Developmental Neurotoxicity Evaluation of Orally Administered Isopropanol in Rats

Isopropanol was administered by gavage to timed-mated rats fromGestation Day (GD) 6 through Postnatal Day (PND) 21. Doses administeredwere 0, 200, 700, or 1200 mg/kg/day in a volume of 5 ml/kg.The dams were allowed to deliver and body weights and food consumptionwere recorded during gestation and lactation. Pups were counted,examined, sexed, and weighed on PND 0, 4, 7, 13, 17, 21, 36,49, and 68. Litters were culled to eight pups (4:4 or 5:3 sexratio) on PND 4 and litters without acceptable numbers of maleand female pups were eliminated from the study. Pups were weanedon PND 22, and two pups from each litter and their dams werekilled. Six of these pups from each dose group were perfusedin Situ for histopatho logical examination of the central andperipheral nervous sys tem. Brains of the remaining pups weredivided into four regions and weighed. Maternal liver and kidneyweights were re corded. Weaned pups were assessed for day oftestes descent or vaginal opening and for motor activity onPNDs 13, 17, 21, 47, and 58; auditory startle on PNDs 22 and60; and active avoidance on PNDs 60–64. These pups wereeuthanized and examined on PND 68. One high-dose dam died onPND 15, but there were no other clinical observations or effectson maternal weight, food consumption, or gestation length. Pupsurvival, weight, sex ratio, and sexual maturation were unaffected.There were no biologically significant findings in the behavioraltests, no changes in organ weights, and no pathological findingsthat could be attributed to isopropanol exposure. In conclusion,there was no evidence of developmental neurotoxicity associatedwith isopropanol exposure as high as 1200 mg/kg/day.     

Evaluation of the Potential for Developmental Toxicity in Rats and Mice following Inhalation Exposure to Tetrahydrofuran

Sprague-Dawley rats and Swiss (CD-1) mice were exposed to 0,600, 1800, or 5000 ppm THF (a four-carbon cyclic ether, widelyused as an industrial solvent) vapors, 6 hr/day, 7 days/week(6–19 days of gestation (DG) for rats; 6–17 DG formice). Body weights of pregnant rats in the 5000 ppm group werereduced at euthanization. There were no effects on the percentageof live rat fetuses/litter or on the fetal sex ratio. Fetalbody weight was significantly reduced for the 5000 ppm group,but the incidence of abnormalities was not increased. Mice inthe 1800 and 5000 ppm groups were sedated during exposure; approximately27% of the mice in the 5000 ppm group died. Mean body and uterineweights of mice were reduced for the 1800 and 5000 ppm groupsat euthanization (18 DG), but adjusted maternal weight gainwas not affected at 1800 ppm. There was a reduction in the percentageof live fetuses/litter for the mice in 1800 and 5000 ppm groups(95% resorptions in the 5000 ppm group). Fetal weight and sexratio in mice were not affected. An increase in the incidenceof reduced sternebral ossifications was correlated to THF concentration,although differences between groups were not statistically significant.There were no increases in the incidences of other malformationsor variations. These results suggest that THF may be embryotoxicin mice, but if the conceptus survives, development as assessedby this experimental design continues in a normal fashion. Theno-observable-adverse-effect level (NOAEL) for maternal toxicitywas 1800 ppm in both rats and mice. The NOAEL for developmentaltoxicity was 1800 ppm in rats and 600 ppm in mice.     

Effects of Prenatal Exposure to Sheesha Smoke: Response of Juvenile Rats to Novel Environment

Abstract

The traditional tobacco smoking known as sheesha, hubble-bubble, or hoaka is a process by which a tobacco-fruit mixture is drawn through a long tube, then passed through a water trap, before its inhalation by the smoker. Recently sheesha has gained substantial popularity among pregnant woman as a safer alternative to cigarette smoking. The aim of the present work is to examine the effect of prenatal exposure to sheesha smoke on growth and locomotor activities of juvenile rats. Two-day-pregnant rats were exposed daily to sheesha smoke for 10 minutes up to day 18 pregnancy. The effect of sheesha smoke on gestation period, progeny number, and body weight was determined. The ambulatory and stereotype behavior of offspring were measured at the age of 30 days. Results show that passive exposure to sheesha smoke during pregnancy had no effects on the gestational period, number of pups, birth weight, and body weight growth. The total ambulatory activity of exposed rats was 21.1% lower than that of matched control, P = .08. The decline rate of ambulatory activity in exposed rats was 27.6% lower than that of nonexposed, P = .09. The total stereotype movements in exposed rats were 26% lower than that of nonexposed, P = .029. The decline rate of the stereotype movements in the exposed rats was 10-fold lower than that of nonexposed, P = .00006. It was concluded that prenatal exposure to sheesha smoke lowers the response of rats tc novel environments.     

Developmental Toxicology Studies of Fluoxetine Hydrochloride Administered Orally to Rats and Rabbits

Pregnant Fischer 344 rats were given fluoxetine orally at doselevels of 0, 2, 5, or 12.5 mg/kg on Gestation Days (GD) 6–15;pregnant Dutch Belted rabbits were given 0, 2.5, 7.5, or 15mg/kg orally on GD 6–18. Cesarean sections were performedon rats and rabbits on GD 20 and 28, respectively. In rats,maternal toxicity was indicated at 12.5 mg/kg by depressionof weight gain and food consumption. Fetal viability, weight,and morphology were not affected at any dose level. Maternaland developmental No Observed Adverse Effect Levels (NOAELs)in the rat were 5 and 12.5 mg/kg, respectively. In rabbits,weight loss occurred at 2.5,7.5, and 15 mg/kg. Food consumptionwas also depressed at 7.5 and 15 mg/kg; abortions and maternalmortality occurred secondarily to anorexia and cachexia at 15mg/kg. Fetal viability, weight, and morphology were not affectedat any dose level. A NOAEL for maternal effects was not establishedin the rabbit; the NOAEL for developmental effects in the rabbitwas 15 mg/kg. Based on these data, fluoxetine did not exhibitany toxicity toward the developing rat or rabbit conceptus atdoses that were maternally toxic.     

Immunological Changes Produced in Rats by Prenatal Exposure to Carbon Monoxide

Abstract: Wistar female rats were exposed to relatively mild concentrations of carbon monoxide (CO) (75 and 150 p.p.m.) from day 0 to day 20 of pregnancy. The results show that splenic macrophage phagocytosis of Candida albicans was significantly decreased in 15 and 21 day old male rats exposed to CO (150 p.p.m.) during pregnancy. Moreover, splenic macrophage killing was significantly reduced in 15 day old male pups prenatally exposed to 75 and 150 ppm of CO. Prenatal CO (150 p.p.m.) significantly decreased splenic macrophage O₂^- release in both 15 and 21 day old pups. CO-induced alterations in the immune system were not observed in 60 day old rats. These findings indicate that gestational exposure to relatively mild concentrations of CO induces in rat offspring reversible immunological changes characterized by an altered splenic macrophage function.     

Developmental Effects Associated with Exposure to Xylene: A Review

ABSTRACT

Data obtained from rodents indicates that maternal exposure to mixed xylenes or individual xylene isomers can have adverse effects on the conceptus. Fetotoxic effects were reported following maternal inhalation exposure to mixed xylenes; altered enzyme activities were also found in rat pups. Dermal application resulted in apparent changes in fetal enzyme activities, while oral treatment was followed by prenatal mortality, growth inhibition, and malformations, primarily cleft palate. Maternal inhalation of individual isomers was associated with all of the above mentioned effects, with the exception of cleft palate. The o^- and p^- isomers appeared more hazardous to offspring than did the m-isomer. Malformations (i.e., cleft palate) associated with mixed or individual isomers were primarily reported at maternally toxic doses. Thus, a clear case for a selective teratogenic effect due to exposure to xylene has yet to be presented.     

二羟基乙二肟肾脏毒性的研究

亚慢性毒性实验结果表明,二羟基乙二肟及其代谢产物主要经肾排出,可引起血清尿素氮增高、肾组织SDH酶活性显著下降;病理检查可见肾小管上皮细胞浊肿变性、线粒体肿胀、溶酶体增多、增大及尿路梗阻性病变和肾结石。     

Developmental Exposure to Lead Causes Persistent Immunotoxicity in Fischer 344 Rats

Lead has been shown to exert toxic effects during early development.In these in vivo and ex vivo experiments, the effect of leadon the immune system of the developing embryo was assessed.Nine-week-old female Fischer 344 rats were exposed to lead acetate(0,100,250, and 500 ppm lead) in their drinking water duringbreeding and pregnancy (exposure was discontinued at parturition).Offspring received no additional lead treatment after birth.Immune function was assessed in female offspring at 13 weeksof age. Dams in lead-exposed groups were not different fromcontrols with respect to the immune endpoints used in theseexperiments; however, in the offspring, lead modulated importantimmune parameters at modest exposure levels. Macrophage cytokineand effector function properties (tumor necrosis factor-     

Development Neurotoxicity Evaluation of Orally Administered Isopropanol in Rats

Developmental Neurotoxicity Evaluation of Orally Administered Isopropanol in Rats. Bates, H. K., McKee, R. H., Bieler, G. S., Gardiner, T. H., Gill, M. W., Strother, D. E., and Masten, L. W. (1994). Fundam. Appl. Toxicol. 22, 152-158.Isopropanol was administered by gavage to timed-mated rats from Gestation Day (GD) 6 through Postnatal Day (PND) 21. Doses administered were 0, 200, 700, or 1200 mg/kg/day in a volume of 5 ml/kg. The dams were allowed to deliver and body weights and food consumption were recorded during gestation and lactation. Pups were counted, examined, sexed, and weighed on PND 0, 4, 7, 13, 17, 21, 36, 49, and 68. Litters were culled to eight pups (4:4 or 5:3 sex ratio) on PND 4 and litters without acceptable numbers of male and female pups were eliminated from the study. Pups were weaned on PND 22, and two pups from each litter and their dams were killed. Six of these pups from each dose group were perfused in situ for histopathological examination of the central and peripheral nervous system. Brains of the remaining pups were divided into four regions and weighed. Maternal liver and kidney weights were recorded. Weaned pups were assessed for day of testes descent or vaginal opening and for motor activity on PNDs 13, 17, 21, 47, and 58; auditory startle on PNDs 22 and 60; and active avoidance on PNDs 60-64. These pups were euthanized and examined on PND 68. One high-dose dam died on PND 15, but there were no other clinical observations or effects on maternal weight, food consumption, or gestation length. Pup survival, weight, sex ratio, and sexual maturation were unaffected. There were no biologically significant findings in the behavioral tests, no changes in organ weights, and no pathological findings that could be attributed to isopropanol exposure. In conclusion, there was no evidence of developmental neurotoxicity associated with isopropanol exposure as high as 1200 mg/kg/day.     

Postnatal Toxicity following Prenatal Reserpine Exposure in Rats: Effects of Dose and Dosing Schedule

Postnatal Toxicity following Prenatal Reserpine Exposure inRats: Effects of Dose and Dosing Schedule. BUELKE-SAM, J., KIMMEL,G. L., WEBB, P. J., SUKKER, W., JR., NEWPORT, G. D., NELSON,C. J., AND KIMMEL, C. A. (1984). Fundam. Appl. Toxicol. 4, 983–991.Pregnant CD rats were treated subcutaneously with 0, 0.1, 0.33,or 1.0 mg reserpine/kg/day either on Days 12–15 or onDays 16–19 of gestation. Dams were allowed to deliverand litters (4 ± 1 of each sex) were weighed weekly andheld to 21 days of age. Basal ornithine decarboxylase (ODC)activity and neurocheraical determinations were made on heartsand brains, respectively, from pups culled from litters on postnatalDay 1, and from two males and two females/litter at 21 daysof age. Following both treatment schedules, the high dose ofreserpine resulted in maternal weight loss during dosing, increasedstillborn pups, reduced pup weight at birth, retarded postnatalgrowth, and decreased survival to 21 days of age. Basal cardiacODC activity was reduced to 33% of control levels only on PostnatalDay 1 in both high-dose groups, while absolute heart weightdecreased and relative heart weight increased in these pups.Whole-brain concentrations of two neurotransmitter metabolites,3–4-dihydroxy-phenylacctic acid (DOPAC) and 5-hydroxyindoleaceticacid (5-HIAA), were increased only at Postnatal Day 1 in thehigh dose group treated on Days 12–15 of gestation. Noother changes were found in concentrations of these metabolitesor in the transmitters dopamine and serotonin. The only effectfound following administration of 0.33 mg/kg reserpine was areduction in maternal weight gained during both dosing periods.No signs of toxicity were observed following low-dose exposureon either schedule. Most previously reported postnatal functionalstudies following reserpine exposure have used mid- to late-gestationaltreatment with 1.0 mg/kg, a dose shown here to result in markedovert maternal and fetal toxicity. Such overt toxicity raisesthe question of whetheT the functional effects of reserpineare primary or may be secondary to general toxic effects. Suchquestions must be considered when interpreting postnatal functionaldata and in the design of further studies.     

In Utero and Lactational Exposure to Fluoxetine in Wistar Rats: Pregnancy Outcomes and Sexual Development

This study evaluated the reproductive effects of fluoxetine exposure in utero and during lactation on pregnancy outcomes and the sexual development of offspring. Pregnant Wistar rats were treated daily with fluoxetine (0.4, 1.7 and 17 mg/kg/day) or distilled water by gavage from gestation day (GD) 7 to lactation day (LD) 21. A significant reduction in maternal body weight was observed during pregnancy and lactation in dams exposed to 17 mg/kg fluoxetine. Hormone analysis revealed an increase in progestagen and glucocorticoid metabolites on GD 15 and oestrogen and progestagen metabolites on LD 7 in dams treated with 17 mg/kg fluoxetine. Oestrogen metabolites also were increased on LD 7 in dams treated with 0.4 mg/kg fluoxetine. Besides that, an increase in the weight of the adrenal glands and a reduction in uterine weight in dams exposed to highest dose of fluoxetine were observed. Finally, pup birthweight and the viability and weaning indices also were reduced in animals exposed to 17 mg/kg fluoxetine. Overall, maternal hormonal changes were only observed at the highest dose tested, which also induced maternal and foetal toxicity. No significant changes were seen in dams or offspring exposed to therapeutic‐like doses.     

药物非临床发育神经毒性研究的神经病理学评价策略

神经病理学评价是药物非临床发育神经毒性评价的重要组成部分和金标准,本文从发育神经毒性神经病理学评价的实验动物设计、优选的动物年龄、神经系统解剖和组织处理、以及病理结果的解释方面概述了标准化的发育神经毒性神经病理学评价原则和方法。介绍了药物非临床发育神经毒性研究神经病理学评价相关国际指导原则要求,为减少我国和其它国家及地区间实验程序的差异,为我国从事药物非临床发育神经毒性研究的病理学家提供一定参考。     

Evaluation of the Effects of Inhalation Exposure to 1,3-Dichloropropene on Fetal Development in Rats and Rabbits

Evaluation of the Effects of Inhalation Exposure to 1,3-Dichloropropeneon Fetal Development in Rats and Rabbits. HANLEY, T. R., Jr.,JOHN-GREENE, J. A., YOUNG, J. T., CALHOUN, L. L., AND RAO, K.S. (1987). Fundam. Appl. Toxicol. 8, 562–570. 1,3-Dichloropropene(DCP), which has found widespread use as a soil fumigant, wasevaluated for its potential effects on embryonal and fetal developmentin rats and rabbits. Pregnant Fischer 344 rats and New ZealandWhite rabbits were exposed to 0, 20, 60, or 120 ppm of 1,3-dichloropropenefor 6 hr/day during gestation Days 6–15 (rats) or 6–18(rabbits). Exposure-related decreases in maternal weight gainand feed consumption were observed in rats at all treatmentlevels. Decreased weight gain was also observed among rabbitsat 60 and 120 ppm. A slight, but statistically significant,increase in the incidence of delayed ossification of the vertebralcentra in rats exposed in ulero to 120 ppm of DCP was consideredof little toxicologic significance in light of the maternaltoxicity observed at this exposure concentration. No evidenceof a teratogenic or embryotoxic response was observed in eitherspecies at any exposure level tested. Thus, it was concludedthat DCP was not teratogenic at exposure levels up to 120 ppmin either rats or rabbits.     

Neurotoxicity Evaluation of N,N-Diethyl-m-toluamide (DEET) in Rats

The neurotoxic potential of N,N-diethyl-m-toluamide (DEET) wasevaluated following acute oral administration or following multigenerationplus chronic dietary administration to the rat. For the acutestudy, rats were administered undiluted DEET at dose levelsof 50, 200, or 500 mg/kg by gavage. A dose level of 500 mg/kgwas considered to be the highest practical dose that could beevaluated in this study based upon observations of overt toxicityat 500 mg/kg and mortality at 1000 mg/ kg in a dose range-findingstudy. The two measures of neurotoxicity evaluated in the acutestudy were functional observational battery (FOB) and motoractivity measurements. An apparent treatment-related effectin thermal response time (increased) was noted for both sexes1 hr after dosing at the 500 mg/kg dose level. A questionableeffect on rearing activity (decreased) also was noted at thesame dose level. For the multigeneration plus chronic dietaryadministration study, rats were administered DEET at dietaryconcentrations of 0, 500, 2000, or 5000 ppm continuously overtwo generations and then chronically for 9 months. A dietaryconcentration of 5000 ppm meets the criteria for a maximum tolerateddose (MTD) based on traditional chronic toxicology assessments.Evaluations included FOB, motor activity, discriminative acquisitionand reversal in an Mmaze, acoustic startle habituation, passiveavoidance acquisition and retention, and microscopic examinationof central and peripheral nervous tissue. The only effect thatwas considered to be possibly treatment-related was a slightincrease in exploratory locomotor activity at the 5000 ppm doselevel. Based on the results of these studies, the nervous systemdoes not appear to be a selective target when DEET is administeredto rats either as a single oral dose at high dose levels orchronically at the MTD.     

Developmental Neurotoxicity: Evaluation of Testing Procedures with Methylazoxymethanol and Methylmercury

Testing procedures for identification of potential developmentalneurotoxicants were evaluated using two prototypical developmentalneurotoxicants, methylazoxymethanol (MAM) and methylmercury(MeHg). Evaluation of offspring of LongEvans rats incorporatedassessments of developmental toxicity, neurochemistry, histology,and behavior, with most testing being completed near weaning.A number of endpoints in the testing strategy were sensitiveto the effects of prenatal exposure to MAM [30 mg/kg on GestationDay (GD) 15]: (1) MAM caused reduced neonatal body weights butdid not effect viability or postnatal survivorship; (2) measurementof total and regional brain weight and histological analysisshowed that a number of regions, the cortex and hippocampusin particular, were affected by MAM exposure; (3) an assay forglial fibrillary acidic protein (GFAP) showed that the concentrationof this protein was significantly increased in the cortex andhippocampus of treated offspring; (4) a T-maze delayed-alternationprocedure indicated that MAM-treated pups were slower in theacquisition phase of the task relative to control pups; (5)motor activity testing revealed hyperactivity in treated offspringthat persisted into adulthood; and (6) acoustic startle proceduresrevealed reduced startle amplitudes in preweanlings. Few endpointswere significantly affected by prenatal MeHg exposure (1, 2,or 4 mg/kg on GD 6–15). High fetal and neonatal mortalityand lower neonatal body weights were detected at the highestdose of MeHg. Although minimal effects of MeHg may reflect arelative insensitivity of the test species and/or the test methods,the combined results from both chemicals suggest that some proceduresnot currently required in the developmental neurotoxicity guidelinemay be useful in hazard identification, and further evaluationwith other chemicals, species, strains, and/or exposure paradigmsmay be warranted.     

Prenatal Exposure to Nicotine Impairs Performance of the 5-Choice Serial Reaction Time Task in Adult Rats

Cigarette smoking is associated with a wide variety of adverse reproductive outcomes, including increased infant mortality and decreased birth weight. Prenatal exposure to tobacco smoke, of which nicotine is a major teratogenic component, has also been linked to the acceleration of the risk for different psychiatric disorders, including conduct disorder and attention deficit hyperactivity disorder (ADHD). Whether this increased risk is influenced by the direct effects of gestational nicotine exposure on the developing fetus remains uncertain. In this study we provide experimental evidence for the effects of prenatal nicotine exposure on measures of attention and impulsivity in adult male rats. Offspring of females exposed during pregnancy to 0.06 mg/ml nicotine solution as the only source of water (daily consumption: 69.6±1.4 ml/kg; nicotine blood level: 96.0±31.9 ng/ml) had lower birth weight and delayed sensorimotor development measured by negative geotaxis, righting reflex, and grip strength. In the 5-choice serial reaction time test, adult rats showed increased numbers of anticipatory responses and omissions errors, more variable response times, and lower accuracy with evidence of delayed learning of the task demands when the 1 s stimulus duration was introduced. In contrast, prenatal nicotine exposure had no effect on exploratory locomotion or delay-discounting test. Prenatal nicotine exposure increased expression of the D5 dopamine receptor gene in the striatum, but did not change expression of other dopamine-related genes (DRD4, DAT1, NR4A2, and TH) in either the striatum or the prefrontal cortex. These data suggest a direct effect of prenatal nicotine exposure on important aspects of attention, inhibitory control, or learning later in life.     

Prenatal Exposure of Rats to Diphenhydramine: Effects of Physical Development, Open Field, and Gonadal Hormone Levels in Adults

Diphenhydramine (DPH), a classical H₁ receptor antagonist, has been used in pregnancy for the treatment of allergies, nausea, and vomiting. It has been reported that 10-20% of pregnant women take antihistamine-containing preparations at some point during pregnancy. The present study analyzed the influence of prenatal exposure to DPH of rats on: 1) maternal behavior and milk production of dams; 2) physical and reflexologic development of offspring; and 3) long-term effects on open field behaviors and gonadal hormone levels in offspring. Female pregnant rats were injected SC, daily, with 20 mg/kg DPH or saline from embryonic day (E) 0 to 21. After delivery, maternal behavior was assessed and offspring physical and reflexologic development was examined. Open field activity of male and female rats was measured at 21 and 75 days of age and plasma hormone levels were evaluated in both sexes at 120 days of age. Neither maternal behavior nor milk production was affected by DPH treatment. Treated offspring showed an accelerated pinna unfolding, eye opening, and a delay of testes descent and vaginal opening. Both righting reflex and negative geotaxis development were accelerated, but prenatal exposure to DPH did not modify offspring locomotor activity. When tested as adults, a lack of sexual dimorphism in the open field activity of males and females was observed. No differences were observed between gonadal hormone levels of control and experimental groups of either sex. The findings suggest that prenatal DPH exposure influences physical and reflex development of rat pups.     

Prenatal Exposure of Rats to Diphenhydramine: Effects on Physical Development, Open Field, and Gonadal Hormone Levels in Adults

Diphenhydramine (DPH), a classical H₁ receptor antagonist, has been used in pregnancy for the treatment of allergies, nausea, and vomiting. It has been reported that 10–20% of pregnant women take antihistamine-containing preparations at some point during pregnancy. The present study analyzed the influence of prenatal exposure to DPH of rats on: 1) maternal behavior and milk production of dams; 2) physical and reflexologic development of offspring; and 3) long-term effects on open field behaviors and gonadal hormone levels in offspring. Female pregnant rats were injected SC, daily, with 20 mg/kg DPH or saline from embryonic day (E) 0 to 21. After delivery, maternal behavior was assessed and offspring physical and reflexologic development was examined. Open field activity of male and female rats was measured at 21 and 75 days of age and plasma hormone levels were evaluated in both sexes at 120 days of age. Neither maternal behavior nor milk production was affected by DPH treatement. Treated offspring showed an accelerated pinna unfolding, eye opening, and a delay of testes descent and vaginal opening. Both righting reflex and negative geotaxis development were accelerated, but prenatal exposure to DPH did not modify offspring locomotor activity. When tested as adults, a lack of sexual dimorphism in the open field activity of males and females was observed. No differences were observed between gonadal hormone levels of control and experimental groups of either sex. The findings suggest that prenatal DPH exposure influences physical and reflex development of rat pups.