Developmental toxicity and uterotrophic studies with di-2-ethylhexyl terephthalate

BACKGROUND: These studies were conducted to evaluate the potential adverse effects of di-2-ethylhexyl terephthalate (DEHT) exposure on in utero development in mice and rats. In addition, a uterotrophic assay for estrogenic activity was conducted in sexually immature rats. METHODS: In the developmental toxicity studies, diet containing DEHT was fed to four groups of mated female Crl:CD(SD)IGS BR rats (25/group) from gestation day (GD) 0-20 or Crl:CD1(ICR) mice (25/group) from GD 0-18. Concentrations within the feed were 0, 0.3, 0.6, and 1.0% for the rats and 0, 0.1, 0.3, and 0.7% for the mice. Laparohysterectomies were carried out on the last day of exposure and the numbers of fetuses, early and late resorptions, total implantations, and corpora lutea were recorded. The fetuses were weighed, sexed, and examined for external, visceral and skeletal malformations, and developmental variations. The dose rate from dietary DEHT exposure was 0, 226, 458, and 747 mg/kg/day in the rats and 197, 592, and 1382 mg/kg/day in the mice for the control, low, mid, and high-exposure groups, respectively. RESULTS: DEHT exposure did not affect clinical observations. A slight reduction in body weight gain was noted in the high-dose level rat group; the remaining groups were unaffected. At necropsy, increased liver weights were noted in the high-dose rat group and the mid- and high-dose mouse groups. Mean numbers of implantation sites and viable fetuses, mean fetal weights, and mean litter proportions of preimplantation loss, early resorptions, late resorptions, and fetal sex ratios were unaffected by DEHT exposures. No test article-related malformations or variations were observed at any concentration level in the rat and mouse developmental toxicity studies. In the uterotrophic assay for estrogenic activity, sexually immature female rats received oral gavage doses 20, 200, or 2000 mg DEHT/kg bw/day from postnatal day (PND) 19-21. A slight reduction in rate of body weight gain was noted on the first day of dosing in the high dose group, but no other indications of toxicity were evident. DEHT exposure did not affect wet or blotted uterine weight parameters in any of these dose groups. The NOEL for developmental toxicity in rats was 747 mg/kg/day and 1382 mg/kg/day in mice. The NOEL for estrogenic activity was 2000 mg/kg/day. The NOEL for maternal toxicity was 458 mg/kg/day in rats and 197 mg/kg/day in mice. CONCLUSIONS: The lack of adverse developmental effects with DEHT exposure are in contrast to the adverse developmental effects noted after di-2-ethylhexyl phthalate (DEHP) exposure. The difference between the effects noted with the ortho-constituent (DEHP) and the lack of effects reported with the para-constituent (DEHT) is due most likely to differences in metabolism and the formation of the stable monoester, mono-2-ethylhexyl phthalate (MEHP) from the DEHP moiety.     

Biometric evidence of diet-induced obesity in Lew/Crl rats

Although Lew/Crl rats are central to a classic model of renal transplantation and may provide a valid system for evaluating the effect of obesity on transplantation outcomes, their response to high-fat diet has not been evaluated sufficiently. The objective of this study was to evaluate biometric and basic metabolic data of Lew/Crl rats fed a 60% kcal, lard-based, very high-fat diet (HFD) compared with those fed a 10% kcal fat control diet (CD). Rats were maintained for 17 wk; body parameters and caloric intake were monitored weekly. Biometric data were collected and calculated before and after euthanasia. Serum was evaluated for liver enzyme activity and total bilirubin, glucose, triglyceride, cholesterol, insulin, leptin, and creatinine concentrations, and urine was evaluated for protein, glucose, specific gravity, and ketones. Tissues were harvested, weighed, and evaluated histologically. Compared with CD rats, HFD rats consumed more calories and weighed more after 3 wk. After 17 wk, HFD rats had significantly increased body weight, girth, volume, epididymal fat pad weight, omental weight, and body fat. In addition, HFD rats had mild elevations in some liver enzymes and a lower serum triglyceride concentration than did CD rats. Histologic assessment and other metabolic markers of disease were not different between the 2 groups. Lew/Crl rats fed a 60% kcal HFD become obese, but they lack significant metabolic abnormalities frequently associated with obesity in other rat strains.     

Incidence of hydronephrosis among several production colonies of outbred Sprague-Dawley rats

The incidence of hydronephrosis was determined in nine production colonies of Crl:CD (SD) BR rats (CD rats). Kidneys from 3909 rats were examined and 79 (2.0%) had unilateral or bilateral hydronephrosis. A colony with a relatively high incidence of hydronephrosis (4.1%) was chosen for further study. In unselected rats from this colony the incidence in females (87/1882, 4.6%) was not significantly different from that in males (79/1862, 4.2%). In the same group of rats, hydronephrosis was observed most frequently in the right kidney only (2.3%), followed by bilateral involvement (1.2%) and the left kidney only (0.8%). By selection and inbreeding, the incidence of hydronephrosis was increased dramatically (to 33.6%) in two generations. Hydronephrosis in the CD rat appears to be a highly heritable trait, most likely involving more than one gene.     

The Effects of Shipping on Early Pregnancy in Laboratory Rats

Although rats in various stages of pregnancy are routinely shipped by vendors, the effects of shipping on pregnancy outcomes have not been reported. This study examined the effects of shipping rats 1 day after mating. Two outbred stocks, (Crl:CD(SD), Crl:WI(Han)) and one inbred strain (F344/Crl) of rats (n = 300/strain) were mated in a vendor barrier room at 3‐month intervals five times, and either shipped the next day (total time in transit ～24 hr) or held in the room of origin until parturition. The pregnancy status, length of gestation, number of pups born per female, sex ratio of pups born, and neonatal mortality were compared between transported and nontransported rats. These pregnancy and litter parameters were also compared among strains and examined for seasonality; no seasonal effects were observed. Neonatal mortality was negligible at less than 2% in any of the groups. All sex ratios were normal. Transportation affected pregnancy rates only in the F344/Crl, in which 81.8% of the nontransported versus 70% of the transported rats had pups (p = 0.025). Overall, slightly fewer transported rats were pregnant, but they had larger litters (10.08 compared with 9.68, p = 0.02, pooling across all three strains) so produced the same numbers of pups. A total of 77 ± 8% of transported rats had gestation periods of 22 days or more compared with only 52 ± 10% in the nontransported rats. The reason for larger litters in transported females is unclear. Longer gestation in transported females may be due to facultative embryonic diapause, which might have implications for reproductive toxicology.     

Variations of sodium, potassium, and chloride plasma levels in the rat with age and sex

Sodium, potassium, and chloride plasma levels were measured in 294 male and 286 female Sprague Dawley rats [Crl:COBS CD(SD)BR]. The rats were distributed between four groups according to age (65-125 days, 235-275 days, 353-482 days, and 665-775 days). The levels of all three ions were higher in males than in females: about 1% higher for sodium and chloride and about 7% higher for potassium. Potassium and chloride values decreased with increasing age in both sexes; potassium decreased 12% and chloride decreased 6%. Distributions were not perfectly Gaussian but the departures from normality were slight. It was concluded, therefore, that determinations based on parametric statistical tests on the data are unlikely to be seriously biased by the distribution.     

Age-Associated Lesions in Barrier-Reared Male Sprague-Dawley Rats: A Comparison Between Hap: (SD) and Crl:COBS[R]CD[R] (SD)Stocks1,6

Age-associated lesions were characterized in two outbred stocks of barrier-reared male Sprague-Dawley rats. Seventy-two virgin Hap:(SD) between 6–29 months of age and 113 retired breeder Crl:COBS^[R]CD^[R](SD) between 12–38 months of age were evaluated for the presence of lesions in all major organ systems. Rats of both stocks developed a spectrum of neoplastic, inflammatory and degenerative diseases with highest prevalence in the oldest age groups. In general, the shorter-lived Hap:(SD) rats had greater incidences and severity of lesions when compared to Crl:COBS^[R]CD^[R]SD of similar ages. Many of these differences were not apparent when the two stocks were compared over their respective life spans. The study provides baseline pathology data relevant to the use of these rats in gerontologic research.     

Developmental toxicity studies in Crl:CD (SD) rats following inhalation exposure to trichloroethylene and perchloroethylene

The potential for trichloroethylene (TCE) and perchloroethylene (PERC) to induce developmental toxicity was investigated in Crl:CD (SD) rats whole-body exposed to target concentrations of 0, 50, 150 or 600 ppm TCE or 0, 75, 250 or 600 ppm PERC for six hours/day, seven days/week on gestation day (GD) 6-20 and 6-19, respectively. Actual chamber concentrations were essentially identical to target with the exception of the low PERC exposure level, which was 65 ppm. The highest exposure levels exceeded the limit concentration (2 mg/L) specified in the applicable test guidelines. Maternal necropsies were performed the day following the last exposure. Dams exposed to 600 ppm TCE exhibited maternal toxicity, as evidenced by decreased body weight gain (22% less than control) during GD 6-9. There were no maternal effects at 50 or 150 ppm TCE and no indications of developmental toxicity (including heart defects or other terata) at any exposure level tested. Therefore, the TCE NOEC for maternal toxicity was 150 ppm, whereas the embryo/fetal NOEC was 600 ppm. Maternal responses to PERC were limited to slight, but statistically significant reductions in body weight gain and feed consumption during the first 3 days of exposure to 600 ppm, resulting in a maternal NOEC of 250 ppm. Developmental effects at 600 ppm consisted of reduced gravid uterus, placental and fetal body weights, and decreased ossification of thoracic vertebral centra. Developmental effects at 250 ppm were of minimal toxicological significance, being limited to minor decreases in fetal and placental weight. There were no developmental effects at 65 ppm.     

Hematology reference values for peripheral blood of laboratory rats

Reference values for peripheral red and white blood cells, platelets and coagulation parameters from 11 and 18-week-old Charles River Sprague Dawley rats [Cr1:COBS CD(SD)] were obtained using automated methods. The Coulter Model S Senior, the Clay Adams Ultra-Flo Platelet Counter and the Sherwood Lancer Coagulyzer, were used to measure these parameters on 25 rats/sex. Detailed information on instrumentation or assay methods, and the animals, their source, environment and blood collection method was given. Platelet counts were in the range of 694 X 10(9)/1 to 1412 X 10(9)/1 which was higher than previously reported. In general, the remaining ranges were similar to previously published reference ranges.     

Comparative effects of single intraperitoneal or oral doses of sodium arsenate or arsenic trioxide during in utero development.

Numerous studies have suggested that single-day intraperitoneal (IP) injection of inorganic arsenic results in failure of neural tube closure and other malformations in rats, hamsters, and mice. Most of these studies involved treatment of limited numbers of animals with maternally toxic doses of arsenic (generally As(V)), without defining a dose-response relationship. In the present Good Laboratory Practice-compliant study, sodium arsenate (As(V)) was administered IP and arsenic trioxide (As(III)) was administered either IP or orally (by gavage) on gestational day 9 to groups of 25 mated Crl:CD(R)(SD)BR rats. Only at dose levels that caused severe maternal toxicity, including lethality, did IP injection of arsenic trioxide produce neural tube and ocular defects; oral administration of higher doses of arsenic trioxide caused some maternal deaths but no treatment-related fetal malformations. In contrast, IP injection of similar amounts of sodium arsenate (based on the molar amount of arsenic) caused mild maternal toxicity but a large increase in malformations, including neural tube, eye, and jaw defects. In summary, neural tube and craniofacial defects were observed after IP injection of both As(V) and As(III); however, no increase in malformations was seen following oral administration of As(III), even at maternally lethal doses. These results demonstrate that the frequently cited association between prenatal exposure to inorganic arsenic and malformations in laboratory animals is dependent on a route of administration that is not appropriate for human risk assessment.     

Experimental Sendai virus infection in laboratory rats. I. Virus replication and immune response

Sixty 5 to 8 week old Sprague-Dawley (Crl:CD(SD)BR) rats were inoculated intranasally with 2000 egg infectious doses of egg-propagated Sendai virus. Virus was recovered from the upper respiratory tract and lungs on days 1 through 8 post-inoculation (PI). Serum antibody responses were measured for 12 rats over a 9 month period PI. Antibody was first detected at 7 days, peaked at 21 days, and was detected in 5 of the 12 rats at 9 months. A cell-mediated response, as measured by lymphocyte blastogenesis, also was detected at 7 days and peaked at 21 days, but was not detected at 6 months PI. Lung and serum interferon (IFN) was first detected at 3 hours and peaked at 6 hours, but was not detected by 160 hours. Lung IFN levels were 4 to 10 times those in the serum. These studies indicate that pathogenesis of Sendai virus infection in the rat is similar to that reported in the mouse, but that there are differences in the kinetics of both viral replication and morphologic changes, as described in the companion paper.     

不同周龄SD大鼠脏器重量及其变化趋势分析

目的分析不同周龄SD大鼠的脏器重量及其变化趋势,为评判药物毒性反应提供理论参考。方法分别选取试验第13、26、52、78和104周对照组动物脑、脾脏、心脏、肺脏、肝脏、肾脏、肾上腺、睾丸、卵巢的重量数据并分析。结果从13～104周SD雌鼠脑、脾脏、心脏、肺脏、肝脏、肾脏、肾上腺、卵巢的重量呈升高趋势。从13～104周SD雄鼠脑、脾脏、心脏、肺脏、肝脏、肾脏重量均重于雌鼠,但雌鼠肾上腺重量、脏体比和脏脑比均显著高于雄鼠。结论本研究首次在国内建立了符合我国实验动物现状的,不同周龄SD大鼠的脏器重量背景数据和参考值范围,并分析了不同周龄SD大鼠脏器重量变化趋势。     

Normal Distribution of Body Weight Gain in Male Sprague‐Dawley Rats Fed a High‐Energy Diet

Objective: To investigate the effect of a high‐energy (HE) diet on caloric intake, body weight, and related parameters in outbred male Sprague‐Dawley (SD) rats. Research Methods and Procedures: Twenty‐eight SD rats were fed either chow (C) for 19 weeks or HE diet for 14 weeks and then C for 5 weeks. Blood hormones and metabolites were assayed, and expression of uncoupling protein‐1 and hypothalamic energy‐balance‐related genes were determined by Northern blotting and in situ hybridization, respectively. Results: HE rats gained body weight more rapidly than C animals with a range of weight gains, but there was no evidence that weight gain was bimodally distributed. Caloric intake was transiently elevated after introduction of the HE diet. Transfer of HE rats back to C resulted in a drop in caloric intake, but a stable body weight. In terminal analysis, two of four dissected adipose tissue depots were heavier in rats that had previously been fed HE diet. Blood leptin, insulin, glucose, and nonesterified fatty acids were not different between the groups. Uncoupling protein‐1 mRNA was elevated in interscapular brown adipose tissue from HE rats. There was a trend for agouti‐related peptide mRNA in the hypothalamic arcuate nucleus to be higher in HE rats. Discussion: Contrary to other studies of the SD rat on HE diet, body weight and other measured parameters were normally distributed. There was no segregation into two distinct populations on the basis of susceptibility to diet‐induced obesity. This characteristic may be dependent on the breeding colony from which animals were sourced.     

Perturbations in polyamines and related enzymes following chlordecone-potentiated bromotrichloromethane hepatotoxicity.

The mechanism by which chlordecone (CD) amplifies the hepatotoxicity of halomethanes such as CCl4, CHCl3, and BrCCl3 has been a subject of intense study. Recent work has shown that suppression of hepatocellular regeneration leads to accelerated progression of liver injury leading to complete hepatic failure due to an unusual interaction between individually nontoxic low-dose combination of CD and CCl4. Since polyamines are involved in cell division, their levels reflect the extent to which there is suppression of hepatocellular regeneration during CD and CCl4 interaction. The present studies were designed to investigate the polyamine levels and associated enzymes in livers of rats treated with BrCCl3 alone or CD and BrCCl3 low-dose combination in order to confirm whether the sequence of events of hepatotoxicity is similar to that seen in CCl4 toxicity or that seen during CD and CCl4 interaction. The extent of liver toxicity in rats fed 10 ppm chlordecone (CD) for 15 days prior to the injection of a single low dose of BrCCl3 (15 microL/kg body weight) or after exposure to a high dose of BrCCl3 (80 microL/kg body weight) without CD pretreatment, was similar 6 and 24 hr later as assessed by plasma transaminase levels. There was also an increase in transaminase levels, in rats exposed to a single low dose of BrCCl3 alone (15 microL/kg body weight) but this increase was far below the high-dose exposure alone or the combination treatment. Hepatic levels of ornithine decarboxylase, S-adenosylmethionine decarboxylase, N1-acetylputrescine, N1-acetylspermidine, putrescine, spermidine, and spermine at the end of 24 hr increased after exposure to a low dose of BrCCl3 alone as compared to exposure to a high dose alone or the low-dose combination of CD and BrCCl3. Liver spermidine N1-acetyltransferase was elevated at 2, 6, and 24 hr after exposure to a high dose of BrCCl3 alone as compared to treatment with a low-dose combination of CD and BrCCl3 suggesting decreased synthesis of this enzyme, in spite of a greater need as seen from liver transaminase levels. In general, it was observed that there is significant elevation in some polyamines and related enzymes during toxicity of a low dose of BrCCl3 which seemed to stabilize within 24 hr. This was not observed with the other two groups of rats exposed either to BrCCl3 high dose alone or the low-dose combination of CD and BrCCl3.(ABSTRACT TRUNCATED AT 400 WORDS)     

Inhalation developmental neurotoxicity study of ethylbenzene in Crl-CD rats

BACKGROUND: This study was conducted to evaluate the potential adverse effects of whole-body inhalation exposure of F0 and F1 parental animals from a 2-generation reproduction study of ethylbenzene on nervous system functional and/or morphologic end points in the F2 offspring from four groups of male and female Crl:CD (SD)IGS BR rats. METHODS: Thirty rats/sex/group for F0 and 25/sex/group for F1 were exposed to 0, 25, 100, and 500 ppm ethylbenzene for six hours daily for at least 70 consecutive days prior to mating for the F0 and F1 generations. Inhalation exposure for the F0 and F1 females continued throughout mating and gestation through Gestation Day (GD) 20. On lactation days (LD) 1-4, the F0 and F1 females received no inhalation exposure, but instead were administered ethylbenzene in corn oil via oral gavage at dosages estimated to result in similar internal maternal exposure based upon PBPK modeling estimates (0, 26, 90, and 342 mg/kg/day, respectively, divided into three equal doses, approximately two hours apart). Inhalation exposure of the F0 and F1 females was reinitiated on LD 5 and continued through weaning on postnatal day (PND) 21. Survival, body weights, and physical landmarks were assessed in selected F2 offspring. Neurobehavioral development of one F2-generation treatment derived offspring/sex/litter was assessed in a functional observational battery (FOB; PND 4, 11, 22, 45, and 60), motor activity sessions (PND 13, 17, 21, and 61), acoustic startle testing (PND 20 and 60), a Biel water maze learning and memory task (initiated on PND 26 or 62), and in evaluations of whole-brain measurements and brain morphometric and histologic assessments (PND 21 and 72). RESULTS: There were no adverse effects on reproductive performance in either the F0 or F1 parental generations exposed to up to 500 ppm ethylbenzene [Faber et al. Birth Defects Res Part B 77:10-21, 2006]. In the current developmental neurotoxicity component, parental ethylbenzene exposure did not adversely affect offspring survival, clinical condition, body weight parameters, or acquisition of developmental landmarks of the F2-generation treatment derived offspring. There were no alterations in FOB parameters, motor activity counts, acoustic startle endpoints, or Biel water maze performance in offspring attributed to parental ethylbenzene exposure. A few isolated instances of statistically significant differences obtained in the treatment-derived groups occurred sporadically, and were attributed to unusual patterns of development and/or behavior in the concurrent control group. There were no exposure-related differences in any neuropathology parameters in the F2-generation treatment derived offspring. CONCLUSIONS: The no observed adverse effect level (NOAEL) for maternal reproductive toxicity, developmental toxicity, and developmental neurotoxicity in this study was considered to be 500 ppm/342 mg/kg/day ethylbenzene, the highest exposure level tested in the study.     

Effects of prolonged water washing of tissue samples fixed in formalin on histological staining

The effects of prolonged water washing after fixation for 48 h in 10% (v/v) phosphate-buffered neutral formalin on the quality of representative histological staining methods were evaluated using samples of liver, kidney, spleen and thymus collected from three male Crl:CD(SD)(IGS) rats and one male beagle dog. Because door-to-door courier services in Japan prohibit handling formalin, our goal was to confirm that formalin fixed wet tissue samples could be stored in tap water rather than formalin during transportation of the samples without decreasing the quality of their staining or immunohistochemistry. Each tissue sample was allocated randomly to one of three groups: 12 min, 3 days and 7 days of washing in running tap water; samples then were routinely embedded in paraffin and sectioned. The sections were stained with hematoxylin and eosin, periodic acid-Schiff, azan, and the TdT-mediated dUTP-biotin nick end labeling (TUNEL) method. Immunohistochemical staining for Factor VIII, ED-1 and CD3 also was assessed. Prolonged water washing for up to 7 days did not affect the morphology or stainability by standard histological methods, or the intensity and frequency of positive reactions using the TUNEL method. Only immunohistochemical staining of Factor VIII was altered in both the rat and dog sections after 7 days of water washing. The intensity of positive reactions of Factor VIII immunohistochemistry after 7 days water washing was still strong enough to detect microscopically. Therefore, prolonged water washing for up to 7 days after formalin fixation does not have seriously detrimental effects on the quality and characteristics of paraffin sections stained by various methods, including immunohistochemistry.     

Analysis of historical control litter parameters of reproduction toxicity studies in Sprague-Dawley derived rats

Control litter data from reproduction toxicity studies in SD derived rats bred in our closed colony were investigated for historical changes, differences due to study design or generations, seasonal variations and effects of vehicle-treatment. The litter size did not change visibly during the entire 16-year period, but the number of live fetuses differed significantly between study designs or generations. The fetal weight gradually increased during these years. The malformation rate decreased, while the rate of 14 th ribs remained stable. There were no seasonal variations and no effects of vehicle-treatment.     

SPF级封闭群SD大鼠血清生化值及凝血酶原时间值的测定

目的建立SPF级（屏障系统）封闭群SD大鼠血液生化及凝血酶原时间正常参考值,为药物长期毒性试验研究者提供参考。方法采用全自动血液生化分析仪检测19周和31周大鼠血液生化值,采用紫外可见分光光度计检测K＋、Na＋、Cl-值和凝血酶原时间值。结果取得19周和31周龄SD大鼠血清生化值和凝血酶原平均值。CR、TG、TC生化指标受年龄及性别因素影响,CR、TG、TC随年龄增长而逐步升高。TBIL、CR、TG、TC、CK、TP、BUN、ALB、AST、K＋、ALP指标雌雄间差异显著（P＆lt;0.05）。结论在药物长期毒性试验中,同一周龄雌、雄SD大鼠K＋、Cl-、Na＋、凝血酶原时间值可合并统计;雌、雄SD大鼠血液生化指标不宜合并统计。在比对正常参考值时应考虑到性别与年龄的因素。     

Hepatic polyamines and related enzymes following chlordecone-potentiated carbon tetrachloride toxicity in rats

Chlordecone potentiation of the hepatotoxic and lethal effects of CCL4 has been well established. Recent studies have shown that the suppression of hepatocellular regeneration results in an accelerated progression of liver injury leading to complete hepatic failure. Since polyamines are involved in cell division, these studies were designed to investigate the polyamine levels and associated enzymes in the livers of rats treated with a low-dose combination of CD and CCl4. For comparison, a large toxic dose of CCl4 was also employed. The extent of liver toxicity in rats fed 10 parts per million chlordecone (CD) for 15 days and subsequently injected with a single dose of CCl4 (100 microL/kg body weight) or a high dose of CCL4 alone (2.5 mL/kg body weight) was similar 6 and 24 hr later as assessed by plasma transaminase levels. There was significant elevation in liver ornithine decarboxylase, S-adenosylmethionine decarboxylase, and putrescine at 24 hr and spermidine N1-acetyltransferase, N1-acetylputrescine, putreanine, putrescine, and N1-acetylspermidine at 6 hr in rats treated with the high dose of CCl4 alone compared to the combination treatment. Spermidine levels decreased up to 6 hr and then increased up to 24 hr for both treatments. Spermine continuously decreased up to 24 hr for the CD and CCl4 low-dose combination treatment compared to rats treated with a high dose of CCl4 alone. Spermidine levels were lower than in controls and rose towards control value between 6 and 24 hr after the combination treatment and the high dose of CCl4. Results indicate that the CD and CCl4 low-dose combination treatment increased liver toxicity, resulting in compromised polyamine metabolism that is coincidental with suppressed hepatocellular regeneration, which leads to an accelerated progressive phase of liver injury and culminates in complete hepatic failure.     

Neonatal rats with outstanding values of brain and body parameters

“Outstanding” newborn rats, with parameter values more than two standard deviations above the mean (OH) or below the mean (OL), were identified in a normal population of 720 animals and were studied for correlations between these parameters: body weight, brain weight, brain DNA (cell number) and brain protein. The animals OH on any one of these parameters were also higher than average on all the others, and some of these animals came from OH litters. The animals OL on one parameter tended to be OL on all the others, and correlations between parameters were higher in this group than in the entire population. Such findings may facilitate the search for OH or OL individuals. The correlations among the OH parameters were not the same as the correlations among the OL. The causes of the occurrence of OH and OL animals are more likely to be environmental than genetic.     

Effects of the opioid analgesic oxymorphone hydrochloride on reproductive function in male and female rats

BACKGROUND: Endogenous opioids seem to regulate hypothalamic gonadotropin release in both males and females, as evidenced by the effects of opioid agonists and antagonists on LHRH release and reproductive hormone levels. The effects of long‐term oral administration of opioid analgesics on reproductive function have not been well characterized. METHODS: The reproductive effects of oxymorphone, a potent opioid agonist, were investigated in male and female Crl:CD(SD) IGS BR rats at oral doses of 0, 5, 10, and 25 mg/kg/day (25 animals/sex/group). Males were treated for approximately 9 weeks (mated after 4 weeks of dosing). Females were treated for 14 days before mating, and through Gestation Day (GD) 7. Estrous cycling was evaluated during the premating period. On GD15, pregnancy status and the numbers of corpora lutea, implantation sites, live and dead embryos were determined. Epididymal and testicular sperm counts and epididymal sperm motility and morphology were evaluated in males. RESULTS: Two males given 25 mg/kg/day died. Behavioral changes and deficits in body weight gain occurred at all doses. There were no effects of oxymorphone on reproductive function or sperm parameters in males. The estrous cycle was prolonged in females given 25 mg/kg/day (mean of 5.3 vs. 4.3 days in controls). A small, but consistent decrease in the numbers of corpora lutea (with associated decreases in implantation sites and embryos) occurred in females given ≥10 mg/kg/day. There were no effects on mating or fertility in females. CONCLUSIONS: Oxymorphone seems to partially inhibit ovulation in female rats, with no significant effects on male reproductive outcome. Birth Defects Res (Part B) © 2007 Wiley‐Liss, Inc.