein isolate (10%), genistein (111 ppm), or 1,4-phenylenebis(methylene)selenocyanate (p-XSC) (5 ppm as selenium) as a positive control was fed to 6-week-old virgin female CD rats for 1 week before carcinogen treatment. Neither soy nor genistein affected the extent of DMBA-DNA binding in liver. In mammary tissue, 111 ppm genistein in the diet was more effective than the soy protein isolate, although the latter contains the same amount of genistein, mainly present as a glucoside conjugate. As shown before, p-XSC inhibited DMBA-DNA binding in mammary tissue. Total binding was inhibited because of reduced formation of three major adducts: anti-diol epoxide deoxyguanosine, syn-diol epoxide deoxyadenosine, and anti-diolepoxide deoxyadenosine. Thus, an additional experiment with 111 and 222 ppm of genistein was performed; 222 ppm genistein had a weaker effect than that observed for 111 ppm. Nevertheless, 111 ppm of genistein in the diet appears to inhibit the initiation phase of DMBA-induced rat mammary tumors and may partially account for the reported inhibitory effect of soy against DMBA-induced rat mammary tumors.     

Highly controlled gene expression using combinations of a tissue-specific promoter, recombinant adenovirus and a tetracycline-regulatable transcription factor

The arterial baroreceptor reflex system is one of the most powerful and rapidly acting mechanisms for controlling arterial pressure. The purpose of the present review is to discuss data relating sympathetic activity to the baroreflex control of arterial pressure in two different experimental models: neurogenic hypertension by sinoaortic denervation (SAD) and high-renin hypertension by total aortic ligation between the renal arteries in the rat. SAD depresses baroreflex regulation of renal sympathetic activity in both the acute and chronic phases. However, increased sympathetic activity (100%) was found only in the acute phase of sinoaortic denervation. In the chronic phase of SAD average discharge normalized but the pattern of discharges was different from that found in controls. High-renin hypertensive rats showed overactivity of the renin angiotensin system and a great depression of the baroreflexes, comparable to the depression observed in chronic sinoaortic denervated rats. However, there were no differences in the average tonic sympathetic activity or changes in the pattern of discharges in high-renin rats. We suggest that the difference in the pattern of discharges may contribute to the increase in arterial pressure lability observed in chronic sinoaortic denervated rats.     

Pieces of a puzzle: Toward a better understanding of intraocular inflammation associated with human immunodeficiency virus disease

Periductal mastitis (mammary duct ectasia) is a little appreciated, often unrecognized entity that may present to the dermatologist. We present our experience with this disease and hope to familiarize the reader with a condition not well known to most dermatologists. Periductal mastitis is a benign mammary duct disease that begins with periductal inflammation and progresses to ductal dilatation with minimal inflammation (ductal ectasia). The clinical and radiographic appearance of this disease can be indistinguishable from carcinoma of the breast.