Isopropanol vapor inhalation oncogenicity study in Fischer 344 rats and CD-1 mice

The potential oncogenic effects of isopropanol, a widely used solvent, were investigated. Four groups of animals, each consisting of 75 CD-1 mice/sex and 75 Fischer 344 rats/sex, were exposed to isopropanol vapor (CAS No. 67-63-0) at target concentrations of 0 (filtered air control), 500, 2500, or 5000 ppm. Animals assigned to the core group (55 mice/sex/group and 65 rats/sex/group) were exposed for 6 hr/day, 5 consecutive days/week for at least 78 weeks for the mice or 104 weeks for the rats. Ten mice/sex/group and 10 rats/sex/group were assigned to an interim euthanasia group and were terminated during Weeks 54 and 73, respectively. In addition, 10 mice/sex/group were assigned to a recovery group and did not receive any further exposure following Week 53 but were retained until the core group of animals was euthanized. Transient signs of narcosis were observed for both mice and rats during exposure to 2500 and 5000 ppm and following exposure for mice from the 5000-ppm group. Increased mortality (100% versus 82% for controls) and a decreased mean survival time (577 days versus 631 days for controls) were noted for male rats from the 5000-ppm group. Increases in body weight and/or body weight gain were typically observed for both sexes of mice and rats from the 2500- and 5000-ppm groups throughout the study. Urinalysis and urine chemistry changes indicative of impaired kidney function (i.e., decreased osmolality and increased total protein, volume, and glucose) were noted for male rats from the 2500-ppm group as well as for male and female rats from the 5000-ppm group. At the interim euthanasia, a concentration-related increase in testes weight (absolute and relative as a percentage of body and brain weight) was observed for male rats. Concentration-related increases in absolute and relative liver weight (as a percentage of body weight) were observed for male and female mice. In addition, increased absolute and/or relative (as a percentage of body and brain weight) liver and kidney weights were observed for male and/or female rats from the 2500- and 5000-ppm groups. At necropsy, an increased incidence of seminal vesicle enlargement was observed grossly for male mice from the 2500- and 5000-ppm groups. Microscopically, some of the nonneoplastic lesions noted for mice included an increased incidence of ectasia of the seminal vesicles for male mice from the 2500- and 5000-ppm groups, minimal renal tubular proteinosis for male and female mice from all isopropanol groups, and renal tubular dilation for female mice from the 5000-ppm group. A number of nonneoplastic lesions were observed for male and female rats from the 2500- and 5000-ppm groups, with the most significant lesions being observed in the kidney and associated with chronic renal disease. The lesions noted with increased severity and/or frequency included mineralization, tubular dilation, glomerulosclerosis, interstitial nephritis, interstitial fibrosis, hydronephrosis, and transitional cell hyperplasia. The only tumor type increased in incidence during the study was interstitial cell adenomas of the testes in male rats. However, the increase in these adenomas was not believed to be exposure-related due to an unusually low incidence observed for the control group. There were no increased frequencies of neoplastic lesions noted for male or female mice or for female rats from any isopropanol exposure group. Chronic renal disease was attributed to be the main cause of death for male and female rats from the 5000-ppm group and was also considered to account for much of the mortality observed for male rats from the 2500-ppm group. In conclusion, the no-observed-effect level (NOEL) for toxic effects for both rats and mice was 500 ppm. The NOEL for oncogenicity effects for both mice and rats was determined to be greater than 5000 ppm.     

Oncogenicity studies of piperonyl butoxide in rats and mice

1. The oncogenicity of Piperonyl butoxide (PBO) has been studied in the mouse and rat. CD-1 mice were administered PBO in the diet at target doses of 0, 30, 100 and 300 mg/kg/day for 79 weeks and Sprague-Dawley rats 0, 30, 100 and 500 mg/kg/day for 104/105 weeks. 2. At termination of the study in the mouse there was evidence of increased liver weights and an increased incidence of eosinophilic adenomas at 100 and 300 mg/kg/day in males and 300 mg/kg/day in females. 3. In rats there was increased liver weights at 100 and 500 mg/kg/day associated with hepatocyte hypertrophy in both male and female rats. There was no increased incidence of neoplasia at any site. Hypertrophy and hyperplasia of thyroid follicles was observed at 500 mg/kg/day in both sexes. 4. The observations reflect the expected changes related to the induction of the mixed function oxygenase group of enzymes. In the mouse the increased incidence of eosinophilic adenomas is not considered relevant for human risk evaluation.     

Protective effects of CD-832 on organ damage in stroke-prone spontaneously hypertensive rats

Effects of a newly developed Ca2+ channel antagonist, (4R)-(-)-2-(nicotinoylamino)ethyl 3 nitrooxypropyl 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl) 3,5-pyridine-dicarboxylate (CD-832), on hypertensive complications in stroke-prone spontaneously hypertensive rats (SHRSPs) were compared with effects of diltiazem. We examined changes in histological and hematological parameters in SHRSPs given the following treatments at 8 to 20 weeks of age: (a) CD-832; (b) diltiazem; (c) no treatment. CD-832 and diltiazem were added to the diet, in doses of 0.05 and 0.15% (approximately 30 and 100 mg/kg per day), respectively, throughout the experimental period. In untreated control SHRSPs, systolic blood pressure increased and severe renal lesions such as fibrinoid necrosis, smooth muscle proliferation, glomerular and tubular lesions and some cardiac fibrosis were observed at age 20 weeks. 12-week repeated-administration of CD-832 and diltiazem led to a comparable hypotension and decreased heart rate. CD-832 and diltiazem decreased the ratios of weights of kidney and heart to body weight and the concentration of blood urea nitrogen and creatinine in serum, compared to values in controls. In SHRSPs treated with CD-832 and diltiazem, the incidence of renal lesions and myocardial fibrosis was significantly reduced when compared with control SHRSPs. These results suggest that 12-week repeated-administration of CD-832 prevents the development of hypertension and the incidence of organ damage in SHRSPs. CD-832 and diltiazem were equally efficacious in preventing organ damage but this organ-protective effect was obtained at a lower dose for CD-832 (30 mg/kg per day) than that of diltiazem (100 mg/kg per day).     

Toxicokinetics of oxazepam in rats and mice

The comparative toxicokinetics of oxazepam were studied in F344 rats, B6C3F1 mice, and Swiss-Webster mice of both sexes after an i.v. dose of 20 mg/kg and oral gavage doses of 50, 200, and 400 mg/kg. In addition, the toxicokinetics of oxazepam in a 3-week dosed-feed study of male B6C3F1 mice at 125 and 2500 ppm were also investigated. Results indicated that the elimination of oxazepam from plasma after i.v. injection in both rats and mice were first-order and could be best described by a two-compartment model with a terminal elimination half-life of 4-5 h for rats and 5-7 h for mice. After oral gavage dosing the peak oxazepam plasma concentrations in most rodents were reached within 2-3.5 h. At all doses studied, female rodents had significantly higher plasma concentrations than males. Absorption of oxazepam was significantly extended at higher oral doses of 200 and 400 mg/kg. At 50 mg/kg, the bioavailability of oxazepam in rats (< 50%) was lower than in Swiss-Webster mice (> 80%). The bioavailability of oxazepam in both B6C3F1 and Swiss-Webster mice decreased with increasing dose. A dose proportionality of Cmax was not observed in rats and mice after gavage doses of 50, 200, and 400 mg/kg. Plasma concentrations of oxazepam in the dosed-feed study increased with the concentration of oxazepam in the feed, a quasi-steady-state of plasma concentrations of oxazepam was reached after approximately 4 days ad libitum exposure. In B6C3F1 mice, the estimated relative bioavailability of oxazepam from dosed feed (relative to gavage study at 50 mg/kg) was about 43%.     

Vitamin E modulation of hepatic focal lesion growth in mice

The effect of DL-alpha-tocopherol acetate (vitamin E) on hepatic focal lesion growth in male B6C3F1 mice previously treated with diethylnitrosamine (DEN) was investigated. After hepatic focal lesions were formed, mice were placed into one of the following dose groups: 0 mg vitamin E/kg NIH-07 diet, 50 mg vitamin E/kg NIH-07 diet (control diet), 250 mg vitamin E/kg NIH-07 diet, and 450 mg vitamin E/kg NIH-07 diet. Mice were euthanized after either 30 or 60 days of dietary treatment. In normal (nonlesion) liver, vitamin E deficiency (0 mg/kg diet) increased hepatic DNA synthesis. In addition, vitamin E supplementation (450 mg/kg diet) decreased the incidence of hepatic apoptosis, while vitamin E deficiency (0 mg/kg diet) increased the incidence of hepatic apoptosis. The effect of vitamin E-induced lesion growth was examined by measuring the number of focal lesions per liver and the relative focal lesion volume. High-dose vitamin E supplementation (450 mg/kg diet) appeared to enhance the growth of hepatic focal lesions. In particular, basophilic lesions appeared to be the most sensitive to high-dose vitamin E modulation (450 mg/kg diet) as evidenced by increased number, volume, and labeling index of hepatic focal lesions. Vitamin E deficiency also appeared to enhance the growth of hepatic focal lesions, though to a lesser extent than vitamin E supplementation (450 mg/kg diet). In the present study, both vitamin E supplementation (450 mg/kg diet) and deficiency (0 mg/kg diet) appeared to enhance focal lesion growth albeit neither treatment enhanced lesion growth as dramatically as known nongenotoxic hepatocarcinogens (e.g., phenobarbital and dieldrin). The data presented here suggest that oxidative stress in focal hepatocytes may be a component of the liver tumor promotion process.     

Repeated dosing with the peroxisome proliferator clofibrate decreases the toxicity of model hepatotoxic agents in male mice

Pretreatment of mice with clofibrate (CFB) has been shown to protect against acetaminophen (APAP) hepatotoxicity. To determine if pretreatment with CFB prevents the toxicity of other model hepatotoxicants, male C57BL6J or CD-1 mice received 500 mg CFB/kg, i.p., daily for 10 days, and then were challenged with either 250 mg bromobenzene (BrB)/kg, 0.025 ml carbon tetrachloride (CCl4)/kg or 0.5 ml chloroform (CHCl3)/kg. Liver and kidney injury was assessed by plasma sorbitol dehydrogenase activity (SDH) and blood urea nitrogen (BUN), respectively and histopathology. Challenge with BrB significantly elevated plasma SDH activity in C57Bl6J mice. This was prevented in CFB pretreated mice receiving the same dose of BrB. Changes in BUN were not detected in either group of BrB treated mice. Similarly, pretreatment of male CD-1 mice with CFB significantly reduced CCl4-induced elevation in plasma SDH activity, with no BUN elevation detected in either group. CFB pretreatment also diminished elevation in plasma SDH activity produced by CHCl3 in CD-1 mice, while BUN was significantly elevated in both groups, indicating that CFB did not protect against CHCl3-induced nephrotoxicity. Histopathological examination of liver and kidney sections confirmed these results. This study shows that mice pretreated with CFB were protected from toxicity at 24 h after challenge with other model hepatotoxic agents besides APAP.     

Comparison of fungizone, Amphotec, AmBisome, and Abelcet for treatment of systemic murine cryptococcosis

Three lipid-based formulations of amphotericin B have been approved for use in various countries. The aim of this study was to compare Amphotec (ABCD; Sequus), AmBisome (AmBi; Nexstar), Abelcet (ABLC; The Liposome Co.), and conventional deoxycholate amphotericin B (Fungizone; Bristol Meyers Squibb) for the treatment of experimental systemic cryptococcosis. A model was established in 10-week-old female CD-1 mice by intravenous (i.v.) injection of 6.25 x 10(5) viable Cryptococcus neoformans yeast cells. Therapy began 4 days later, with i.v. administration three times per week for 2 weeks. Mice received either no treatment, 1 mg of Fungizone per kg of body weight, or 1, 5, or 10 mg of ABCD, AmBi, or ABLC per kg. Ninety percent of control mice died between days 15 and 34. All treatment regimens except ABLC at 1 mg/kg prolonged survival compared with no treatment (P < 0.01 to 0.001). All mice receiving 5 or 10 mg of ABCD or AmBi per kg and 90% of mice given 10 mg of ABLC per kg survived, whereas < or =50% of those given other treatment regimens survived. Fungizone was the least effective of the four formulations, with 5 or 10 mg of ABCD, AmBi, or ABLC per kg resulting in a significantly better outcome than Fungizone (P < 0.001). Among the three formulations, ABCD and AmBi were equally effective, both being better than ABLC at equal 5- or 10-mg/kg doses (P < 0.001). Comparison of residual infectious burdens in various organs showed that each drug had some dose-responsive efficacy in three or more organs at escalating doses. In the brain, ABCD or AmBi at 5 or 10 mg/kg or ABLC at 10 mg/kg was more effective than Fungizone at 1 mg/kg or no treatment, while ABCD or AmBi at 1 mg/kg was as effective as ABLC at 10 mg/kg. Similar results were obtained for the kidneys and lungs. In the spleen, ABCD at 10 mg/kg cured all mice of infection and was superior to all other regimens. In the liver, AmBi at 5 mg/kg was superior to an equal dose of ABCD or ABLC. Overall, the efficacies of ABCD and AmBi were equal to that of Fungizone at 1 mg/kg and were about 10-fold better than that of ABLC, particularly in the brain; a comparative rank order of efficacies was ABCD approximately equal to AmBi > ABLC > Fungizone. This is the first study that compared all four amphotericin B formulations.     

Inhibition of WY-14,643 induced hepatic lesion growth in mice by rotenone

The effect of rotenone treatment on [4-chloro-6-(2,3-xylidino)-2-pyrimidinylthio] acetic acid (WY-14,643) hepatic lesion growth in male B6C3F1 mice was investigated. Following induction of hepatic focal lesions by diethylnitrosamine (DEN) 35 mg/kg twice a week for 8 weeks, mice were placed into one of the four treatment groups: group I, control NIH-07 diet (control diet), group II, rotenone (600 mg/kg diet), group III NIH-07 diet containing WY-14,643 (1000 mg/kg diet), and group IV, NIH-07 diet containing WY-14,643 (1000 mg/kg diet) and rotenone (600 mg/ kg diet). Mice were killed after 30 and 60 days of dietary treatment. The effect of treatment with WY-14,643 and rotenone on hepatic lesion growth was examined by estimating the number of focal lesions per liver and the relative volume of focal lesions. WY-14,643 (group III) increased both the number and the volume of focal lesions. In particular, an increase in number and volume of basophilic lesions was seen. Co-treatment with WY-14,643 and rotenone (group IV) decreased both the number and the volume of the total number of focal lesions and basophilic foci compared with WY-14,643 treatment alone (group II). Alterations in the growth of hepatic focal lesions was further investigated by examining DNA synthesis and apoptosis within individual lesions. WY-14,643 (group III) treatment increased the DNA synthetic labeling index in all foci. Co-treatment of rotenone and WY-14,643 (group IV) decreased focal DNA synthesis and mitosis and increased the incidence of apoptotic hepatocytes. These data suggest that rotenone's ability to inhibit WY-14,643-induced hepatic focal lesion growth was mediated through a decrease in hepatic focal proliferation and an increase in focal apoptosis.     

Spontaneous glucose intolerance in the progeny of low dose streptozotocin-induced diabetic mice

Multiple low doses of streptozotocin (LDS) induce low-incidence diabetes mellitus in Balb/cHan and high-incidence diabetes in CD-1 mice. We studied offspring of diabetic parents in both strains. Group 1 consisted of litters from control mice with no streptozotocin treatment. Group 2 litters had an LDS diabetic mother and a control father, group 3 litters had control mother with LDS diabetic father, and group 4 litters had both, LDS diabetic mother and father. Diabetes was induced by 5 x 40 mg streptozotocin per kg on five consecutive days. Progeny of diabetic mothers showed a state of reduced glucose tolerance associated with reduced glucose disappearance during intravenous glucose tolerance test and increased insulin secretion of isolated islets of Langerhans. These metabolic abnormalities predominated in the male litters of both strains of mice. Amniotic insulin was increased in diabetic mothers during pregnancy. No histologic abnormalities were observed in group 2 progeny. Pancreases in male offspring of LDS diabetic CD-1 fathers (group 3) were studied for insulitis. Insulitis was found in 40% of mice with normal glucose tolerance. A single subdiabetogenic dose of streptozotocin (40 mg/kg) induced insulitis in 90% of pancreases accompanied by reduced insulin release of isolated islets. By contrast, male Balb/cHan progeny of diabetic fathers failed to develop insulitis. In conclusion, we found (1) parental LDS diabetes was transmitted more often to male offspring, (2) maternal LDS diabetes was associated with hyperinsulin secretion and glucose intolerance in the offspring and (3) paternal LDS diabetes was accompanied by insulitis and insulin secretion deficiency in CD-1 progeny.     

Protein kinase C isotypes theta, delta and eta in human lymphocytes: differential responses to signalling through the T-cell receptor and phorbol esters

CD-1 mice received daily subcutaneous injections of either cocaine (20 mg/kg or 40 mg/kg) or saline solution (0.9% NaCl) from postnatal days 2 to 15. Pups were tested on days 16-17 for learning and 24-h retention of a passive avoidance task, where entering a dark compartment was punished with a mild foot shock. Locomotor activity and general behaviour in an open field arena were assessed on day 21, following administration of either the muscarinic blocker scopolamine (0.8 mg/kg) or saline solution. In addition, immunostaining for the enzyme choline acetyltransferase (ChAT) was measured in different basal forebrain areas (medial septum, striatum, and nucleus basalis) on day 30. Cocaine treatment failed to affect either learning or retention capabilities. Nonetheless, neophobic behaviour during the learning session was enhanced in control nonpunished mice exposed to the 20-mg/kg dose. In the open field test, although baseline activity levels were unaffected by cocaine exposure, the 40-mg/kg cocaine-treated pups showed decreased sensitivity to the hyperkinetic effects of scopolamine. ChAT immunocytochemistry revealed a significant reduction of the number of ChAT-immunopositive neurons in the nucleus basalis but not in the other cholinergic basal forebrain regions.     

d-Amphetamine conditioned place preference in developing mice: Relations with changes in activity and stereotypies.

Conditioned place preference (CPP) with both visual and tactile cues, hyperactivity, and stereotypies produced by d-amphetamine (1–20 mg/kg) were studied in CD-1 mice at 2, 3, and 4 wks from birth. CPP was shown from the youngest age onward in female mice and from 3 wks in male mice. Hyperactivity was much more pronounced in postweanlings (3 and 4 wks) than in preweanlings. Stereotypies (at 3.3 and 10 mg/kg) occurred from the youngest age and tended to peak at 3 wks. Stereotypies may indicate a sickness experience or "poor welfare" due to an aversive component of amphetamine's action. Therefore, the delayed development of fully fledged amphetamine CPP, relative to cocaine CPP, may be due to an age-dependent diminution of the positive hedonic value of the former drug by negative effects that are minimal or absent in the case of the latter drug. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Absorption, disposition kinetics, and metabolic pathways of cyclohexene oxide in the male Fischer 344 rat and female B6C3F1 mouse

Cyclohexene oxide (CHO) is a monomer intermediate used in the synthesis of pesticides, pharmaceuticals, and perfumes. Although CHO has a variety of industrial uses where direct human exposure is possible, very little is known about its fate in the body. Therefore, the objectives of this study were to determine the absorption, distribution, metabolism, and excretion of cyclohexene oxide after oral, intravenous, and dermal exposure in male Fischer 344 rats and female B6C3F, mice. After intravenous administration of [14C]CHO (50 mg/kg), CHO was rapidly distributed, metabolized, and excreted into the urine. Plasma concentrations of CHO rapidly declined and were below the limit of detection within 60 min. Average (+/- SD) values for terminal disposition half-life, apparent volume of distribution at steady-state, and systemic body clearance were: 19.3 +/- 1.6 min; 0.44 +/- 0.08 liter/kg; and 31.3 +/- 0.5 ml/kg * min, respectively. After oral administration of [14C]CHO (10 and 100 mg/kg), it was found that 14C-equivalents were rapidly excreted in the urine of both species. At 48 hr, the majority of the dose (73-93%) was recovered in urine, whereas fecal elimination accounted for only 2-5% of the dose. At no time after oral administration was parent CHO detected in the blood. However, its primary metabolite cyclohexane-1,2-diol was present for different lengths of time depending on the dose. Four metabolites were detected and identified in mouse urine by MS: cyclohexane-1,2-diol; cyclohexane-1,2-diol-O-glucuronide; N-acetyl-S-(2-hydroxycyclohexyl)-L-cysteine; and cyclohexane-1,2-diol-O-sulfate. The sulfate conjugate was not present in rat urine. Topical application of [14C]CHO (60 mg/kg) provided poor absorption in both species. The majority of 14C-equivalents applied dermally were recovered from the charcoal skin trap (approximately 90% of the dose). Only 4% of the dose was absorbed, and the major route of elimination was via the urine. To evaluate the toxicity of CHO, animals were given daily doses of CHO orally and topically for 28 days. No statistically significant changes in final body weights or relative organ weights were noted in rats or mice treated orally with CHO up to 100 mg/kg or up to 60 mg/kg when given topically. Very few lesions were found at necropsy, and none were considered compound related. In conclusion, regardless of route, CHO is rapidly eliminated and excreted into the urine. Furthermore, after either oral or dermal administration, it is unlikely that CHO reaches the systemic circulation intact due to its rapid metabolism, and is therefore unable to cause toxicity in the whole animal under the test conditions used in this study.     

Effects of prenatal exposure to 5-fluoro-2'-deoxyuridine on developing central nervous system and reproductive function in male offspring of mice

The effect of 5-fluoro-2'-deoxyuridine (FrdU) on the developing brain and postpubertal reproductive function of male mouse offspring treated prenatally was investigated. FrdU was administered intraperitoneally to pregnant ICR mice at 1.5, 3, 6, 12.5, 25, and 50 mg/kg/day on days 8 through 13 of gestation or 12.5, 25, and 50 mg/kg/day on days 14 through 18 of gestation. Dams were allowed to deliver spontaneously. Dams treated with FrdU at 12.5, 25, and 50 mg/kg/day on days 8 through 13 of gestation did not deliver because of entire intrauterine death of embryos. Male offspring were aged for 10 or 15 weeks and then cohabited with untreated female mice for assessment of reproductive performance. Histological examination of the testis, epididymis, prostate, and seminal vesicle of offspring at 12 weeks of age, and sperm analysis of offspring at 12 or 17 weeks of age were performed. Dose-dependent decreases in body weight gain were noticed throughout the life of offspring. A marked decrease in the copulation rate was noted in the group treated with FrdU at 6 mg/kg/day on days 8 through 13 of gestation. However, neither histological examination of testes and sex-accessory glands nor sperm analysis revealed adverse effects of FrdU on the reproductive function in the male offspring of dams treated with FrdU at 6 mg/kg/day on days 8 through 13 of gestation. There were no significant differences in the relative weight of testes and epididymides between the group treated with FrdU at 6 mg/kg/day on days 8 through 13 of gestation and the control group. Absolute brain weight in the groups treated with FrdU on days 8 through 13 of gestation significantly decreased, while relative brain weight increased in the group treated at 6 mg/kg/day on days 8 through 13, and at 25 and 50 mg/kg/day on days 14 through 18 of gestation. Dilatation of the lateral and third ventricles was observed in all of the male offspring of dams treated with FrdU at 6 mg/kg/day on days 8 through 13 of gestation, when inspected at 12 and 17 weeks of age. In the subsequent study, ICR mice were treated intraperitoneally with FrdU at 6.25-100 mg/kg on day 12 of gestation, and the fetuses obtained 24 h after treatment. Histological observation was performed in the ventricular zone of telencephalon, and in the ependymal and mantle layers of diencephalon in the fetal brain. The incidence of pyknotic cells in these areas was increased linearly with increasing FrdU dose. From these results and our previous findings, we suggest that damage to the central nervous system, a substantial neuronal deficit, resulting from excessive cell death in the developing brain may lead to reproductive dysfunction after puberty.     

Effects of dopaminergic drugs on innate pheromone-mediated reward in female mice: A new case of dopamine-independent "liking."

Male sexual pheromones are innately rewarding to adult female mice, but the role of dopamine in this natural reward is unknown. The authors have tackled this issue by assessing the effects of intraperitoneal injections of dopamine D? (SCH 23390, 0.02- 0.05mg/kg) and D? (sulpiride, 20.00 mg/kg) antagonists, a dopamine releasing agent (amphetamine, 0.50 -2.00 mg/kg), and D? (SKF 38393, 10.00 -20.00 mg/kg) and D? (quinpirole, 0.20 -1.00 mg/kg) agonists on the chemoinvestigation displayed by female mice in male- versus female-soiled bedding 2-choice tests. Dopamine antagonists and quinpirole failed to affect the unconditioned preference displayed by females towards male chemosignals, whereas both amphetamine and SKF 38393 abolished it. Finally, D? and D? antagonists did not block the induction of operant place conditioning by male chemosignals. As the female mice were tested in their first encounter with male sexual pheromones, their behavior can only be influenced by the "liking" component of reward. Therefore, the results suggest that dopamine mediates neither the hedonic properties of male sexual pheromones nor the acquisition of conditioned place preference. However, dopamine acting on D1 receptors might inhibit female mice attraction towards male chemosignals. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The disposition of allyl isothiocyanate in the rat and mouse

The urine was the major route of excretion of radioactivity (50-80% of dose) following the oral administration (2.5 and 25 mg/kg body weight) of allyl[14C]isothiocyanate (AITC) to male and female Fischer 344 rats and B6C3F1 mice. Smaller amounts were found in the faeces (6-12%) and expired air (3-7%). The major difference between the two species was the greater retention of radioactivity after 4 days within rats (18-24% of dose) when compared with mice (2-5% of dose). Three radioactive components were found in the urine of mice and two in rats. The three components were inorganic thiocyanate, allylthiocarbamoylmercapturic acid and allylthiocarbamoylcysteine in mice, but no cysteine conjugate was found in rat urine. In the mouse, approximately 80% of the 14C was present in the urine as the thiocyanate ion whereas in the rat some 75% was as the mercapturate. This indicates that in the mouse, hydrolysis of AITC was the major metabolic pathway whereas in the rat glutathione conjugation was the major route. A species difference was seen in the amount of [14C]AITC-derived radioactivity present in the whole blood of rats and mice; measurable levels of radioactivity remained within rat blood for a longer time period (up to 240 hr) when compared with mice (96 hr). Examination of the urinary bladders of male and female rats following oral dosing with [14C]AITC showed a sex difference with greater amounts of [14C]AITC and/or its metabolites within the bladder tissue of male rats. This data is discussed in terms of the known species- and sex-specificity of the urinary bladder tumours, which occurred after long-term administration to male rats, but not to female rats or mice of either sex, in a carcinogenicity study conducted by the National Toxicology Program in the USA.     

Prenatal cocaine, alcohol, and undernutrition differentially alter mineral and protein content in fetal rats

Alcohol exposure and undernutrition during pregnancy have been associated with altered fetal body composition. Recent observations suggest that cocaine exposure during pregnancy may impair delivery of nutrients to the fetus and could thereby alter body growth and composition. Such effects are important because they can adversely influence physical and neural development. Consequently, we investigated the dose-dependent effects of cocaine on fetal body composition in an animal (rat) model and compared such effects with those caused by prenatal alcohol exposure and undernutrition. Pregnant Sprague-Dawley rats received either 20, 30, 40, or 50 mg/kg cocaine HCl (SC) twice daily from gestation days 7 through 19. Pair-fed (undernutrition) and untreated control groups and a group receiving 3.0 g/kg alcohol (PO) twice daily served as comparison groups (n = 11 to 14/group). Females were sacrificed on gestation day 20. One male and one female fetus was removed from each dam. The fetuses were minced, dehydrated, defatted, and analyzed for content of protein and the minerals Zn, Ca, Fe, Mg, K, and Na. In terms of concentration per unit of fat-free dry solids, male fetuses in the cocaine groups showed significant decreases in protein compared to untreated controls (15+/-3 to 20+/-2 mg/g vs. 24+/-4 mg/g, p = 0.01). There was a significant treatment effect for Ca (p < 0.05), reflecting a trend for decreased Ca concentrations in the fetuses of the cocaine and undernutrition groups. Male fetuses in the alcohol group had significantly elevated Mg levels compared to male fetuses in the other groups (3.0+/-0.8 vs. 1.0+/-0.2 to 2.3+/-0.7 mg/g, p < 0.05). There were some sex differences, with female fetuses having significantly lower concentrations of Mg, Fe, K, and higher protein concentrations than male fetuses. Although the effects were few and modest, these results suggest that prenatal cocaine, alcohol, and undernutrition can differentially alter fetal body weight and composition and, therefore, adversely influence fetal development.     

Overexpression of transforming growth factor !a in transgenic mice alters nonreproductive, sex-related behavioral differences: Interaction with gonadal hormones.

Sexually dimorphic differences in voluntary sodium intake, locomotor activity, immobility in the swim test, and aggressive behavior were found to be altered in transgenic CD-1 mice that overexpressed transforming growth factor α (TGFα). In contrast to nontransgenic CD-1 mice, immobility in the swim test was longer and sodium intake higher in the male TGFα mice than in the female TGFα mice. These findings indicate that the male TGFα mice exhibited feminization of some behaviors. Furthermore, the male TGFα mice were highly aggressive. Castration reversed the behavioral effects in the adult male transgenic mice, but ovariectomy did not reverse the behavioral effects in the adult female transgenic mice. Thus, the feminizing effect of TGFα on some nonreproductive behaviors and increased aggressive behavior in male mice may be mediated through an interaction between this growth factor and gonadal hormones. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Levonorgestrel as a postcoital contraceptive

Time-release pellets of levonorgestrel (LNG), the progestogenic hormone contained in the contraceptive system Norplant, were implanted subdermally in mice, after the animals had mated and ovulated but before uterine implantation of embryos would have occurred, to examine whether the hormone could reduce the number of embryos that subsequently implanted and, if so, when it had to be administered in the postcoital period to achieve that effect. Hybrid female mice (C57BL x CBA) were paired with breeder males (CD-1) and LNG pellets were implanted on day 0, the day on which copulation plugs were found, or on day 2 or day 3 in the postcoital period. Mice in some groups were sacrificed on day 14 of the gestation period, and numbers of fetuses and/or resorption sites were counted, while mice in other groups were allowed to go to term. When LNG pellets were implanted subdermally on day 0 of the postcoital period, pellets designed to release 1.5 mg of hormone in 21 days failed to exhibit a contraceptive effect, but pellets designed to release 5 mg of hormone in 90 days were totally effective in preventing uterine implantation of embryos. Although the 5 mg pellets did not prevent embryos from implanting in all cases when administered on day 2, they prevented pregnancies from going to term by causing resorption of those embryos that did implant. When the pellets were implanted as late as day 3 in the postcoital period, uterine implantation of embryos occurred and fetuses were carried to term. Results of the study indicate that subdermal implants of LNG inserted postcoitally can prevent uterine implantation of embryos in mice, and thereby prevent pregnancy, despite fertilization of oocytes having occurred, if the hormone implants are inserted before day 3 of the postcoital period.     

Lordosis behaviour in male, female and androgenized female rats

Sex differences in the lordodis response of adult rats to ovarian hormones were studied in a series of experiments. Male rats were less sensitive to oestradiol benzoate (OB, a single injection of 10, 100 or 1000 mug/kg or seven daily injections of 2, 10, or 50mglkg)then were female rats. Oestradiol benzoate-primed (10 mglkg)female, but not male, rats showed dose-dependent responses to progesterone (0-4, 2-0 or 10-0 mg/kg/. male rats responded clearly to progesterone (2 mg/rat) only when primed with a high dose of OB (100 mug/rat). Display of the whole pattern of female sexual behaviour was induced in male rats by treatment with 100 mug OB and 2 mg progesterone. Female rats treated with 1 mg testosterone propionate (TP) on day 4 of life, ovariectomized as adults and tested under the same endocrine conditions as the rats described above, retained behavioural OB sensitivity but responded poorly to progesterone. Evidence is presented that ovarian secretions during development significantly modify the response of neonatally TP-treated and normal female rats to OB in adulthood.     

T validity of the diagnosis of urinary tract infection in children under two years of age]

To examine the toxicity of cyclosiloxanes (CSs), the predominant low molecular weight cyclic silicones found in breast implants, we injected female CD-1 mice intraperitoneally with different doses of distillate (3.5-35 g/kg body weight) containing cyclosiloxane D3 (hexamethylcyclotrisiloxane; CS-D3), cyclosiloxane D4 (octamethylcyclotetrasiloxane; CS-D4), cyclosiloxane D5 (decamethylcyclopentasiloxane; CS-D5), and cyclosiloxane D6 (dodecamethylcyclohexasiloxane; CS-D6). The distillate was found to be lethal and all the mice injected with 35 g/kg died within 5-8 days. The median lethal dose (LD50) for distillate was estimated to be approximately 28 g/kg. These mice developed inflammatory lesions of the lung and liver as well as liver cell necrosis with elevated serum levels of alanine aminotransferase, aspartate aminotransferase, and lactic acid dehydrogenase. Administration of CS-D4 alone also produced lethality in these mice with an LD50 of 6-7 g/kg. CS-D4-treated mice also exhibited pulmonary and hepatic lesions and elevated serum enzymes. Analysis of LD50 data indicates that CS-D4 is about as toxic as carbon tetrachloride or trichloroethylene. We measured hydroxyl radical formation in CS-D4-treated mice and found increases of approximately 20-fold in liver and approximately 7-fold in lung on day 4 following injection. Our findings are significant because in vitro experiments have demonstrated that CSs can migrate out of breast implants, and in mouse experiments CSs have been shown to be widely distributed in many organs after a single subcutaneous injection and to persist for at least a year.