Developmental toxicity of Spinosad administered by gavage to CD® rats and New Zealand White rabbits

The insecticide Spinosad was administered by gavage to pregnant CD® rats at 0, 10, 50 or 200 mg/kg/day on gestation days (gd) 6–15 and to New Zealand White rabbits at 0, 2.5, 10 or 50 mg/kg/day on gd-7–19. Rats and rabbits were monitored for clinical signs of toxicity and body weight gains. At gd-21 (rats) or gd-28 (rabbits), maternal organ weights, reproductive parameters, fetal body weights, and fetal external, visceral and skeletal structures were evaluated. Rats given 200 mg/kg/day exhibited a 4% lower body weight on gd-12 and decreased body weight gains on gd-6–16 relative to controls. There was no maternal toxicity at 10 or 50 mg/kg/day, and no developmental toxicity in rats at any dose level. Rabbits given 50 mg/kg/day exhibited decreased feed consumption, reduced fecal output, body weight loss during the initial dosing period (gd-7–10) and a non-statistically significant decrease (31%) in body weight gain during the dosing period (gd-7–20). Two litters aborted due to maternal inanition. There were no maternal effects at lower doses, and no signs of developmental toxicity at any dose. Thus, the maternal no-observed-effect levels (NOEL) were 50 and 10 mg/kg/day in rats and rabbits, respectively, and the embryonal/fetal NOELs were 200 mg/kg/day in rats and 50 mg/kg/day in rabbits.     

Effects of melamine on pregnant dams and embryo‐fetal development in rats

There are worldwide concerns regarding the potential adverse effect of melamine. This study investigated the potential effects of melamine on pregnant dams and embryo‐fetal development in Sprague–Dawley rats following maternal exposure on gestational days (GD) 6–20. Melamine was administered to pregnant rats by gavage at doses of 0, 200, 400 and 800 mg kg^?1 per day (n = 8–10 for each group). All dams were subjected to a Caesarean section on GD 21 and their fetuses were examined for morphological abnormalities. With administration of melamine at 800 mg kg^?1 per day, maternal toxicity manifested as increased incidences of clinical signs and death, lower body weight gain and food intake, and increases in heart, adrenal gland and kidney weights. Histopathological examinations revealed an increase in incidences of congestion, tubular necrosis/degeneration, crystals, casts, inflammatory cells in tubules, tubular dilation and tubular hyaline droplets in the maternal kidneys, while fetal kidneys (one fetus/litter) did not show any histopathological changes. Developmental toxic effects included a decrease in fetal weight, an increase in the incidence of skeletal variations and a delay in fetal ossification. No treatment‐related maternal or developmental effects were observed at doses ≤400 mg kg^?1 per day. These results show that 15‐day repeated oral dosing of melamine is embryo‐/fetotoxic at a maternotoxic dose, but not teratogenic in rats. The no‐observed‐adverse‐effect level of melamine for pregnant dams and embryo‐fetal development is considered to be 400 mg kg^?1 per day. Copyright © 2011 John Wiley & Sons, Ltd.     

Fetal toxicity of kepone in rats and mice.

Doses of 10, 6, and 2 mg/kg/day of Kepone in CD rats and 12, 8, 4, and 2 mg/kg/day in CD-1 mice were administered to pregnant animals by gastric intubation during the major period of organogenesis, Days 7–16 of gestation. Fetal toxicity was produced in both rats and mice at doses which caused significant reductions in maternal weight gains during gestation and increased liver/body weight ratios. In rats, fetuses from dams receiving the highest dose (which also resulted in 19% maternal mortality) exhibited significant incidences of reduced fetal weight, reduced degree of ossification, edema, undescended testis, enlarged renal pelvis, and enlarged cerebral ventricles. Lower dose levels which also produced maternal weight loss and liver/body weight ratio increase, but no mortality, caused only reduced fetal weight and reduced degree of ossification. Male rats born to dams treated with Kepone during gestation showed no reproductive impairment. In the mouse, fetotoxicity only occurred in the highest dose group and was manifested by increased fetal mortality and clubfoot.     

Analogs of the abortifacient aminoglutethimide

The abortifacient properties of analogs of aminoglutethimide were tested in rats. Aminoglutethimide is nonsteroidal and nonestrogenic, and induces abortion in pregnant rats by interfering with the conversion of cholesterol to delta5-pregnenolone. However, the spread between efficacy (100 mg/kg) and toxicity (200 mg/kg) is not large, thus limiting its potential use in humans. A series of derivatives, Schiff b ases and an unsaturated ring system were prepared. None of the prepared analogs demonstrated the abortifacient activity of aminoglutethimide. It is concluded that the abortifacient activity of aminoglutethimide is highly specific, and that all changes made caused the activity to be lost. The experimental procedures involved in preparing the analogs are described.     

Prenatal toxicity of Ascaris pepsin inhibitor in mice

The developmental toxicity of pepsin inhibitor isolated from Ascaris suum, a gastrointestinal nematode parasite, was evaluated. An embryo–fetal development study was conducted in BALB/c mice. Groups of 21 mated females were treated by intraperitoneal injection (0.3 ml/30 g body weight) with 0.9% NaCl solution vehicle or isolated Ascaris pepsin inhibitor (API) at dose levels of 50, 100, 150 or 200 mg/kg body weight/day on gestation days (GD) 6–15. Maternal food consumption, body weight, and clinical signs were monitored throughout gestation. Cesarean sections were performed on GD 18 and gravid uterine weight, implantation sites, early and late resorptions, live and dead fetuses were collected. Live fetuses were weighed and examined for external, visceral and skeletal variations and malformations. Maternal body weight gain, gravid uterine weight, food consumption were significantly decreased after injection of higher doses of API (100–200 mg/kg/day). All doses of API exhibited an embryotoxic effect (high rate of intrauterine resorption). The percentage of postimplantation loss in the groups with administered API was higher (over 4–11 times) than that in control group. Fetotoxicity was observed in all treatment groups in a dose-related manner and it was evidenced by increased dead fetuses, decreased fetal weight, increased visceral variations and reduced skeletal ossification. Fetal hydronephrosis and internal hydrocephalus were noted at 150, and 200 mg/kg/day. In summary, the maternal toxicity no-observed-adverse-effect level (NOAEL) was 50 mg/kg/day and the low-observed-adverse-effect level (LOAEL) was 100 mg/kg/day under the conditions of this study. However, the developmental toxicity LOAEL was 50 mg/kg/day based on decreased fetal body weight and prenatal mortality.     

Evaluation of the teratogenic potential of the oxidative dye N-phenyl-para-phenylenediamine

The oxidative dye N-phenyl-para-phenylenediamine was evaluated for teratogenic potential. The dye was administered by gavage to pregnant Sprague-Dawley rats at dose levels of 50, 100, and 200 mg/kg on gestation days six through fifteen. No signs of toxicity were observed during the treatment period. A significant reduction in mean maternal weight gain was noted during treatment at the high dose level of 200 mg/kg. The test material did not produce embryotoxic nor fetal toxic effects at dose levels utilized. Evaluation of fetal external, visceral, and skeletal anomalies revealed no statistically significant differences between dye treated and control groups. Oral exposure of dams to the positive control, Vitamin A, resulted in a significant increase in the number of litters with fetuses having external, visceral, and skeletal anomalies.     

Dichloroacetonitrile induces oxidative stress and developmental apoptotic imbalance in mouse fetal brain

Dichloroacetonitrile (DCAN) is one of the disinfection by-products of chlorination of drinking water. Limited mechanistic studies exist on the developmental toxicity of haloacetonitriles (HANs). The present study was designed to investigate the potential adverse effects of maternal exposure to DCAN on mouse fetal brain. Based on initial dose-response experiment, DCAN (14 mg/kg/day) was administered orally to pregnant mice at gestation day (GD) 6, till GD 15. Maternal exposure to DCAN resulted in redox imbalance in fetal cortex and cerebellum, characterized by significant decrease in reduced glutathione (GSH), and elevation of malondialdehyde (MDA) level and superoxide dismutase (SOD) activity. Further, DCAN induced apoptosis indicated by significant enhancement of DNA fragmentation and active caspase-3 level in fetal cortex and cerebellum. Neuronal degeneration was indicated by positive cupric silver staining. In conclusion, maternal exposure to DCAN adversely affects mouse fetal brain as evidenced by induction of oxidative stress, apoptotic imbalance and neurodegeneration.     

Distribution and accumulation of 10 nm silver nanoparticles in maternal tissues and visceral yolk sac of pregnant mice,and a potential effect on embryo growth

We examined the distribution of silver in pregnant mice and embryos/fetuses following intravenous injections of 10?nm silver nanoparticles (AgNPs) or soluble silver nitrate (AgNO₃) at dose levels of 0 (citrate buffer control) or 66?µg Ag/mouse to pregnant mice on gestation days (GDs) 7, 8 and 9. Selected maternal tissues and all embryos/fetuses from control, AgNP- and AgNO₃-treated groups on GD10 and control and AgNP-treated groups on GD16 were processed for the measurement of silver concentrations, intracellular AgNP localization, histopathology and gross examination of tissue morphology. Inductively-coupled plasma mass spectrometry revealed silver in all examined tissues following either AgNP or AgNO₃ treatment, with highest concentrations of silver in maternal liver, spleen and visceral yolk sac (VYS), and lowest concentrations in embryos/fetuses. For VYS, mean silver concentration following AgNO₃ treatment (4.87?ng Ag/mg tissue) was approximately two-fold that following AgNP treatment (2.31?ng Ag/mg tissue); for all other tissues examined, mean silver concentrations following either AgNP or AgNO₃ treatment were not significantly different from each other (e.g. 2.57 or 2.84?ng Ag/mg tissue in maternal liver and 1.61 or 2.50?ng Ag/mg tissue in maternal spleen following AgNP or AgNO₃ treatment, respectively). Hyperspectral imaging revealed AgNP aggregates in maternal liver, kidney, spleen and VYS from AgNP-treated mice, but not AgNO₃-treated mice. Additionally, one or more embryos collected on GD10 from eight of ten AgNP-treated mice appeared small for their age (i.e. Theiler stage 13 [GD8.5] or younger). In the control group (N?=?11), this effect was seen in embryos from only one mouse. In conclusion, intravenous injection of 10?nm AgNPs to pregnant mice resulted in notable silver accumulation in maternal liver, spleen and VYS, and may have affected embryonic growth. Silver accumulation in embryos/fetuses was negligible.     

Effects of 2-bromopropane on pregnant dams and embryo-fetal development in the ICR mouse

2-Bromopropane (2-BP), a halogenated propane analogue, is a substitute for chlorofluorocarbones (CFCs) which have a great potential to destroy the ozone layer and to warm the earth’s environment. The present study was carried out to investigate the potential adverse effects of 2-BP on pregnant dams and embryo–fetal development after maternal exposure during the gestational days (GD) 6–17 in ICR mice. The test chemical was administered subcutaneously to pregnant mice at dose levels of 0, 500, 1000, and 1500 mg/kg per day. All dams were subjected to caesarean section on GD 18 and their fetuses were examined for external, visceral and skeletal abnormalities. Throughout the study period, no treatment-related deaths were found in the groups treated with 2-BP. Pregnant mice of the 1000 and 1500 mg/kg groups showed treatment-related clinical signs such as rough fur and swelling, induration, crust formation, and ulceration in the injection sites which were dose dependent in incidence and severity. A decrease in fetal weight, an increase in fetal malformation, and an increase in fetal ossification delay were found at a dose level of 1500 mg/kg per day in a dose-dependent manner. On the contrary, there were no adverse effects on body weight, body weight gain, gravid uterine weight, food consumption, gross finding at any dose tested. In addition, no treatment-related effects on the number of corpora lutea, implantations, resorptions, dead fetuses, live fetuses, and sex ratio of live fetuses were observed. These findings suggest that 2-BP was embryotoxic and teratogenic at a minimally maternally toxic dose (i.e., 1500 mg/kg per day) in ICR mice. In the present experimental conditions, the no-observed-adverse-effect level of 2-BP is considered to be 500 mg/kg per day for dams and 1000 mg/kg per day for fetuses, respectively.     

米非司酮合并米索前列醇终止10～16周妊娠的疗效

目的：观察口服米非司酮合并米索前列醇终止１０～１６ｗｋ妊娠的临床疗效。方法：１７５例妊娠１０～１６ｗｋ妇女用２种不同剂量米非司酮（组Ⅰ２５ｍｇｂｉｄ×３ｄ，总量１５０ｍｇ；组Ⅱ２００ｍｇ单次用药），合并米索前列醇（最大剂量不超过１．６ｍｇ）口服。结果：２组流产成功率分别为８９％和８４％，Ｐ＞０．０５。组Ⅰ胎儿排出时间（７ｈ）明显短于组Ⅱ（９ｈ），Ｐ＜０．０１。组Ⅰ米索前列醇用量（０．７ｍｇ）明显少于组Ⅱ（１．０ｍｇ），Ｐ＜０．０１。结论：口服米非司酮合并米索前列醇终止１０～１６ｗｋ妊娠是安全有效的；给药方法以米非司酮小剂量多次给药法更可取。     

Exposure to perfluorooctane sulfonate during pregnancy in rat and mouse. I: maternal and prenatal evaluations.

The maternal and developmental toxicities of perfluorooctane sulfonate (PFOS, C8F17SO3-) were evaluated in the rat and mouse. PFOS is an environmentally persistent compound used as a surfactant and occurs as a degradation product of both perfluorooctane sulfonyl fluoride and substituted perfluorooctane sulfonamido components found in many commercial and consumer applications. Pregnant Sprague-Dawley rats were given 1, 2, 3, 5, or 10 mg/kg PFOS daily by gavage from gestational day (GD) 2 to GD 20; CD-1 mice were similarly treated with 1, 5, 10, 15, and 20 mg/kg PFOS from GD 1 to GD 17. Controls received 0.5% Tween-20 vehicle (1 ml/kg for rats and 10 ml/kg for mice). Maternal weight gain, food and water consumption, and serum chemistry were monitored. Rats were euthanized on GD 21 and mice on GD 18. PFOS levels in maternal serum and in maternal and fetal livers were determined. Maternal weight gains in both species were suppressed by PFOS in a dose-dependent manner, likely attributed to reduced food and water intake. Serum PFOS levels increased with dosage, and liver levels were approximately fourfold higher than serum. Serum thyroxine (T4) and triiodothyronine (T3) in the PFOS-treated rat dams were significantly reduced as early as one week after chemical exposure, although no feedback response of thyroid-stimulating hormone (TSH) was observed. A similar pattern of reduction in T4 was also seen in the pregnant mice. Maternal serum triglycerides were significantly reduced, particularly in the high-dose groups, although cholesterol levels were not affected. In the mouse dams, PFOS produced a marked enlargement of the liver at 10 mg/kg and higher dosages. In the rat fetuses, PFOS was detected in the liver but at levels nearly half of those in the maternal counterparts, regardless of administered doses. In both rodent species, PFOS did not alter the numbers of implantations or live fetuses at term, although small deficits in fetal weight were noted in the rat. A host of birth defects, including cleft palate, anasarca, ventricular septal defect, and enlargement of the right atrium, were seen in both rats and mice, primarily in the 10 and 20 mg/kg dosage groups, respectively. Our results demonstrate both maternal and developmental toxicity of PFOS in the rat and mouse.     

Developmental toxicity of orally administered thiabendazole in ICR mice.

Thiabendazole (TBZ) is a potent anthelmintic and fungicide used in the treatment of parasitic infections in humans and domestic animals and post-harvest protection of agricultural commodities. TBZ is not teratogenic or selectively foetotoxic in rats or rabbits, in contrast to several other benzimidazole derivatives. However, when administered orally to pregnant (Jcl:ICR) mice at lethal dosages, malformations were observed in treated fetuses. To assess whether the effects found in this previous study were attributable to maternal toxicity or TBZ the present study was conducted. TBZ doses of 25, 100 or 200 mg/kg/day were selected based on a preliminary range-finding study in which maternotoxicity was evident at doses of 200 mg/kg/day or above. The compound was administered during gestation days 6-15 as a solution in olive oil. Caesarean sections were completed on gestation day 18 and complete fetal examinations conducted. Decreases in maternal weight gain relative to controls were found at doses of 100 mg/kg/day or above, which paralleled decreases in foetal weights in these same dose groups. However, there were no treatment-related external, visceral or skeletal anomalies in any treatment group. Therefore, TBZ was not teratogenic or selectively foetotoxic in mice, with no-observed-effect levels (NOEL) of 25 and greater than 200 mg/kg/day for maternal and fetal weight effects and teratogenicity, respectively. These results indicate that foetal effects noted in previous studies in mice were probably secondary to severe maternal toxicity.     

Evaluation of the developmental toxicity of formamide in New Zealand white rabbits.

Naturally mated female New Zealand White (NZW) rabbits (24/group) received formamide (35, 70, or 140 mg/kg/day) or vehicle (1 ml/kg deionized/distilled water) by gavage on gestational days (GD) 6 through 29. The study was conducted using a 2-replicate design. Maternal food consumption (absolute and relative), body weight, and clinical signs were monitored at regular intervals throughout gestation. One and four maternal deaths occurred at the low and high doses, respectively. Abortions or early deliveries were noted in 0, 2, 2, and 8 females in the 0, 35, 70, and 140-mg/kg/day dose groups, respectively. Other clinical signs associated with formamide exposure were minimal: primarily reduced or absent fecal output at the high dose (2-13 animals/day). Also at the high dose, maternal body weight was significantly depressed on GD 21, 24, and 27 (87-90% of the control value); maternal body weight gain was significantly reduced for GD 12 to 15, 18 to 21, and 21 to 24 (treated animals gained less than 1 g, or lost up to 100 g). In addition, maternal body weight gain was reduced at the middle dose for GD 18 to 21. Maternal body weight gain, corrected for gravid uterine weight, was unaffected. Relative maternal food consumption in the high-dose group was 34-59% of control intake from GD 12 through GD 24, but was comparable to controls thereafter. At termination (GD 30), confirmed-pregnant females (9-20 per group) were evaluated for clinical status, liver weights, and gestational outcome; live fetuses were examined for external, visceral, and skeletal malformations and variations. Maternal liver weight (absolute or relative to body weight) was unaffected by treatment, but gravid uterine weight at the high dose was 71% of the control value. A significantly increasing trend was noted for the percent non-live implants per litter. In addition, although not statistically significant from the control group, the values for the percent late fetal deaths per litter and percent non-live implants per litter in the 140-mg/kg/day group were higher than maximum historical values, suggesting an increase in late gestational deaths in the surviving high-dose animals. Formamide decreased the mean number of live fetuses per litter at the high dose to 66% of the control value. Mean fetal body weight per litter for males and the sexes combined was significantly decreased at the high dose; mean female fetal body weight was also decreased, although the difference did not reach statistical significance. There was no effect of treatment on the incidence of external, visceral, or skeletal malformations or variations in animals surviving to scheduled necropsy. In summary, the no-observed-adverse-effect level (NOAEL) for maternal toxicity was 70 mg/kg/day and the lowest-observed-adverse-effect level (LOAEL) was 140 mg/kg/day under the conditions of this study. Similarly, the NOAEL for developmental toxicity was 70 mg/kg/day and the LOAEL was 140 mg/kg/day.     

Induction of maternal toxicity in the rat by dermal application of retinoic acid and its effect of fetal outcome

Time-mated Sprague-Dawley rats were administered all-trans-retinoic acid (RA)_dermally on gestational days 11 through 14 at three dosage levels (25, 100, and 250 mg/kg body weight). Dams administered ethylenethiourea (ETU) dermally on gestational days 11 to 12 or RA orally on day 12 were used to indicate the strain's sensitivity to teratogenesis. The chemicals were dissolved in dimethylsulfoxide (DMSO) for dermal application or suspended in corn oil for treatment by gavage. The maternal weight gain, pup weight, number of resorptions and number of fetuses with gross malformations, and skeletal/organ-level anomalies were determined. Beginning with day 15, dams dermally treated with RA exhibited dermal lesions at the site of application, most dams showed vaginal bleeding by day 16, and approximately 20% did not survive to day 19. Relative to the DMSO control group, maternal weight gain in the dermal RA groups was decreased by approximately 50% at the lowest dose, with essentially no weight gain at the intermediate- and high-dose levels. The decrease in average fetal weight at the two higher doses was significant, whereas the resorption and malformation frequencies were not significantly increased by dermal treatment with RA. Without significantly affecting fetal weight or resorption frequency, dermal application of ETU significantly increased the frequency of skeletal anomalies, primarily tail defects. Oral administration of RA did not increase the malformation frequency nor produce significant maternal or fetotoxic effects. In summary, treatment of pregnant Sprague-Dawley rats by dermal application of RA dissolved in DMSO resulted in significant toxicity to the dam. The absence of a significant teratogenic effect following oral or dermal RA treatment may have been due to strain insensitivity or duration/timing of treatment. Whether the fetal weight reduction was a primary effect of treatment on the fetal/placental unit or simply secondary to maternal toxicity will require further investigation.     

The Effect of Maternal Restraint on Developmental Toxicity of Aluminum in Mice

Both aluminum (Al) and maternal restraint have been reported to cause developmental toxicity in mammals. This study assessed in pregnant mice the potential interaction between Al and maternal restraint. Four groups of plug-positive female mice were given IP injections of AlCl₃ at 37.5 and 75 mg/kg/day on days 6–15 of gestation. Two of these groups were also subjected to restraint for 2 h/day during the same gestational days. Control groups included restrained and unrestrained pregnant mice nonexposed to Al. Cesarean sections were performed on gestation day 18, and the fetuses were weighed and examined for morphological defects. Maternal toxicity was significantly enhanced by restraint at 75 mg AlCl₃/kg/day. No increases in the number of resorptions or dead fetuses per litter were observed following exposure to Al, maternal restraint, or combined Al and restraint. However, a significant decrease in fetal body weight, as well as a significant increase in the number of litters with morphologic defects, was observed in the group exposed to 75 mg AlCl₃/kg/day plus maternal restraint. The current results suggest that maternal restraint could enhance the metal-induced developmental toxicity (reduced fetal body weight, increase in the number of litters with morphologic defects) only at high doses of the metal, which are also toxic to the dam.     

Breast cancer resistance protein 1 limits fetal distribution of nitrofurantoin in the pregnant mouse.

The efflux transporter, the breast cancer resistance protein (BCRP), is most abundantly expressed in the apical membrane of the placental syncytiotrophoblasts, indicating that it could play an important role in protecting the fetus by limiting xenobiotic/drug penetration across the placental barrier. In the present study, we examined whether Bcrp1, the murine homolog of human BCRP, limits fetal distribution of the model BCRP/Bcrp1 substrate, nitrofurantoin (NFT), in the pregnant mouse. NFT was administered i.v. to FVB wild-type and Bcrp1(-/-) pregnant mice. The maternal plasma samples and fetuses were collected at various times (5-60 min) after drug administration. The NFT concentrations in the maternal plasma samples and homogenates of fetal tissues were determined by a high-performance liquid chromatography/UV assay. Although the maternal plasma area under the concentration-time curve (AUC) of NFT in the Bcrp1(-/-) pregnant mice (97.4 +/- 10.0 microg . min/ml plasma) was only slightly (but significantly) higher than that in the wild-type pregnant mice (78.4 +/- 6.0 microg . min/ml plasma), the fetal AUC of NFT in the Bcrp1(-/-) pregnant mice (1493.0 +/- 235.3 ng . min/g of fetus) was approximately 5 times greater than that in the wild-type pregnant mice (298.6 +/- 77.4 ng . min/g of fetus). These results clearly suggest that Bcrp1 significantly limits fetal distribution of NFT in the pregnant mouse, but has only a minor effect on the systemic clearance of the drug.     

Teratological study of 4-ethoxy-2-methyl 5-morpholino-3(2H)-pyridazinone (M73101) in mice and rats (author's transl)]

M73101 was given orally to pregnant mice (0, 100, 400 and 800 mg/kg/day) and rats (0, 100, 300 and 600mg/kg/day) during the major organogenesis to assess the influences of prenatal and postnatal development of progeny. There were no apparent effects of M73101 on litter size, fetal mortality or sex ratio in both species, although slight decrease in body weight occurred in fetuses of mice and rats exposed to the largest dose. No external, internal or skeletal malformations attributable to M73101 were observed in mouse and rat fetuses. No apparent influences of M73101 on postnatal development of mouse or rat offspring were seen.     

In utero exposure to chloroquine alters sexual development in the male fetal rat

Chloroquine (CQ), a drug that has been used extensively for the prevention and treatment of malaria, is currently considered safe for use during pregnancy. However, CQ has been shown to disrupt steroid homeostasis in adult rats and similar compounds, such as quinacrine, inhibit steroid production in the Leydig cell in vitro. To explore the effect of in utero CQ exposure on fetal male sexual development, pregnant Sprague-Dawley rats were given a daily dose of either water or chloroquine diphosphate from GD 16-18 by oral gavage. Chloroquine was administered as 200 mg/kg CQ base on GD 16, followed by two maintenance doses of 100 mg/kg CQ base on GD 16 and 18. Three days of CQ treatment resulted in reduced maternal and fetal weight on GD 19 and increased necrosis and steatosis in the maternal liver. Fetal livers also displayed mild lipid accumulation. Maternal serum progesterone was increased after CQ administration. Fetal testes testosterone, however, was significantly decreased. Examination of the fetal testes revealed significant alterations in vascularization and seminiferous tubule development after short-term CQ treatment. Anogenital distance was not altered. Microarray and RT-PCR showed down-regulation of several genes associated with cholesterol transport and steroid synthesis in the fetal testes. This study indicates that CQ inhibits testosterone synthesis and normal testis development in the rat fetus at human relevant doses.     

Developmental and reproductive toxicity evaluation of toluene vapor in the rat II. Developmental toxicity

The developmental toxicity of toluene was evaluated via whole body inhalation exposure, in pregnant Sprague Dawley rats exposed to toluene (99.9% pure) from gestation day (GD) 6–15 inclusive, 6 h/day, at concentrations of 0, 250, 750, 1500 and 3000 ppm (0, 938, 2812, 5625 and 11250 mg/m³). Doses were selected from a preliminary study performed over a range of concentrations from 0 to 5000 ppm, in which maternal and fetal toxicity were observed at 2000 ppm and above. This study has been cited in various regulatory documents and is presented here to allow greater accessibility to results and conclusions.

Toluene induced clinical signs in pregnant dams (ataxia, hyper-responsivity, increased water intake, decreased food consumption) at 3000 ppm, ataxia and hyper-responsivity at 1500 ppm, and reduced maternal body weight gain at 1500 during the exposure period only and at 3000 ppm from initiation of exposure to GD20. At Caesarean section on GD20, no adverse effects on implantation, number and viability of fetuses, or fetal sex distribution were observed. Litter weight and mean fetal weight was reduced at 3000 ppm and mean fetal weight was reduced at 1500 ppm. Instances of reduced or unossified skeletal elements occurred at the same dose levels. Mean fetal weight was also reduced at 250 ppm but not at 750 ppm. Extensive statistical analysis of fetal body weight data support the conclusion that there is no toxicologically significant dose-related effect on fetal body weight at or below 750 ppm. Low incidences (≤2.5%) of various malformations occurred in the 250, 1500, and 3000 ppm groups; there was no increase in the incidence of specific or total malformations with increased exposure and thus these were not attributed to toluene.

In this Toluene study, the maternal toxicity NOAEL was 750 ppm with a defined maternal and developmental toxicity LOAEL of 1500 ppm.     

N-乙酰半胱氨酸在脂多糖诱发的胚胎损害中的双向作用

目的研究N-乙酰半胱氨酸(NAC)预处理和后处理对细菌脂多糖(LPS)引起宫内胎鼠死亡(IUFD)和生长发育迟缓(IUGR)的影响。方法实验1:LPS组小鼠于妊娠d15～17经腹腔注射LPS(75μg·kg-1),LPS+NAC组在LPS处理前和(或)处理后经腹腔注射给予NAC。所有孕鼠于妊娠d18处死。实验2:LPS组小鼠于妊娠d15注射LPS,LPS+NAC组在LPS处理前和(或)处理后经腹腔注射给予NAC。LPS处理后1.5h或6h处死孕鼠。结果LPS+NAC预处理组平均每窝死胎数明显低于LPS组;LPS+NAC后处理组平均每窝死胎数与LPS组比较无差异,LPS+NAC后处理组流产率高于LPS组;LPS+NAC预处理和后处理均抑制LPS引起IUGR。NAC预处理抑制LPS引起母肝、胎肝和胎盘组织脂质过氧化,LPS+NAC后处理抑制LPS引起母肝组织脂质过氧化,但对LPS引起的胎肝和胎盘组织脂质过氧化无抑制作用。进一步研究发现,母鼠妊娠期给予LPS后,血清TNF-α水平上升,NAC预处理抑制LPS引起血清和羊水TNF-α水平上升,而NAC后处理对LPS引起血清TNF-α水平上升无影响。结论NAC预处理预防LPS引起IUFD和IUGR;NAC后处理对LPS引起IUFD和IUGR无影响,反而加重早产。