Effects of pyridine exposure upon structural lipid metabolism in Swiss Webster mice

Pyridine is a prototypical inducer of cytochrome P450 (CYP) 2E1, an enzyme associated with cellular oxidative stress and membrane damage. To better understand the effect of this treatment on cellular lipids, the influence of pyridine exposure (100 mg/kg/day i.p. for 5 days) on fatty acids, fatty esters, and fatty alcohol ethers in brain, heart, liver, and adipose tissue from male Swiss Webster mice was investigated. Lipid levels in cholesterol esters, triglycerides, free fatty acids, cardiolipin, sphingomyelin, and glycerylphospholipids were quantified. Pyridine altered the level and composition of lipids involved in membrane structure (i.e., sphingomyelin, phosphatidylethanolamines, and plasmalogens), energy metabolism (i.e., free fatty acids), and long-chain fatty acid transport (i.e., cholesterol esters) in a tissue-specific manner. Subtle changes in cholesterol esters were observed in all tissues. Sphingomyelin in the brain and heart were depleted in monounsaturated fatty acids (1.4- and 1.5-fold, respectively), while the liver sphingomyelin concentrations increased (1.5-fold). Pyridine exposure also increased heart free fatty acids by 1.3-fold, enriched cardiac phosphatidylethanolamine in long-chain polyunsaturated fatty acids by 1.3-fold, and depleted cardiolipin-associated plasmalogens by 3.8-fold. Phosphatidylethanolamines in the brain were also enriched in both saturated fatty acids (1.2-fold) and polyunsaturated fatty acids (1.3-fold) but were depleted in plasmalogens (2.9-fold). In particular, the levels of phosphatidylethanolamine-associated arachidonic (AA) and docosahexaenoic acid (DHA) in both brain and cardiac tissues significantly decreased following pyridine exposure. Considering the hypothetical role of plasmalogens as membrane-bound reactive oxygen scavengers, the current findings suggest that the brain and heart should be the focus of future studies on the toxicity of pyridine, as well as other CYP 2E1 inducers.     

Chronic exposure to cannabidiol induces reproductive toxicity in male Swiss mice

Children and adults with frequent and severe episodes of epilepsy that do not respond to standard treatments (such as carbamazepine, phenytoin and valproate) have long been prescribed cannabidiol (CBD) as an anticonvulsant drug. However, the safety of its chronic use in relation to reproduction has not been fully examined. This study aimed to assess the effects of chronic CBD exposure on the male reproductive system. CBD was orally administered to 21‐day‐old male Swiss mice at doses of 15 and 30 mg kg^?1 daily (CBD 15 and 30 groups, respectively), with a control group receiving sunflower oil, for 34 consecutive days. After a 35 day recovery period, the following parameters were evaluated: weight of reproductive organs, testosterone concentration, spermatogenesis, histomorphometry, daily sperm production and its morphology. The CBD 30 group had a 76% decrease in total circulating testosterone, but it remained within the physiological normal range (240–1100 ng dl^?1). CBD treatment induced a significant increase in the frequency of stages I–IV and V–VI of spermatogenesis, and a decrease in the frequency of stages VII–VIII and XII. A significant decrease in the number of Sertoli cells was observed only in the CBD 30 group. In both CBD groups the number of spermatozoa in the epididymis tail was reduced by 38%, sperm had head abnormalities, and cytoplasmic droplets were observed in the medial region of flagellum. These results indicated that chronic CBD exposure was associated with changes in the male reproductive system, suggesting its reproductive toxicity.     

Macrocytic-megaloblastic anemia in male NIH Swiss mice following repeated exposure to 1,3-butadiene

Thymic lymphoma/leukemia is the major cause of death in B6C3F1 mice chronically exposed to 1,3-butadiene (BD). Similar to radiation-induced murine thymic lymphoma, the bone marrow is also a major target organ. Because of the association of murine thymic lymphoma with endogenous type-C murine leukemia retroviruses (MuLV) present in the germ line of most strains of laboratory mice, including B6C3F1 and its parent strains, we examined the effects of BD exposure on NIH Swiss mice which do not possess intact endogenous ecotropic MuLV. Male NIH Swiss mice exhibited a macrocytic-megaloblastic anemia following inhalation of 1250 ppm BD for 6 weeks. Treatment-related changes included decreases in circulating erythrocytes, total hemoglobin, and hematocrit and an increase in mean corpuscular volume. An eightfold increase in circulating micronuclei was also observed. The anemia was not accompanied by a significant alteration in mean corpuscular hemoglobin concentration, an increase in circulating reticulocytes, or an increase in circulating nucleated erythrocytes. These findings are consistent with a treatment-related macrocytic-megaloblastic anemia and indicate that the bone marrow is an important target for BD toxicity in mice independent of MuLV background and expression.     

The influence of dextromethorphan on morphine analgesia in Swiss Webster mice is sex-specific

NMDA (N-methyl-d-aspartate) antagonists are known to enhance the analgesic effects of opioids. However, virtually, all studies of this phenomenon have been done using male subjects. Here, the noncompetitive NMDA receptor antagonist dextromethorphan (DEX) was tested over a range of doses (10-200 microg intracerebroventricularly [i.c.v.]) in male and female Swiss Webster mice in combination with 5 mg/kg intraperitoneal (i.p.) morphine. Males exhibited enhanced morphine analgesia following either 100 or 200 microg DEX, but there was no evidence of DEX-mediated potentiation in females at any dose. Instead, DEX attenuated morphine analgesia in females. We also evaluated the effect of 100 microg i.c.v. DEX with different doses of morphine (1, 5 and 10 mg/kg). Again, DEX significantly enhanced morphine analgesia in male mice and attenuated it in females. Next, ovariectomized (OVX) female mice were compared to males following 5 mg/kg i.p. morphine and 100 microg i.c.v. DEX. Male and OVX females exhibited equivalent maximal levels of analgesia following administration of DEX. Morphine analgesia was not enhanced by DEX in sham-treated females and OVX mice with estradiol treatment (5 microg i.p. once daily for 7 days) also did not show DEX enhancement. These experiments demonstrate that the ability of NMDA receptor antagonists to potentiate morphine analgesia is modulated by an estrogen-sensitive mechanism and suggest that sex differences may play a critical role toward a more general understanding of the potentiation of opioid-induced analgesia through NMDA receptor antagonists.     

Impact of repeated exposure on the toxicokinetics of BDE 47 in mice.

2,2',4,4'-Tetrabromodiphenyl ether (BDE 47) is the major polybrominated diphenyl ether (PBDE) found in environmental samples and human tissue despite its small contribution to global production and usage. Currently, three toxicokinetic studies are available investigating single-dose exposures; this is the first study to investigate toxicokinetic parameters following repeated exposure to BDE 47. The disposition and excretion of BDE 47 was monitored in adult female C57BL/6 mice for 5 days following ten consecutive 1.0-mg/kg oral doses and compared with results from our previous study. Results of the present study suggest greater retention of BDE 47 and nonlinear disposition patterns following repeated exposure to this dose in mice. No target tissues of sequestration or potential toxicity were determined; however, some tissues, such as the liver, demonstrated patterns of interest following repeated exposure that were not previously observed in acute toxicokinetic studies. Repeated exposure to BDE 47 results in higher concentrations remaining in adipose tissue, which demonstrates its potential for bioaccumulation. The data also suggest that excretion of BDE 47 may be decreased following repeated exposure. These results, in combination with evidence of its persistence and toxicity, underlie the need to further understand BDE 47 toxicokinetics across species at steady-state conditions.     

Long-term consequences of developmental exposure to aluminum in a suboptimal diet for growth and behavior of Swiss Webster mice

Swiss Webster mice received diets containing 7 (control), 100, 500, or 1000 microg aluminum (Al)/g throughout development (conception to 35 days of age) and were tested behaviorally as adults (>90 days of age). The basal diet contained the same percent of recommended dietary amounts of phosphate, calcium, iron, magnesium, and zinc as young women usually consume. These "realistic" dietary conditions led to 12--15% growth retardation in the Al1000 group at the time of testing. Females were evaluated in a cognitive task (Morris water maze) at 3 months of age and males were evaluated in a motor test battery at 5 months of age. Al1000 females (n=16) were slower than controls in learning the Morris maze, as suggested by fewer mice with low latencies during the first three sessions of the four-session learning series. Influences of Al on cue utilization were also found in probe sessions eliminating salient or nonsalient cues. With motor testing, the Al1000 males (n=20) had significantly lower hindlimb grip strength than controls, an effect that was eliminated by covariance analysis with body weight. Subtle influences of Al on rotarod and wire suspension tests were also noted. The data suggest that developmental Al exposure under normal, but less than optimal, dietary conditions can lead to subtle but long-term effects on growth and brain function in adulthood.     

Reproductive toxicity of piperine in Swiss albino mice

Piperine (CAS 94-62-2) is a constituent of various spices which are used as common food additives all over the world. The reproductive toxicity of piperine was studied in Swiss albino mice. Relevant short-term tests were employed to assess the effect on estrous cycle, mating behaviour, toxicity to male germ cells, fertilization, implantation and growth of pups. Piperine (10 and 20 mg/kg b.w.) increased the period of the diestrous phase which seemed to result in decreased mating performance and fertility. Post-partum litter growth was not affected by the piperine treatment. Sperm shape abnormalities were not induced by piperine at doses up to 75 mg/kg b.w. Considerable anti-implantation activity was recorded after five days post-mating oral treatment with piperine. The sex ratio and post-implantation loss were unaffected after treatment with piperine. Intrauterine injection of piperine caused the total absence of implants in either of the uterine horns (16.66%) or one of the horns (33%) of treated females. No histopathological changes were detected in the ovary and the uterus at the cellular level. Prostaglandin E1-induced acute inflammation of rat paw was significantly reduced after piperine treatment. Our results show that piperine interferes with several crucial reproductive events in a mammalian model.     

Heat production and heat loss in d-amphetamine hyperthermia in aggregated Swiss Webster and BDF mice

Heat Production and Heat Loss in d-Amphetamine Hyperthermia in Aggregated Swiss Webster and BDF₁ Mice. The difference in response of aggregated Swiss Webster and BDF₁ mice to the hyperthermic effects of d-amphetamine was investigated. Heat production via motor activity and plasma free fatty acid stimulation were studied. The concentration of plasma free fatty acids in aggregated amphetaminetreated Swiss Webster and BDF₁ mice did not follow any consistent relationship with either the dose of amphetamine or the hyperthermia produced by it. Motor activity measurements also failed to show any differences that would account for the differential hyperthermia caused by amphetamine. Differences in heat production via free fatty acids and motor activity did not explain the differences in hyperthermia.Heat production was also estimated by oxygen utilization in aggregated Swiss Webster and BDF₁ mice. The indirect calorimetric oxygen utilization studies failed to show any strain difference which would account for the differences in hyperthermia. Heat loss by evaporative water loss was also measured after amphetamine administration. At room temperatures of 19° and 27°C, the BDF₁ mice were found to lose more heat through evaporation than the Swiss Webster mice after 20 mg/kg d-amphetamine sulfate. Thus, the pharmacogenetic difference in toxic and hyperthermic responses of aggregated Swiss Webster and BDF₁ mice was explained by a difference in evaporative water loss (heat loss) between the two strains.     

Effect of route of exposure and repeated doses on the acute toxicity in mice of the cyanobacterial nicotinic alkaloid anatoxin-a

Anatoxin-a (ANTX-a) is a potent nicotinic cholinergic alkaloid produced by some toxigenic strains of cyanobacteria. We have examined i.p. and oral LD50 values of two ANTX-a producing Anabaena sp. and synthetic (+)-ANTX-a in outbred Swiss Webster mice. All three appeared equivalent by i.p. injection, but Anabaena flos-aquae NRC-44-1 was approximately twice as potent orally as the other two. Additionally, we were unable to demonstrate development of any biologically significant tolerance to acute ANTX-a exposure using two different repeated dose regimens.     

妊娠中期可卡因对小鼠的发育毒性

目的:探讨可卡因对小鼠妊娠中期的发育毒性,尤其是对脑发育的影响.方法:建立妊娠中期给药的小鼠动物模型,体重相近的妊娠母鼠被分为三组:(1)可卡因注射自由饮食组(COC);(2)盐水注射伴有饮食对照组(SPF),饮食参考体重相近、妊娠时间相同的COC组母鼠;(3)盐水注射自由饮食组(SAL).从妊娠第8天(E8)至第12天(E12)给药,记录母鼠、胎鼠和仔鼠的各项生理指标,并用HPLC分析各组胎鼠纹状体中多巴胺、5-HT含量的变化.结果:尽管COC和 SPF组母鼠与 SAL组母鼠相比摄食量少,体重增加量少,但E17 天取材时,仅COC组胎鼠表现为脑和纹状体重量低;COC组仔鼠生后第 1天(P1)双顶径(BPD)也小于其它两组仔鼠.此外,COC组胎鼠表现出脑/体重比的降低,说明宫内暴露可卡因引起的胎鼠的发育迟缓是一个不平衡过程,脑组织的受累比其它组织严重.神经递质分析和组织学分析表明 COC组胎鼠脑内多巴胺和5-羟色胺的水平增高,肝脏呈现出形态学改变.结论:妊娠中期暴露可卡因可引起胎鼠宫内发育迟缓,尤其是脑发育迟缓.单纯母体营养不良在宫内暴露可卡因引起的后代发育迟缓过程中不能起决定性作用,而可能是药物直接作用的结果.     

The Inhalation toxicity of di- and triethanolamine upon repeated exposure

Systemic and respiratory tract (RT) toxicity of triethanolamine (TEA) was assessed in a 28-day nose-only inhalation study in Wistar rats (10 animals/sex, concentrations: 0, 20, 100, 500 mg/m³; 5 days/week, 6 h/day). In two nose-only 90-day inhalation studies, with similar exposure design, Wistar rats were exposed to 0, 15, 150, 400 mg/m³ diethanolamine (DEA) (DEA Study 1:13 animals/sex, general subchronic study) and to 0, 1.5, 3, 8 mg/m³ (DEA Study 2:10 animals/sex) to specifically investigate respiratory tract toxicity. Only DEA induced systemic toxicity at or above 150 mg/m³ (body and organ weight changes, clinical- and histo-pathological changes indicative for mild blood, liver, kidney and testicular effects). Neurotoxicity was not observed for both substances. Exposure to both substances resulted in laryngeal epithelial changes starting from 3 mg/m³ for DEA (reversible metaplasia at the base of the epiglottis, inflammation at higher concentrations extending into the trachea) or from 20 mg/m³ for TEA (focal inflammation, starting in single male animals). TEA appears to be less potent with respect to systemic toxicity and RT irritancy than DEA. The 90-day no adverse effect concentration” (NOAEC) for changes due to TEA exposure in the respiratory tract was 4.7 mg/m³ derived by extrapolation from the NOAEC of the 28 day study.     

Methylphenidate inhibits cytochrome P450 in the Swiss Webster mouse

Drug interactions have previously been reported following the co-administration of methylphenidate (MPH) and drugs metabolized by the cytochrome P450 (CYP450) system such as imipramine. Therefore, this study used the Swiss Webster mouse to determine the effect of MPH on CYP450 isozymes likely to be important in the interaction between MPH and imipramine. Single high doses of MPH (25, 50 and 100 mg/kg, i.p.) were administered to simulate the abuse of MPH. Under these conditions, MPH decreased total hepatic CYP450 to 50% of control. Additionally, MPH inhibited the catalytic activity of CYP1A and CYP2E1 by 50%, and decreased the polypeptide levels of CYP3A by 30%. In a second study designed to simulate more closely therapeutic use, MPH was administered orally for two weeks at 10-fold lower doses (2.5, 5 and 10 mg/kg/day). MPH decreased total hepatic CYP450 at both 5 and 10 mg/ kg/day (0.96 +/- 0.01 and 0.96 +/- 0.06 nmol/mg versus 1.34 +/- 0.01 nmol/mg for saline control, P<0.05). The catalytic activity and protein levels of CYP1A were diminished by up to 50% of control, while catalytic activity and polypeptide levels for CYP2E1 and CYP3A remained unchanged. These results indicate that MPH inhibits the CYP450 system following both abuse and therapeutic scenarios. However, this effect was dependent on both the isoform of CYP450 and the duration of MPH administration.     

Comparative subacute toxicity of all-trans- and 13-cis-retinoic acid in Swiss mice

Swiss mice were treated once a day for 21 days with all-trans- or 13-cis-retinoic acid administered ip or po. The LD50 of all-trans-retinoic acid was 31 mg/kg ip and 1100 mg/kg po; the LD50 of 13-cis-retinoic acid was 140 mg/kg ip and 26,000 mg/kg po. However, after 21 consecutive days of treatment, fractured bones were observed in treated animals at all tested doses of 13-cis-retinoic acid and at doses of all-trans-retinoic acid higher than 3 mg/kg ip or 10 mg/kg po. By either route of administration, 13-cis-retinoic acid produced the same number and incidence of fractures at doses three to five times that of all-trans-retinoic acid administered by the same route. Treatment with 13-cis-retinoic acid ip resulted in a dose-related decrease in the red blood cell count, but ip administration of all-trans-retinoic acid did not. The concentration of albumin, the serum transport protein for these compounds, was changed only after low oral doses of all-trans-retinoic acid. The appearance of fractured bones was not always associated with elevated plasma alkaline phosphatase concentrations. Based on these parameters of toxicity, 13-cis-retinoic acid was less toxic than all-trans-retinoic acid.     

Increased immunoreactivity of glutathione-S-transferase in the retina of Swiss Webster mice following inhalation of JP8+100 aerosol

The current study was designed to determine whether exposure of mice to aerosolized jet fuel (JP8 + 100) resulted in changes in the cellular distribution or immunoreactivity of the enzyme glutathione S-transferase (GST), a biomarker of toxicant exposure. Male mice were exposed to JP8 + 100 at 1000 mg/m3 or 2500 mg/m3 in aerosol for 1 h per day for 7 days and then sacrificed. The retinas were studied by immunohistochemical methods. The JP8 + 100 exposure caused a marked increase in the immunoreactivity of anti-GSTM antibodies with the radial glial cells of the retina, the Müller cells. These results are consistent with the hypothesis that JP8 + 100 acts as a toxicant to mouse retina by permitting the flux of materials across the blood-retina barrier. The findings are relevant to humans because recent studies indicate that Air Force personnel assigned to clean and maintain fuel pods may be exposed to concentrations of JP8 + 100 exceeding 1000 mg/m3.     

The Behavioral Effects of Perinatal Methimazole Administration in Swiss Webster Mice

The Behavioral Effects of Perinatal Methimazole Administrationin Swiss Webster Mice. RICE, S. A., MILLAN, D. P., AND WEST,J. A. (1987). Fundam. Appl. Toxicol. 8, 531–540. Methimazolewas tested for use as a positive control agent in behavioralstudies of mice. Continuous administration of the antithyroidagent via drinking water (0.1 mg/ml) from Day 16 of pregnancythrough Day 10 postpartum produced developmental delays in miceoffspring. Ten methimazole and 12 untreated litters were studied.Developmental milestones were unaltered; i.e., time of pinnadetachment, incisor eruption, eye opening, vaginal patency,and testicular descent were not different between groups. Meanbody weights of methimazole offspring were consistently reduced,but significant differences were isolated to a few days in thepreweaning period and a few weeks during the postweaning period.There was no enduring effect. All preweaning tests showed somesignificant treatment-related changes; methimazole pups weredevelopmentally delayed. Surface righting time was increasedwhile time pivoting and the number of quadrants traveled weredecreased in methimazole pups. Negative geotaxis showed significanttreatment-related increases in the time to orient 180° uphill,the percentage of pups orienting 180° uphill, and the percentageof pups orienting <180°. Ontogeny of swimming abilityalso showed significant delays. The only postweaning test evaluated,time on a rotating rod, showed no treatment-related effects.Brain weights Postnatal Day (PND) 120 were not different betweengroups. In this study, methimazole produced developmental delaysin mice that were detectable by behavioral tests. Thus, methimazolehas potential as a positive control agent for mice, not onlyto validate preweaning test sensitivity, but also to validatea laboratory's ability to perform preweaning behavioral studies.     

Review of the epidemiologic literature on residential exposure to perchloroethylene

Perchloroethylene is a solvent that is widely used for dry cleaning. There has been considerable interest in the toxicity of this chemical because of the potential for low-level exposure among a large portion of the US population. Although substantial epidemiologic literature exists on high-level occupational exposure to perchloroethylene, there are relatively few studies dealing with lower-level residential exposure. In the current paper, the author reviews this limited residential literature, with special emphasis on strengths, limitations, and consistency. Reviewed studies primarily address neurobehavioral, cancer, and reproductive endpoints. Most studies used an ecological or cross-sectional design, with exposure defined by either drinking-water contamination or proximity to dry cleaning. In general, reviewed studies were highly exploratory, with inconsistencies and potential for bias that detract from interpretation of study findings. The magnitudes of reported effects are frequently incompatible with the effects reported from much higher occupational and human-chamber exposures. Overall, few reliable conclusions can be drawn from this sparse and highly limited body of literature.     

Review of the epidemiologic literature on residential exposure to perchloroethylene

Perchloroethylene is a solvent that is widely used for dry cleaning. There has been considerable interest in the toxicity of this chemical because of the potential for low-level exposure among a large portion of the US population. Although substantial epidemiologic literature exists on high-level occupational exposure to perchloroethylene, there are relatively few studies dealing with lower-level residential exposure. In the current paper, the author reviews this limited residential literature, with special emphasis on strengths, limitations, and consistency. Reviewed studies primarily address neurobehavioral, cancer, and reproductive endpoints. Most studies used an ecological or cross-sectional design, with exposure defined by either drinking-water contamination or proximity to dry cleaning. In general, reviewed studies were highly exploratory, with inconsistencies and potential for bias that detract from interpretation of study findings. The magnitudes of reported effects are frequently incompatible with the effects reported from much higher occupational and human-chamber exposures. Overall, few reliable conclusions can be drawn from this sparse and highly limited body of literature.     

Zoledronic acid induces cytogenetic toxicity in male germline cells of Swiss albino mice

This study mainly focuses on the cytogenetic toxicity induction by zoledronic acid (ZA), a nitrogen containing bisphosphonate (N-BPs) in the male germline cells of Swiss albino mice. A single intraperitoneal exposure with three different doses of ZA (2, 4, and 8?mg/kg body weight), toxicity was assessed by analyzing spermatogonial metaphase chromosome aberrations at 24?h, aberrant primary spermatocytes at week 4, and abnormal spermatozoa at week 8 posttreatment. Cyclophosphamide (40?mg/kg) and 0.9% NaCl were used as positive and vehicle controls respectively in the study. The results showed that there was a significant induction in the number of chromosomal aberrations especially at two doses of ZA (4 and 8?mg/kg) after 24?h in the spermatogonial cells (p?<?0.001) compared to vehicle control. The transmission genetic damages were noticed as aberrant spermatocytes with atypical bivalents (X-Y/autosomal asynapsis) at 4?mg/kg of ZA (p?<?0.01) and at 8?mg/kg of ZA (p?<?0.001) at week 4 posttreatment. A statistically significant higher number of abnormal spermatozoa (sperm) were also noticed at week 8 posttreatment of both at 4 and 8?mg/kg of ZA (p?<?0.001). Hence, from these genotoxicity studies, it can be concluded that ZA is genotoxic in male germline cells and has the potential of transmitting the genotoxic effects from spermatogonial cells to sperm in male Swiss mice.