Estrus- and ovariectomy-induced body weight changes: Evidence for two estrogenic mechanisms.

Estrogenic modulation of body weight in female rats is usually thought to result indirectly from estrogenic modulation of food intake. However, present data from 5 experiments with 79 female albino rats suggest that estrogens influence body weight by at least 2 mechanisms, 1 of which is independent of changes in food intake. When Ss were ovariectomized (Ovx) and food intake was limited to preoperative levels, Ovx Ss nonetheless gained large amounts of body weight. Although Ovx Ss gained more weight than controls on the same amount of food, during 33 hrs of food deprivation Ovx and control Ss lost weight at the same rate, indicating that the prefasting metabolic rates of the 2 groups were similar. During the 1st 40 days after surgery, the ano-nasal lengths of Ovx Ss increased twice as fast as that of intact Ss, which suggests a mechanism for the gradual increase in weight induced by Ovx. The weights of intact Ss followed a regular 4-day cycle during ad lib feeding, but when the estrus-associated decrease in food intake was prevented, the cyclic weight changes were altered. Thus estrogens appear to regulate body weight by modulation of food intake and modulation of ano-nasal growth or other metabolic processes. (22 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Selective block of tetramethrin-modified sodium channels by (+/-)-alpha-tocopherol (vitamin E)

Pyrethroids exert their hyperexcitatory effects by prolonging the open time of individual neuronal sodium channels. Occupational exposure to pyrethroids frequently leads to abnormal skin sensation or paresthesia. Vitamin E is known to reduce the cutaneous paresthesia. However, the mechanism of action has been totally unclear. Because the sodium channel is the major target site of pyrethroids, it is possible that vitamin E interferes with pyrethroid modification of the sodium channel. Patch clamp experiments were performed using rat dorsal root ganglion neurons and cerebellar Purkinje cells. (+/-)-alpha-Tocopherol (vitamin E) selectively blocked the tetramethrin(type I pyrethroid)-modified sodium channels in a dose-dependent, but voltage-independent manner without affecting normal sodium channels. The concentration-response curves for tetramethrin modification of the sodium channels were shifted in the direction of higher concentrations by (+/-)-alpha-tocopherol in a competitive manner. Elevated depolarizing after-potential or repetitive after-discharges caused by tetramethrin were effectively blocked by (+/-)-alpha-tocopherol. (+/-)-alpha-Tocopherol did not reverse the tetramethrin-induced shift in the current-voltage curve for peak sodium current, but partially reversed the shift in the steady-state sodium channel inactivation curve. Vitamin A and its metabolic derivative, retinoic acid, slightly reduced both normal and tetramethrin-modified sodium currents. The selective block of tetramethrin-modified sodium channels by (+/-)-alpha-tocopherol is one of the important mechanisms underlying (+/-)-alpha-tocopherol alleviation of paresthesia.     

Effects of green tea and black tea on 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone bioactivation, DNA methylation, and lung tumorigenesis in A/J mice

Previous studies in our laboratory showed that decaffeinated green tea and black tea extracts inhibited 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced tumorigenicity in A/J female mice. In order to understand the mechanism of the inhibitory action, we examined the effects of decaffeinated green tea, black tea, and tea components on the metabolic activation of NNK in vitro and in vivo in this animal model. When added to incubation mixtures containing mouse lung microsomes, decaffeinated green tea and black tea extracts and their fractions, at concentrations up to 0.4 mg/ml, inhibited NNK oxidation and NNK-induced DNA methylation. Among the tea components examined, (-)-epigallocatechin-3-gallate was the most potent inhibitor with 50% inhibitory concentrations of about 0.12 mM for both NNK oxidation and DNA methylation. At these concentrations, (-)-epigallocatechin-3-gallate inhibited the catalytic activities of several P450 enzymes and was more potent against P450 1A and 2B1 than 2E1. When decaffeinated green or black tea extracts were given to female A/J mice as the sole source of drinking fluid before an i.p. injection of NNK (100 mg/kg body weight), a statistically significant inhibition of lung DNA methylation, however, was not observed, although a significant reduction in lung tumor multiplicity was observed. The results suggest that, although inhibition of the metabolic activation of NNK and the subsequent DNA alkylation by tea extracts can be demonstrated in vitro, this mechanism may not be important for the inhibitory action of tea against lung tumorigenesis.     

Developmental and behavioral effects of prenatal primidone exposure in the rat

Pregnant Sprague-Dawley rats were administered primidone (PRM) by oral gavage on gestation days 8-17 in doses of 0.40, and 80 mg/kg. Although these doses of PRM did not produce significant differences in litter size, birth weight, mortality, date of attainment of developmental landmarks or measures of preweaning reflex and motor development, there were a number of significant differences that developed as the animals approached and entered adulthood. When tested as adults, the 80 mg/kg male rats showed a deficit in the performance of an eight-arm radial maze task. These same animals showed a significant reduction in open field activity when tested as adults. In addition, both male and female PRM-treated animals showed reduced body weights at different periods corresponding to onset of sexual maturation during development. These findings are consistent with the larger body of literature reporting on the neurobehavioral teratology of phenobarbital, including its ability to produce lesions in the hippocampus and endocrine dysfunction resulting in reproductive deficits. These results suggest that PRM produces its adverse effects as a result of its metabolism to phenobarbital, which in turn affects the limbic system.     

Differential responses of estrogen target tissues in rats including bone to clomiphene, enclomiphene, and zuclomiphene

The substituted triphenylethylene antiestrogen clomiphene (CLO) prevents cancellous bone loss in ovariectomized (OVX'd) rats. However, CLO is a mixture of two stereoisomers, enclomiphene (ENC) and zuclomiphene (ZUC), which have distinctly different activities on reproductive tissues and tumor cells. The purpose of the present dose response study was to determine the effects of ENC and ZUC on nonreproductive estrogen target tissues. These studies were performed in 7-month-old female rats with moderate cancellous osteopenia that was established by ovariectomizing rats 1 month before initiating treatment. OVX resulted in increases in body weight, serum cholesterol, endocortical resorption, and indices of cancellous bone turnover, as well as decreases in uterine weight, uterine epithelial cell height, bone mineral density, bone strength, and cancellous bone area. Estrogen treatment for 3 months restored body weight, uterine histology, dynamic bone measurements, and osteoblast and osteoclast surfaces in OVX'd rats to the levels found in the age-matched sham-operated rats. In contrast, estrogen only partially restored cancellous bone volume and uterine weight, and it reduced serum cholesterol to subnormal values. CLO was a weak estrogen agonist on uterine measurements and a much more potent agonist on body weight, serum cholesterol, and dynamic bone measurements. CLO increased trabecular thickness in osteopenic rats and was the most effective treatment in improving cancellous bone volume and architecture. ZUC was a potent estrogen agonist on all tissues investigated and had dose-dependent effects. In contrast, ENC had dose-dependent effects on most measurements similar to CLO and decreased the uterotrophic effects of ZUC. It is concluded that ENC antagonizes the estrogenic effects of ZUC on the uterus but that the beneficial effects of CLO on nonreproductive tissues in OVX'd rats is conferred by both isomers. Furthermore, the combined actions of the two isomers on bone volume and architecture were more beneficial than either isomer given alone.     

Development of a physiologically based model for the toxicokinetics of C(+/-)P(+/-)-soman in the atropinized guinea pig

A physiologically based model was developed which describes the in vivo toxicokinetics of the highly reactive nerve agent C(+/-)P(+/-)-soman at doses corresponding to 0.8-6 LD50 in the atropinized guinea pig. The model differentiates between the summated highly toxic C(+/-)P(-)-soman stereoisomers at supralethal doses and the individual nontoxic C(+/-)P(+)-isomers. Several toxicant-specific parameters for the soman stereoisomers were measured in guinea pig tissue homogenates. Cardiac output and blood flow distribution were measured in the atropinized, anesthetized, and artificially ventilated guinea pig. The model was validated by comparison of the time courses for the blood concentrations of the two pairs of stereoisomers in the guinea pig after i.v. bolus administration with the blood concentrations predicted by the model. The predictions put forward for the summated C(+/-)P(-)-isomers are in reasonable agreement with the experimental data obtained after doses corresponding to 2 and 6 LD50. In view of large differences in the rates of hydrolysis of the C(+/-)P(+)-isomers, these two isomers had to be differentiated for satisfactory modeling of both isomers. In order to model the toxicokinetics of C(+/-)P(-)-soman at a dose of 0.8 LD50, the almost instantaneous elimination of the C(+)P(-)-isomer at that dose had to be taken into account. The sensitivity of the predictions of the model to variations in the parameters has been studied with incremental sensitivity analysis. The results of this analysis indicate that extension to a model involving four individual stereoisomers is desirable in view of large differences in the biochemical characteristics of the two C(+/-)P(-)- and C(+/-)P(+)-isomers.     

Effects of p,p'-DDE on male reproductive organs in peripubertal Wistar rats following a single intraperitoneal injection

The effects of p,p'-DDE on male reproductive organs were investigated in detail in peripubertal Wistar rats following a single intraperitoneal injection. 220 mg/kg of p,p'-DDE (1/4 of LD50) were injected once into prepubertal and postpubertal Wistar rats and its effects were observed until 20 weeks of age. Weights of the body and reproductive organs in p,p'-DDE-injected rats were similar to those in control rats, who were injected with corn oil only. Sperm profile parameters such as spermatid number within the testis, sperm number within the epididymis, sperm motility and its morphology were not different between the prepubertal or postpubertal p,p'-DDE-exposed group and the control group. Like-wise, the histopathological examination at stage VII of the seminiferous epithelium cycle, when the germ cells are sensitive to testosterone, was similar in all three groups during the observation period. Serum levels of testosterone also showed no significant changes by exposure to p,p'-DDE under the conditions of this study. From these results, the antiandrogenic or estrogenic activity attributed to p,p'-DDE was not confirmed in male reproductive organs and no impairment of sperm profile was observed. This study confirmed that the reproductive functions of matured animals are scarcely affected by p,p'-DDE exposure during the peripubertal period and revealed that they might be relatively resistant to exogenous endocrine-disrupting chemicals. p,p'-DDE may threaten the hormonal equilibrium required for normal gonadal development during the organogenesis period, at an earlier stage of life. Further studies are necessary to fully reveal all the effects of p,p'-DDE on male reproductive organs and sperm profile.     

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.     

Estrogen effects on the hyperactivity induced by (+)-MDMA and cocaine in female rats.

This study compared the effects of estrogen (E) on the hyperactivity induced by (+)-3,4-methylenedioxymethamphetamine (MDMA) with E effects on cocaine-evoked hyperactivity in female rats. Sprague-Dawley rats were ovariectomized (OVX); half of them received a 17β-estradiol (E?) implant (OVX + E). Three weeks later, rats received saline, (+)-MDMA (1, 2, or 4 mg/kg) or cocaine (5, 10, or 20 mg/kg), and locomotor activity was monitored. OVX + E rats exhibited greater locomotor hyperactivity in response to both psychostimulants than did OVX rats. The enhanced response to cocaine appeared within 5 min following drug injection whereas the enhanced response to (+)-MDMA was delayed for approximately 30 min. The differential effects of E on hyperactivity may be due to the unique profiles of dopamine (DA) and serotonin (5-HT) in response to (+)-MDMA and cocaine. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Effects of androgens on dietary self-selection and carcass composition in male rats.

In 3 experiments the aromatizable androgen testosterone propionate (TP, .2 mg/day) increased protein (P) and carbohydrate (C) intake and stimulated body weight gain (BWG) in gonadectomized CD-strain male rats. A higher dose (2.0 mg/day) increased P but not C intake and was less effective in stimulating BWG. Postmortem carcass analyses revealed that the elevated P intake of both TP-treated groups was associated with increased carcass P content. The decreased weight of Ss treated with the high dose of TP was due to a reduction in body fat content. The nonaromatizable androgen 5-α-dihydrotestosterone propionate (DHTP, .2 or 2.0 mg/day) also increased P, (but not C intake) and BWG, but it did not alter carcass composition. Unlike TP, the 2 doses of DHTP were equally effective, but neither dose of DHTP was as effective as the low dose of TP in stimulating P and C intake and BWG. Results suggest that (a) androgens can increase selection of dietary P whether or not they exert significant P anabolic effects; (b) DHTP is not the major metabolite responsible for the increases in P and C intake and in BWG caused by TP; and (c) the decreases in C intake and adiposity in rats treated with the high dose of TP may be mediated by aromatized (estrogenic) metabolites of the androgen. (38 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Parathyroid hormone (1-34) and (1-84) stimulate cortical bone formation both from periosteum and endosteum

The anabolic effect of intermittent treatment with parathyroid hormone (PTH) on cortical bone was investigated. Groups of rats were injected with human PTH (1-34) or PTH (1-84), 1.1, 3.3, 10, and 30 nmol/kg/day for 30 days. A dose-related increase in bone formation rate at the femoral middiaphysis was found at both the periosteum and the endosteum and also an increase in bone mass, with no change in the bone lengths or body weight gain of the rats. The highest mineral apposition rate, as analyzed by tetracycline labeling, was found at the periosteal postero-medial aspect and at the endosteal anterior aspect. This pattern of bone modeling was also found in the PTH-treated animals, although more and more areas were included in bone mineral apposition. The PTH treatments did not change the porosity of the cortical bone nor the concentration and biochemical stability of the collagen. The highest doses of PTH resulted in a slight reduction in the ash concentration of cortical bone. No differences were found between the effects of PTH (1-34) and PTH (1-84) on bone formation rate, bone mass, porosity, and biochemical parameters. Consequently, intermittent treatment with PTH increased the formation of cortical bone dose dependently, at both the periosteum and the endosteum and increased the bone mass of these growing rats, with no change in the body weight gain or femoral growth rate compared with the control animals. The responses of the cortical bone modeling were increased by the PTH treatments without changing its direction or pattern.     

Inhalation teratology and reproduction studies with 1,1-dichloro-2,2,2-trifluoroethane (HCFC-123)

HCFC 123 is one of the chemicals being developed as a replacement for CFC 11 in refrigerant and solvent applications. Supplementing earlier rat teratology studies, a rabbit inhalation teratology study was conducted. In addition, one-generation and two-generation inhalation reproduction studies were conducted. In the teratology study, the pregnant rabbits were exposed to levels of 0 (control), 500, 1500, and 5000 ppm, 6 hr per day from Days 6 through 18 of gestation. Slight body weight losses and reduced food consumption were seen in does in all three exposure level groups. This response followed an exposure-related pattern. There were no other signs of maternal toxicity. There was also no evidence of treatment-related effects on the kits. A probe one-generation reproduction study was conducted. In this study four groups of 12 male and 12 female rats were exposed to vapors of HCFC 123 6 hr per day, 7 days per week from 4 weeks prior to mating through weaning of their offspring. The exposure levels for this study were 0 (control), 300, 1000, and 5000 ppm. There were no effects on mating and fertility, or on pup survival or birth weight. A two-generation study was subsequently conducted. In this study, five groups of 32 male and female rats were exposed to HCFC 123 from 6 weeks of age through weaning. From the offspring of these animals, groups of 28 males and females were selected for the F1 generation. These animals were exposed to HCFC 123 from weaning (4 weeks of age) through weaning of the F1 generation. All exposures were 6 hr per day, 7 days per week. The exposure levels for this study were 0 (control), 30, 100, 300, and 1000 ppm. There were no effects on any of the fertility or reproductive indices measured. As with prior studies, decreases in serum triglyceride levels were seen. Pup survival and birth weight were unaffected by treatment. Pup body weight gain was lower in all treatment groups during nursing, following an exposure-related pattern. Since weight gain for the F1 animals was normal following weaning, this depression of body weight gain may be related to the depression of serum triglycerides. In addition, liver weights of the adult rats exposed to levels of 100 ppm and higher of HCFC 123 were higher than controls, histological examination revealed only hepatic enlargement and vacuolation. It was concluded that exposure to HCFC 123 did not cause reproductive effects although it did effect the body weight gain of the offspring during lactation.     

Argon laser punctal therapy versus thermal cautery for the treatment of aqueous deficiency dry eye syndrome

1. Pregnant Wistar rats were treated orally with a single dose of 100 microg 3,3',4,4'-tetrachlorobiphenyl (PCB 77)/kg b.w. or 10 microg 3,3',4,4',5 pentachlorobiphenyl (PCB 126)/kg b.w. on day 15 of pregnancy. The control rats received peanut oil at the same day. Developmental landmarks were assessed in all offspring rats and reproductive effects of PCB 77 and PCB 126 on male offspring were studied on postnatal day 65 (at puberty) and on postnatal day 140 (at adulthood). 2. The ano-genital distance as well as the ratio ano-genital distance to body length was reduced in male pups of the PCB 126 group and the age at vaginal opening was significantly delayed in the female pups. 3. Testis, brain weights and daily sperm production were permanently increased and seminal vesicle weights were decreased in male offspring of the PCB 77 group. In male rats of PCB 126 group, the brain weights were permanently increased and ventral prostate weights permanently reduced. In both PCB groups, however, serum testosterone concentration was reduced only at adulthood. Additionally, the male rats of the PCB 126 group showed alterations in sexual behavior. In these rats the number of mounts with intromissions was significantly increased. 4. The results of this study show that PCB 126 elicits some TCDD-like reproductive effects after in utero exposure, while the reproductive effects of in utero exposure to PCB 77 on male offspring may be attributed to the neonatal hypothyroidism induced by the substance during early fetal development. Further studies using multiple doses and providing thyroid hormone data will be necessary to support this hypothesis.     

Effect of cimetidine on weight gain in rats

Effect on food intake and body weight was studied in rats after oral administration of cimetidine. Rats in experimental (E) group exhibited less increase in food intake (20%) compared to control (C) rats (43.8%). Mean body weight showed first reduction (-9.56%) and then very small increment in experimental animals compared to gradual gain in body weight in control animals. At the end of 6 weeks, total gain in body weight was 22.5 gm in rats of E group against 53.8 gm in rats of C group. Food efficiency ratio (FER) showed much reduction (1.13) in E group against 2.07 in C group. These results demonstrate that cimetidine (H2-receptor blocker) may have ability to reduce food intake and body weight in rats.     

The xenoestrogen bisphenol A induces growth, differentiation, and c-fos gene expression in the female reproductive tract

The xenoestrogen bisphenol A (BPA) has been shown to mimic estrogen both in vivo and in vitro. BPA stimulates PRL secretion and the expression of a PRL regulating factor from the posterior pituitary in the estrogen-sensitive Fischer 344 rat (F344), but not in Sprague-Dawley (SD) rats. The goal of the present studies was to examine the in vivo actions of BPA on the reproductive tract. The specific objectives were 1) to characterize the short term effects of BPA on cell proliferation and c-fos expression in the uterus and vagina, and 2) to compare the effects of prolonged exposure to low doses of BPA on the reproductive tract of F344 and SD rats. Treatment with single high doses of BPA induced cell proliferation in the uterus and vagina of ovariectomized F344 rats, as determined by bromodeoxyuridine immunostaining. This proliferation was dose dependent (from 37.5-150 mg/kg) and followed a time course similar to that of estradiol (E2). Quantitative RT-PCR revealed that both BPA and E2 increased c-fos messenger RNA levels in the uterus 14- to 16-fold within 2 h, which returned to basal levels after 6 h. In the vagina, BPA-induced c-fos expression remained elevated for up to 6 h, compared with the transient increase caused by E2. Treatment of F344 rats for 3 days with continuous release capsules that supplied a much lower dose of BPA (approximately 0.3 mg/kg x day) resulted in hypertrophy, hyperplasia, and mucus secretion in the uterus and hyperplasia and cornification of the vaginal epithelium. The reproductive tract of SD rats did not respond to this treatment paradigm with BPA. These studies demonstrate that 1) the molecular and morphological alterations induced by BPA in the uterus and vagina are nearly identical to those induced by estradiol; 2) the vagina appears to be especially sensitive to the estrogenic actions of BPA; 3) the reproductive tract of the inbred F344 rat appears more sensitive to BPA than that of the outbred SD rat; and 4) continuous exposure to microgram levels of BPA is sufficient for exerting estrogenic actions.     

Effect of quinidine on the interconversion kinetics between haloperidol and reduced haloperidol in humans: implications for the involvement of cytochrome P450IID6

Unequal metabolic responses to trauma by women and men have been suggested, but an explicit investigation demonstrating this conjecture has not been made. The responses of resting energy expenditure (REE) and nitrogen balance for 3 days before and 7 days after skeletal trauma were determined for female and male rats. Food intake and body weight were recorded daily, and 24-h urine samples were collected. Baseline REE and nitrogen balance were obtained for 3 consecutive days before induction of trauma. Then rats were divided into female trauma (n = 8), male trauma (n = 7), female control (n = 8), and male control (n = 7) groups. Trauma was produced by bilateral femoral fracture to anesthetized rats. Control rats were anesthetized without skeletal trauma. Traumatized rats were fed ad libitum for 7 days, and control rats were pair fed with the traumatized rats. The results showed that REE increased and nitrogen balance decreased in traumatized male rats relative to their controls. Traumatized female rats had increased REE and unchanged nitrogen balance compared with their controls. Traumatized female rats had a larger percentage increase in REE on days 5 through 7 than did traumatized male rats. These findings demonstrate a difference between female and male rats in response to trauma. Female rats use more energy and lose less nitrogen after trauma than do male rats. The results suggest that recommendations for increased energy and protein needs after trauma should consider the sex of the subject intended to be fed.     

A physiologically based approach to the study of bisphenol A and other estrogenic chemicals on the size of reproductive organs, daily sperm production, and behavior

Two chemicals previously shown to have estrogenic activity, bisphenol A and octylphenol, were examined for their effects on accessory reproductive organs and daily sperm production in male offspring of mice fed these chemicals during pregnancy. These chemicals are used in the manufacture of plastics and other products, and have been detected in food and water consumed by animals and people. From gestation day 11-17 female mice were fed an average concentration (dissolved in oil) of bisphenol A or octylphenol of 2 ng/g body weight (2 ppb) and 20 ng/g (20 ppb). The 2 ppb dose of bisphenol A is lower than the amount reported to be swallowed during the first hour after application of a plastic dental sealant (up to 931 micrograms; 13.3 ppb in a 70 kg adult). We found that the 2 ng/g dose of bisphenol A permanently increased the size of the preputial glands, but reduced the size of the epididymides; these organs develop from different embryonic tissues. At 20 ng/g, bisphenol A significantly decreased efficiency of sperm production (daily sperm production per g testis) by 20% relative to control males. The only significant effect of octylphenol was a reduction in daily sperm production and efficiency of sperm production at the 2 ng/g dose. A new approach to studying physiologically relevant doses of environmental endocrine disruptors is discussed, particularly with regard to the development of the reproductive organs, the brain, and behavior.     

Repeated intracerebroventricular administration of glucagon-like peptide-1-(7-36) amide or exendin-(9-39) alters body weight in the rat

Central nervous system glucagon-like peptide-1-(7-36) amide (GLP-1) administration has been reported to acutely reduce food intake in the rat. We here report that repeated intracerebroventricular (i.c.v.) injection of GLP-1 or the GLP-1 receptor antagonist, exendin-(9-39), affects food intake and body weight. Daily i.c.v. injection of 3 nmol GLP-1 to schedule-fed rats for 6 days caused a reduction in food intake and a decrease in body weight of 16 +/- 5 g (P < 0.02 compared with saline-injected controls). Daily i.c.v. administration of 30 nmol exendin-(9-39) to schedule-fed rats for 3 days caused an increase in food intake and increased body weight by 7 +/- 2 g (P < 0.02 compared with saline-injected controls). Twice daily i.c.v. injections of 30 nmol exendin-(9-39) with 2.4 nmol neuropeptide Y to ad libitum-fed rats for 8 days increased food intake and increased body weight by 28 +/- 4 g compared with 14 +/- 3 g in neuropeptide Y-injected controls (P < 0.02). There was no evidence of tachyphylaxis in response to i.c.v. GLP-1 or exendin-(9-39). GLP-1 may thus be involved in the regulation of body weight in the rat.     

Flaxseed and its lignan precursor, secoisolariciresinol diglycoside, affect pregnancy outcome and reproductive development in rats

Flaxseed is the richest source of the mammalian lignan precursor secoisolariciresinol diglycoside (SDG). Because lignans have estrogen agonist or antagonist properties, the objective of this study was to determine whether feeding flaxseed to rats during a hormone-sensitive period has reproductive effects. Rat dams were fed a basal diet or the basal diet supplemented with 10% flaxseed, 5% flaxseed or SDG at the level in 5% flaxseed during pregnancy and lactation. At weaning, the offspring were fed the basal diet. Flaxseed had no effect on pregnancy outcome except that the 10% flaxseed diet lowered birth weight (P < 0.05), compared with other treatments, and produced hormonal effects. The female offspring had shortened anogenital distance, greater uterine and ovarian relative weights, earlier age and lighter body weight at puberty, lengthened estrous cycle and persistent estrus (P < 0.05), whereas the males had reduced postnatal weight gain and, at postnatal d 132, greater sex gland and prostate relative weights (P < 0.05), suggesting estrogenic effects. In contrast, compared with the basal diet, 5% flaxseed reduced immature ovarian relative weight by 29% (P < 0.05), delayed puberty by approximately 5 d (P < 0.05) and tended to lengthen diestrus, indicating an antiestrogenic effect. The SDG produced results similar to those of 5% flaxseed, suggesting that lignans were responsible for the observed effects. Lignans were transferred to the offspring via rat dam's milk as indicated by the recovery of radioactivity in the offspring of lactating dams given 3H-SDG. Because flaxseed affects the reproductive development of offspring, caution is suggested when consuming flaxseed during pregnancy and lactation.     

Effect of the high-affinity estrogen receptor ligand ICI 182,780 on the rat tibia

We examined the specificity of the steroidal antiestrogen ICI 182,780 (ICI) on bone and reproductive tissues in adult and growing female rats. Using a 1.5-mg/kg dose (s.c.), we evaluated the effects of ICI on the bone, body weight, uterine weight, serum cholesterol, and serum estradiol in either adult and/or growing rats. ICI increased serum estradiol cholesterol in ovary-intact rats, had no effect on uterine weight in ovariectomized rats, and resulted in uterine atrophy in ovary-intact animals comparable with ovariectomy. In contrast, ICI had no effect on body weight. In bone, ICI significantly increased the rate of periosteal bone formation in long bones of growing and mature female rats. In contrast, ICI had no effect on longitudinal bone growth in rapidly growing rats. When ICI was administered to mature rats with or without ovaries, two-factor ANOVA revealed significant interaction (P < or = 0.05) between ovariectomy and ICI treatment for cancellous bone area and labeled bone perimeter. ICI increased skeletal indices of bone turnover in the cancellous bone of ovary-intact rats but reduced these indices of bone turnover in the cancellous bone of ovariectomized rats. The increase in bone turnover was associated with a reduction in cancellous bone area in the ovary-intact rats. A reduction in bone turnover was similarly associated with an increase in bone area in the ICI-treated ovariectomized rats. In summary, ICI exhibited complete estrogen antagonism in cortical and cancellous bone, partial agonism in cancellous bone, and no activity on tibial longitudinal growth rate of growing ovary-intact rats. The effects in adult rats were influenced by circulating levels of estradiol. ICI had no activity on body weight and complete antagonism on uterine weight. These results demonstrate that a ligand with high binding affinity to the estrogen receptor(s) can elicit an array of estrogen-mediated regulation of bone metabolism.