Postnatal closure of membranous ventricular septal defects in Sprague-Dawley rat pups after maternal exposure with trimethadione

BACKGROUND: Congenital membranous ventricular septal defects (VSD) have been shown to close during postnatal development in rats [Solomon et al., Teratology 55:185-194, 1997]. Although they may differ in size, spontaneous and treatment-related VSD are histologically similar; however, the postnatal fate of treatment-induced VSD is not known. The objective of this study was to determine if treatment-induced VSD persist throughout postnatal development. METHODS: Groups of 40 female rats were given oral doses of trimethadione (TMD) at 400 mg/kg/day (200 b.i.d.) or 600 mg/kg/day (300 b.i.d.) on Gestation Days (GD) 9 and 10. Twenty dams in each group were designated for Cesarean section and 20 were allowed to deliver and rear their offspring to Postnatal Day (PND) 21. The integrity of the ventricular septum was evaluated in fetuses (GD 21) and pups (PND 21). RESULTS: The incidence of membranous VSD was 0.6, 7.6, and 49.8% per litter in the Control, 400, and 600 mg/kg groups, respectively, on GD 21. Both the incidence and severity of VSD increased with dose. The VSD at 400 mg/kg were small in size and initially detected by the presence of blood flowing through the defect from the closed right ventricle. In the 600 mg/kg dose group, the VSD, although still membranous, were larger and more readily detected without the need to examine the blood flow. At 600 mg/kg, not only were the VSD larger than those in the Control or the 400 mg/kg group, 10.1% per litter of the affected fetuses had other vessel anomalies associated with the VSD, which were incompatible with pup survival. On PND 21, VSD was noted in 0.3, 0, and 6.4% per litter evaluated in the Control, 400, and 600 mg/kg groups, respectively. This demonstrates that the small, isolated treatment-related VSD can resolve postnatally; however, the closure of the larger or more severe VSD may be prolonged or may not occur at all. Although TMD exposure reduced group mean fetal weights at both dose levels, there was no difference between the mean weight of fetuses with VSD and those fetuses without VSD in the same group. CONCLUSION: Treatment-induced VSD close postnatally, and appears to be a delay in cardiac development not associated with fetal weight. The timing of closure and survivability during closure is dependent on the severity of the VSD. Further characterization of the two sizes of VSD may provide diagnostic clarity; however, the current data support the smaller VSD as a variation with no significant impact on viability and growth, and the more severe VSD to be a malformation.     

Prenatal epoxiconazole exposure effects on rat postnatal development

Although some studies have pointed out to embryo/fetal toxicity, knowledge about the potential toxicity of the fungicide epoxiconazole is still limited. Once the results of these previous studies have raised some concern, this study studied the effects of epoxiconazole maternal exposure on the physical endpoints in the development of rat pups. To accomplish that, the effects of epoxiconazole (50.0, 100.0, and 150.0 mg/kg) were examined when rats were exposed at two different developmental stages: during the first 6 days of pregnancy or in the organogenesis period (6-15 days). After parturition, pups were tested for growth and maturational milestones. Maternal exposure to the fungicide, independently of phase, resulted in significantly early mean time to vaginal opening and delayed time to testes descent in pups. Weight gain rate in pups and their mothers was not affected for the tested exposure period. The findings of this study emphasize that epoxiconazole maternal exposure may lead to alterations in developmental patterns in nursing pups, consistent with the known influence of epoxiconazole on steroid hormone synthesis.     

Lack of adverse effects in pregnant/lactating female rats and their offspring following pre- and postnatal exposure to ELF magnetic fields

We have recently reported that exposure of pregnant rats to 60 Hz at field strengths up to 0.5 mT during the entire period of pregnancy did not induce any biologically significant effects on both pregnant dams and embryo-fetal development. The present study was carried out to investigate the potential effects of gestational and lactational MF exposure on pregnancy, delivery, and lactation of dams and growth, behavior, and mating performance of their offspring in rats. Timed-pregnant female Sprague-Dawley (SD) rats (24/group) received continuous exposure to 60 Hz magnetic field (MF) at field strengths of 0 (sham control), 5 microT, 83.3 microT, or 0.5 mT. Dams received MF or sham exposures for 21 h/day from gestational day 6 through lactational day 21. Experimentally generated MF was monitored continuously throughout the study. No exposure-related changes in clinical signs, body weight, food consumption, pregnancy length, and necropsy findings were observed in dams. Parameters of growth, behavior, and reproductive performance of offspring showed no changes related to MF exposure. There were no adverse effects on embryo-fetal development of F2 offspring from dams exposed to MF. In conclusion, exposure of pregnant SD rats to 60 Hz at field strengths up to 0.5 mT from gestational day 6 to lactational day 21 did not produce biologically significant effects in dams, F1 offspring, or F2 fetuses.     

Species Differences in Developmental Toxicity of Epoxiconazole and Its Relevance to Humans

Epoxiconazole, a triazole‐based fungicide, was tested in toxicokinetic, prenatal and pre‐postnatal toxicity studies in guinea pigs, following oral (gavage) administration at several dose levels (high dose: 90 mg/kg body weight per day). Maternal toxicity was evidenced by slightly increased abortion rates and by histopathological changes in adrenal glands, suggesting maternal stress. No compound‐related increase in the incidence of malformations or variations was observed in the prenatal study. In the pre‐postnatal study, epoxiconazole did not adversely affect gestation length, parturition, or postnatal growth and development. Administration of epoxiconazole did not alter circulating estradiol levels. Histopathological examination of the placentas did not reveal compound‐related effects. The results in guinea pigs are strikingly different to those observed in pregnant rats, in which maternal estrogen depletion, pathological alteration of placentas, increased gestation length, late fetal death, and dystocia were observed after administration of epoxiconazole. In the studies reported here, analysis of maternal plasma concentrations and metabolism after administration of radiolabeled epoxiconazole demonstrated that the different results in rats and guinea pigs were not due to different exposures of the animals. A comprehensive comparison of hormonal regulation of pregnancy and birth in murid rodents and primates indicates that the effects on pregnancy and parturition observed in rats are not applicable to humans. In contrast, the pregnant guinea pig shares many similarities to pregnant humans regarding hormonal regulation and is therefore considered to be a suitable species for extrapolation of related effects to humans. Birth Defects Res (Part B) 98:230–246, 2013. © 2013 Wiley Periodicals, Inc.     

Postnatal development of phospholipids and their fatty acid profile in rat heart

The aim of this study was to determine the concentration of phospholipids (PL), plasmalogen components of choline (PC) and ethanolamine (PE) phosphoglycerides (PLPC, PLPE) and fatty acid profile of PL and triacylglycerols (TAG) in developing rat left ventricular myocardium between postnatal day (d) 2 and 100. The steepest increase of total PL (TPL) concentration occurs between d2 and d5, followed by a further slower increase between d20 and d40. Similar developmental changes were observed in PC and PE. The PLPE concentration rises by d10, whereas PLPC does not change during the whole period investigated, except for the transient decline on d5. The concentration of diphosphatidylglycerol (DPG) increases by d60; the steepest rise occurs between d20 and d40. Phosphatidylinositol (PI) concentration rises only by d5. The concentration of phosphatidylserine (PS) decreases between d5 and d10 and then it does not change. Sphingomyelin (SM) concentration is maintained till d10, it declines on d20 and does not change thereafter. The proportion of saturated fatty acids (SFA) increases by d5 in PC, PE, PS and TAG, and by d10 in DPG and PI. After d20 the SFA proportion gradually decline in all lipids. Monounsaturated FA (MUFA) proportion decreases in PC, PE, PI and PS from d2 till d10, and in the weaning period it tends to rise again. In contrast, in DPG and TAG the proportion of MUFA declines during the whole postnatal period. N-6 polyunsaturated FA (PUFA) decrease in all PL by d20 and rise again thereafter; in TAG they decline between d2 and d10 and return to the initial level by d100. N-3 PUFA increase in all PL during the suckling period and decline after weaning; in TAG they increase only by d5 and then they decline. This remodeling of myocardial PL and TAG composition during postnatal development may affect membrane properties and contribute to developmental changes in the function of membrane proteins and cell signaling.     

Effects of tert-butyl acetate on maternal toxicity and embryo-fetal development in Sprague-Dawley rats

This study investigated the potential adverse effects of tert-butyl acetate (TBAc) on maternal toxicity and embryo-fetal development after maternal exposure of pregnant rats from gestational days 6 through 19. TBAc was administered to pregnant rats by gavage at 0, 400, 800, and 1,600 mg/kg/day. All dams were subjected to a Caesarean section on day 20 of gestation, and their fetuses were examined for any morphological abnormalities. At 1,600 mg/kg, maternal toxicity manifested as increases in the incidence of clinical signs and death, lower body weight gain and food intake, increases in the weights of adrenal glands and liver, and a decrease in thymus weight. Developmental toxicity included a decrease in fetal weight, an increase in the incidence of skeletal variation, and a delay in fetal ossification. At 800 mg/kg, only a minimal developmental toxicity, including an increase in the incidence of skeletal variation and a delay in fetal ossification, were observed. In contrast, no adverse maternal or developmental effects were observed at 400 mg/kg. These results show that a 14-day repeated oral dose of TBAc is embryotoxic at a maternally toxic dose (i.e., 1,600 mg/kg/day) and is minimally embryotoxic at a nonmaternally toxic dose (i.e., 800 mg/kg/day) in rats. However, no evidence for the teratogenicity of TBAc was noted in rats. It is concluded that the developmental findings observed in the present study are secondary effects to maternal toxicity. Under these experimental conditions, the no-observed-adverse-effect level of TBAc is considered to be 800 mg/kg/day for dams and 400 mg/kg/day for embryo-fetal development.     

大鼠脑干听觉诱发电位和中潜伏期反应的生后发育

目的：探讨大鼠脑干听觉诱发电位（BAEP）和听觉中潜伏期反应(MLR)生后发育模式的异同。方法：在同一批新生SD纯种大鼠连续10周同时观察BAEP和MLR生后发育的变化。结果：BAEP和MLR分别在生后14d和17d出现;BAEP各波峰潜伏期（PL）随鼠龄增长而递减,生后3－4周是PL缩短的主要时期,I波PL在生后29d达成年值,其余各波PL在生后70d全部达成年值;首次出现的MLR,其Po和Na两波PL已达成年值,而Pa、Nb和Pb和PL也随鼠龄增长而缩短,但生后20－23d很快就达成年值;BAEP的Ⅰ、Ⅲ、Ⅳ波和MLR的Nb、Pb波波幅在生后3－4周期间迅速递增,且峰值明显大于成年值,然后逐渐回降。结论：大鼠MLR和BAEP生后发育的模式基本相同,但MLR各波PL较早达成年值。     

Interactive effects of prenatal cocaine and nicotine exposure on maternal toxicity,postnatal development,and behavior in the rat

Two experiments were performed to investigate the interactive effects of prenatal coadministration of cocaine hydrochloride (C) and nicotine tartrate (N). Experiment I was designed to determine doses of C and N that could be coadministered without altering maternal gestational parameters and/or fetal viability. Exposure of Sprague-Dawley rats to combined high-dose C (20 mg/kg) and high-dose N (5.0 mg/kg) on gestation days 8–21 was not more toxic to dam or fetus than that of exposure to C alone. Experiment II investigated pregnancy outcome, postnatal development, and behavior of the offspring following drug exposure to either high-dose cocaine (20 mg/kg: CS), high-dose nicotine (5.0 mg/kg: NS), or both (NC) on gestation days 8–21. N was administered by osmotic minipump and C by sc injection. Saline-injected dams, fitted with saline-filled pumps (SS), and untreated dams, pair-fed (PF) to NC females, served as controls. Alterations in maternal variables were limited to a 10–15% decrease in food consumption in NC and CS groups. Pregnancy outcome and birth statistics were unaffected by prenatal treatment, as was offspring body weight during the first four postnatal weeks. However, the development of surface righting was delayed in CS pups, and only CS offspring were underresponsive to the stimulatory effects of dopamine agonists on activity and stereotypy. Behavioral responses to N challenge were similar in all groups. In addition, only CS offspring showed altered behavioral responses in a spontaneous alternation task. Treatment effects on dopamine D₁ and D₂ binding in the caudate nucleus were not observed. The combination of N and C did not exacerbate any of the behavioral changes seen in CS offspring. These results support the hypothesis that C is a behavioral teratogen in rodents, and suggest that in the present model, nicotine can mitigate some of the consequences ofin utero exposure to cocaine.     

Developmental immunotoxicity investigations in the SD rat following pre- and post-natal exposure to cyclosporin

BACKGROUND: The development and function of the immune system was assessed in juvenile SD rats following pre- or post-natal exposure to cyclosporin. The main objective was to assess the feasibility of the methods available for the detection of adverse effects on the development of the immune system for use in the safety assessment of medicines. METHODS: In a pre-natal experiment, 15 pregnant rats were given 10 mg/kg/day of cyclosporin by gavage from day 6 of gestation until 4 days after parturition. A control group received olive oil. In a post-natal experiment, the pups from 35 litters were given 10 mg/kg/day of cyclosporin by gavage from 4 to 28 days of age. Half of the pups in each litter were given water and acted as controls. Immune endpoints were determined in the pups in both experiments from two to 10 weeks of age, including: lymphocyte subsets, serum immunoglobulin titres, serum autoantibodies, primary antibody response to sheep red blood cells (SRBC), delayed-type hypersensitivity response, humoral response to keyhole limpet haemocyanin, spleen cellularity, immune organ weights, and histopathology. RESULTS: Pre-natal exposure caused no effects on immune function. Post-natal exposure caused immune depression during the treatment period and a persistent impairment of the immune system characterised by lymphoid hyperplasia in the spleen and a reduced primary antibody response to SRBC at 10 weeks of age. CONCLUSIONS: These results demonstrate the importance of a post-treatment follow-up period in developmental immunotoxicity studies, in order to distinguish between the transient effects of immune modulation and the persistent consequences of developmental toxicity.     

ILSI/HESI maternal toxicity workshop summary: maternal toxicity and its impact on study design and data interpretation

Workshops on maternal toxicity were held at the annual Society of Toxicology, Teratology Society, and European Teratology Society meetings in 2009. Speakers presented background information prior to a general discussion on this topic. The following recommendations/options are based on the outcome of the discussions at the workshops:

• 1. A comprehensive evaluation of all available data from general toxicity studies, range‐finding Developmental and Reproductive Toxicology (DART) studies, class effects, structure–activity relationships, exposure studies, etc. is essential for appropriate dose selection for definitive DART studies. The intent is to avoid marked maternal toxicity leading to mortality or decreased body weight gains of greater than 20% for prolonged periods.

• (a) Evaluate alternative endpoints for dose selection and data interpretation (e.g., target tissue effects and pharmacology) for biotherapeutics.
• (B) Evaluate additional maternal parameters based on effects and/or target organs observed in short‐term (e.g., 2‐ or 4‐week) general toxicity studies.

• 2. Evaluate all available data to determine a cause–effect relationship for developmental toxicity.

• (a) Conduct a pair‐feeding/pair‐watering study as a follow‐up.
• (b) Evaluate individual data demonstrating maternal toxicity in the mother with adverse embryo–fetal outcomes in the litter associated with the affected mother.
• (c) Conduct single‐dose studies at increasing doses as a complement to conventional embryo–fetal toxicity studies for certain classes of compounds that affect the hERG channel.

• 3. Support statements that embryo–fetal effects are caused by maternal toxicity and/or exaggerated pharmacology, especially for malformations.

• (a) Provide mechanistic or other supporting data.
• (b) Establish the relevance of the DART findings in animals for human exposures. Birth Defects Res (Part B) 92:36–51, 2010. © 2011 Wiley‐Liss, Inc.

     

Postnatal growth of the rat palatine gland

To elucidate how the palatine glands grow postnatally, the palatine glands of rats from 0 to 8 weeks of age were investigated histologically and immunohistochemically. Under light microscope, three dimensions of the right part of the palatine glands were measured and the total number of excretory ducts of the glands was counted from the parasagittal serial sections. Immunohistochemistry with anti-5-bromo-2'-deoxyuridine (BrdU) monoclonal antibody was also employed to detect the cellular proliferative activity. At birth (0 weeks), the palatine glands consisted of ducts and immature acini. The ducts in the glands were connected with excretory ducts. After 2 weeks, there was no duct in the glands. Most acinar cells became mature as mucous cells and took the form of tubulo-acini connected directly with excretory ducts. In the posterior region of the glands, serous acinar cells forming demilunes were occasionally seen. All three dimensions of the palatine glands became longer, and the number of excretory ducts tended to increase. Immunohistochemistry showed acinar and duct cells were highly proliferative in early stage of postnatal life and their proliferative activity decreased thereafter. This study demonstrated that immature rat palatine glands of newborn rats grow three-dimensionally during maturation, and that the parenchymal cell proliferation contributes to the growth of the rat palatine glands. In addition, it is suggested that the glandular tissue arises from the excretory ducts formed postnatally.     

Cross-generational effect of prenatal morphine exposure on neurobehavioral development of rat pups

Prenatal exposure to opiates can have devastating effects on the development of human fetuses and may induce long-term physical and neurobehavioral changes during postnatal maturation. The present study was aimed at identifying cross-generational effects of prenatal morphine exposure in Sprague-Dawley rats. Pregnant rats were injected subcutaneously with either saline or morphine (10 mg/kg) twice daily during gestational days 11-18. Litter size, percentage of males and females, anogenital distances (AGDs), righting reflex, and body weight were assessed in prenatally morphine-exposed pups (first generation) and their offspring (second generation). Both prenatally morphine-exposed pups and offspring of prenatally morphine-exposed dams exhibited an increased latency to right. Additionally, second generation pups were slower in righting than first generation pups. During the early postnatal period the second generation pups weighed less than the first generation regardless of drug exposure. The AGDs of second generation male pups were decreased relative to the first generation. Our data provide important novel information about the trans-generational effects of maternal opiate abuse that may be useful for understanding/evaluating the teratogenic effects of prenatal opiate exposure.     

An Evaluation of Reproductive and Developmental Toxicity of Sitaxentan (Thelin) in Rats

Sitaxentan sodium (Thelin) is a once daily, orally bioavailable, highly selective endothelin A receptor antagonist. Initially approved for the treatment of pulmonary arterial hypertension, sitaxentan was withdrawn in 2010 following the recognition of a pattern of idiosyncratic liver injury. During development of this drug, a series of nonclinical studies investigated the effects of orally administered sitaxentan on fertility, embryofetal development, and pre‐ and postnatal development in the rat; results of these studies are reported here. In the fertility study, sitaxentan did not affect mating behavior, fertility, sperm morphology, or estrous cycle. Sitaxentan was teratogenic in the embyrofetal development study, which was expected based on its pharmacologic mechanism of action. Teratogenic effects included malformations of the head, mouth, face, and large blood vessels. In the pre‐ and postnatal study, sitaxentan administration was associated with reduced pup survival, large or abnormally shaped livers, and delays in markers of auditory and sexual development. Sitaxentan was detected in plasma of suckling pups receiving milk from females dosed with sitaxentan. These nonclinical study findings were reflected in the sitaxentan product label warnings. Birth Defects Res (Part B) 00:1‐10, 2012. © 2012 Wiley Periodicals, Inc.     

Peculiarities of proteasome pool formation in rat spleen and liver during postnatal development

Changes in the specific activity and amounts of 26S and 20S proteasome pools in rat spleen and liver during postnatal development and appearance in them of immune subunits were studied. Two decreases in chymotrypsin-like activity of the proteasome pools were recorded during the first three weeks after birth. The activity minimum fell on the 11th and 19th days, and the first decrease was more prolonged and pronounced than the second. The decrease in the specific activity of the 26S proteasome pools was associated with a reduction of their quantity. The 20S proteasome pools displayed no such decreases. Noticeable quantities of immune subunits LMP7 and LMP2 were revealed by Western blotting in the spleen on the 7th day and on the 19th day in the liver, concurrently with the beginning of the decrease in the proteasome activity. It was concluded that during the first three weeks of postnatal development the proteasome pools in rat spleen and liver were replaced twice, and in the spleen (a lymphoid organ) a qualitatively new pool containing immune subunits appeared nearly two weeks earlier than in the liver (a non-lymphoid organ). The appearance of immune proteasomes in different organs and tissues during some weeks after birth seems to explain the immune system inefficiency during embryogenesis and early postnatal development.     

Influence on Stress on Postnatal Growth of Body and Adrenal Gland Weight in Rats

Seven-week male Wistar rats weighing 145–155 g were housed 10 (control) or 20 (crowded) per cage (50 × 35 × 15 cm). Groups of control and crowded animals were decapitated within 0.5, 1, 3, 7, 14, 21, 28, 35, 56, 70, and 98 days of experiment. The keeping of rats in crowding conditions induced chronic stress, which developed, according to phase changes in plasma concentration of corticosterone and adrenal content of cholesterol, through the stages alarm, resistance, and exhaustion. The postnatal growth of body weight in the stressed rats was behind that in the control. Under the crowding conditions, the adrenal weight did not undergo significant increase, since the stress-induced hypertrophy of the zona fasciculata was compensated by the proportional suppression of the postnatal growth of the zona reticularis. After 56 days, the postnatal growth of the hypertrophied fascicular zone was delayed in the experimental rats.     

Postnatal changes of cathepsin D activity in rat liver and brain

Total and specific activity of cathepsin D (EC. 3.4.23.5) were measured in rat liver and brain from 1 to 98 days of age. The activity of cathepsin D in the liver of adult and newborn rats was the same while in the rat brain it was higher in adult than in newborn rats. In the liver maximum specific activity of cathepsin D occurred on the 10th postnatal day and minimum on the fourth day of age. In the brain maximum specific activity of the enzyme occurred on the 14th postnatal day. Total activity of cathepsin D increased after birth in rat liver and brain. These results are discussed in relation to the functional role of cathepsin D in the rat liver and the brain.     

Lack of effects on fertility and developmental toxicity of a quadrivalent HPV vaccine in Sprague‐Dawley rats

Human papillomavirus (HPV) infection is one of the most common sexually transmitted diseases, with approximately half of the HPV‐infected people being adolescents and young adults. A recently developed quadrivalent HPV vaccine, GARDASIL^®, has been shown to be highly effective in the prevention of a number of HPV‐mediated diseases. The objective of the present study was to evaluate the potential effects of the vaccine on female fertility and F1 development, growth, behavior, and reproductive performance. In addition, anti‐HPV antibodies in the F0 females and F1 offspring were measured during the study. Two groups of 65 virgin Sprague‐Dawley rats were administered two or four intramuscular injections of the vaccine (full human dose of 0.5 mL at 5 and 2 weeks prior to mating, on Gestation Day [GD] 6, and Lactation Day [LD] 7; or GD 6 and LD 7 only). Additional groups of rats were administered phosphate‐buffered saline or Merck Aluminum Adjuvant (MAA) at the same four times. All females were mated to males of the same stock. Cesarean sections were performed on 22/group on GD 21, 22/group were allowed to deliver, and remaining females used for blood collections or replacements. F0 female fertility parameters were evaluated. An extensive number of prenatal, perinatal, and postnatal parameters were evaluated in the F1 generation. There were no unscheduled deaths during the study. There was no evidence of toxicity in the F0 females given either MAA or vaccine. There were no effects on the fertility or reproductive performance of the F0 females. There was no evidence of developmental toxicity to the F1 generation, including fetal body weight and morphology, postnatal growth and development, behavior, and reproductive performance. The quadrivalent vaccine induced a specific antibody response to the four HPV types in the F0 female rats following one or multiple injections. Antibodies against all four HPV types were transferred to the F1 generation during gestation and/or lactation, likely via the placenta and milk, respectively. The passively transferred antibodies persisted up to Postnatal Day 77 when they were last measured. These results demonstrate that this quadrivalent HPV vaccine had no detectable adverse effects in either the treated F0 female rats or the F1 generation. Birth Defects Res (Part B) 83:561–572, 2008. © 2008 Wiley‐Liss, Inc.     

Maternal exposure to multi-wall carbon nanotubes does not induce embryo-fetal developmental toxicity in rats

BACKGROUND: Although the potential risk of carbon nanotubes (CNTs) to humans has recently increased due to expanding production and widespread use, the potential adverse effects of CNTs on embryo–fetal development have not yet been determined. METHODS: This study investigated the potential effects of multi‐wall CNTs (MWCNTs) on pregnant dams and embryo–fetal development in rats. MWCNTs were administered to pregnant rats by gavage at 0, 40, 200, and 1,000 mg/kg/day. All dams were subjected to Cesarean section on day 20 of gestation, and the fetuses were examined for any morphological abnormalities. RESULTS: All animals survived to the end of the study. A decrease in thymus weight was observed in the high dose group in a dose‐dependent manner. However, maternal body weight, food consumption, and oxidant–antioxidant balance in the liver were not affected by treatment with MWCNTs. No treatment‐related differences in gestation index, fetal deaths, fetal and placental weights, or sex ratio were observed between the groups. Morphological examinations of the fetuses demonstrated no significant difference in incidences of abnormalities between the groups. CONCLUSIONS: The results show that repeated oral doses of MWCNTs during pregnancy induces minimal maternal toxicity and no embryo–fetal toxicity at 1,000 mg/kg/day in rats. The no‐observed‐adverse‐effect level of MWCNTs is considered to be 200 mg/kg/day for dams and 1,000 mg/kg/day for embryo–fetal development. In this study, the dosing formulation was not analyzed to determine the degree of reaggregation (or not), nor were blood levels of CNT's measured in the dosed animals to verify or characterize absorption. Birth Defects Res (Part B) 92:69–76, 2011. © 2011 Wiley‐Liss, Inc.     

The role of maternal toxicity in lovastatin-induced developmental toxicity

The role of maternal toxicity in lovastatin-induced developmental toxicity in rats was examined in a series of studies. The first study administered lovastatin at 100, 200, 400, or 800 mg/kg/day (mkd) orally to mated rats from Gestation Day (GD) 6 through 20. Maternal toxicity was observed as transient dose-related body weight losses at the initiation of dosing; there were also deaths and/or morbidity at 400 and 800 mkd. These toxicities occurred in conjunction with forestomach lesions. Mean fetal weights were decreased in all groups (-5 to -16%), and the incidence of skeletal malformations, variations, and incomplete ossifications was increased. The 2 highest doses produced the most severe maternal and developmental effects. Using the same dosages, the second study avoided gestational maternal weight losses and morbidity by starting treatment 14 days before mating with dosing continued to GD 20. There were transient dose-related body weight losses after the start of dosing and deaths in the 400- and 800-mkd groups; however, there was no evidence of maternal toxicity during gestation. Developmental toxicity was evident only as slight, but generally significant (p< or =0.05) decreases in mean fetal weights in groups given > or =200 mkd (-2 to -5%). Significantly, no skeletal abnormalities were observed. A third study administered the pharmacologically active metabolite of lovastatin subcutaneously at dose levels that matched oral maternal drug exposures. In the high-dose group, maternal weight gain and mean fetal weight were slightly decreased but there were no treatment-related skeletal abnormalities. Finally, a series of toxicokinetic studies assessed whether the 2 different developmental toxicity profiles were due to differences in drug exposure between the developmentally toxic and non-toxic dosing regimes. The data showed that groups with no skeletal abnormalities had maternal and embryonic/fetal drug concentrations similar to or even greater than the groups with fetal abnormalities. These results indicate that fetal skeletal abnormalities observed at lovastatin dose levels > or =100 mkd are not due to a direct teratogenic effect, but are the result of excessive maternal toxicity, which most likely involves a nutritional deficiency associated with forestomach lesions and reduced maternal food intake.     

产前轻微应激易化由围产期注射引起的行为改变并弱化奥氮平的作用

产前母体处于应激状态下,可以削弱子代的神经系统对外界不良刺激影响的抵抗能力．但产前应激状态是否可以影响抗精神疾病药物对动物行为的增益作用,目前还没有明确的结论．此外,在动物实验中,动物需要经常接受注射操作,注射操作本身是否会影响动物行为,尚未有相关研究．在本实验中,探索了产前轻微应激状态、围产期注射操作和抗精神疾病药物对动物行为可能的交互影响．母鼠在经历产前轻微应激状态后生产子代,雄性仔鼠在围产期(日龄第7, 9, 11天)不接受注射或接受盐水或奥氮平注射(2 mg/kg,腹腔注射)．在其亚成年期(日龄第35天)和成年期(日龄第60天),观察其社交和嗅觉辨识行为,分析了总探索时间和对新旧刺激的偏好程度两个参数．我们发现,围产期重复注射操作可以改变产前应激组大鼠在社交和嗅觉辨识实验中的偏好程度,对无应激组大鼠没有影响．奥氮平注射可以增长无应激组大鼠在社交活动中的总探索时间,对应激组大鼠没有影响．研究表明,产前轻微应激状态可以易化诸如围产期注射操作等不良环境刺激导致的行为异常,并减弱抗精神疾病药物的对神经系统的影响．