碳铂对大鼠胚胎毒性与致畸作用的研究

碳铂(卡铂,Carboplatin)是继顺铂之后第二代铂类抗癌新药,它与顺铂有相似的抗癌谱,而消化道和肾毒性明显较低,国内自80年代末广泛用于临床。本文报道它的胚胎毒性和致畸作用。 材料与方法 碳铂,水溶性白色粉末,溶于6％葡萄糖溶液中使用,昆明贵金属研究所杨懿昆和熊惠周等同志合成和提供。动物用Wistar大鼠,体重223±229(X±SD)。方法参照Keller等[1～3]。雌雄2:     

二硫化碳对大鼠的行为致畸学研究

SD母鼠于孕6～15天分别吸入0、30、155及760mg/m~3的CS_2,观察其子代行为功能状况,孕期吸入30mg/m~3可致仔鼠学习能力缺陷;155、760mg/m~3可致仔鼠发育迟缓和功能缺陷(如空中翻正、归巢、游泳、开阔场及方位水迷宫等测试)。     

美洛昔康对大鼠致畸敏感期的毒性试验研究

美洛昔康在受孕大鼠致畸敏感期（受孕后第6－15天）给药,剂量分别为7.0,3.5,1.8mg/kg。结果未发现美洛昔康对胎鼠有致畸作用,但该药可使胎鼠体重减轻,吸收胎和死胎增多,骨骼发育迟缓,尤以给予高剂量美洛昔康时明显。     

抗坏血酸钛果蝇致畸效应的观察

近年来,我国将抗坏血酸钛(Ti Vc)用于农牧养殖业,已取得明显的增产效益。本文以果蝇作为致畸快速筛选系统对Ti Vc的致畸效应进行初步研究。     

汉黄芩素对大鼠致畸敏感期的毒性试验

目的：观察汉黄芩素对大鼠致畸敏感期的毒性反应。方法：将SD大鼠随机分为4组,每组16只,设空白对照组和汉黄芩素40,13．3,4．4mg·kg^-1剂量组,在受孕大鼠致畸敏感期（受孕第6～15d）给药,观察各组孕鼠的毒性情况。结果：汉黄芩素高剂量组孕鼠体重增长缓慢,躯干骨的胸骨数、骶尾椎数,前肢手掌骨的中手骨数、指骨总数和后肢脚掌骨的中足骨数、趾骨总数减少,与空白对照组相比差异也有显著性意义;高、中剂量组胎鼠的头顶骨、侧头骨和后头骨骨化不全数,与空白对照组相比差异有显著性意义（P〈0．01）。结论：未发现汉黄芩素对胎鼠有明显致畸作用。但该药高剂量可使胎鼠骨骼发育迟缓。     

美洛昔康对大鼠致畸敏感期的毒性试验研究

美洛昔康在受孕大鼠致畸敏感期(受孕后第6～15天)给药,剂量分别为7.0,3.5,1.8 mg/kg.结果未发现美洛昔康对胎鼠有致畸作用,但该药可使胎鼠体重减轻,吸收胎和死胎增多,骨骼发育迟缓,尤以给予高剂量美洛昔康时明显.     

右旋烯丙菊酯原药对大鼠的致畸作用

右旋烯丙菊酯(d-Allethrin)主要用于防治家蝇、蚊虫、虱和蟑螂等家庭害虫,现研究右旋烯丙菊酯原药对大鼠的致畸作用,说明其是否具有胚胎毒性和致畸作用,求出其致畸作用的最大无作用剂量(NOAEL),为其安全使用提供依据.目前文献中尚未发现关于右旋烯丙菊酯原药对大鼠的致畸作用毒性资料.     

Effects of methylmercury on postnatal neurobehavioral development in mice

Eighty ICR mice were randomly assigned to one of four groups given daily intraperitoneal injections of 0, 0.1, 1 or 3 mg/kg MeHg chloride respectively from postnatal days (PD) 15–17, and then tested with the Morris water maze on PD45. After that the mice were sacrificed by cervical dislocation, and the protein levels of NMDA receptor subtypes in the hippocampus were measured by Western blot analysis. A significant increase in the latency (F = 2.88, P < 0.05) before finding the platform was observed in the 1 and 3 mg/kg MeHg exposure groups. Further, the 3 mg/kg MeHg exposure group also had a longer swim distance (F = 2.97, P < 0.05) for finding the platform. In the probe test, the MeHg exposure groups displayed a smaller number of platform crossings when the hidden platform was moved, but this did not reach statistical significance. Western blot analysis results showed significant increases in the levels of NR1, NR2A and NR2B proteins of the hippocampus in the 1 and 3 mg/kg MeHg exposure groups. Overall, the current study found that MeHg exposure at 1 and 3 mg/kg doses during the postnatal brain growth spurt induces subtle and persistent learning deficits, and the neurobehavioral abnormalities of MeHg-exposed mice might be ascribed to alteration of the gene expression of specific NMDA receptor subunits in the hippocampus.     

d-Amphetamine unmasks postnatal consequences of exposure to methylmercury in utero: methods for studying behavioral teratogenesis

Pregnant rats were given various doses of methylmercury (MM) at three different stages of gestation (Days 0, 7 or 14). Administration of 56% or 27% of the dose given on the first day (Day 0) of pregnancy to 7 or 14 day pregnant rats, respectively, resulted in equivalent concentrations of MM ni 19 day old feti and 1 day and 1 week old neonates. A single, 5 mg MM/kg, oral dose on Day 0, or its equivalent on Days 7 or 14 of gestation did not produce any signs of toxicity in pregnant dams or their offspring. Weight gain of pregnant dams, litter size, litter weights at birth or at weaning and gross physical appearance were not different amongst the various treated groups and their respective controls. Operant level of bar pressing and acquisition of a discrete trial autoshape task indicated no differences with respect to operant levels, rate of acquisition or asymptotic performance resulting from exposure to MM in utero. The operant (autoshaped) behavior showed sex related differences to the disrupting influence of d-amphetamine (d-A); females were significantly more sensitive than males. Moreover, both males and females whose dams were treated with MM on Day 0 or 7 of pregnancy were significantly less affected by the d-A when compared with controls. Offspring born to dams given MM on Day 14 of pregnancy did not show a differential effect of d-A. It is concluded that early prenatal exposure to low doses of MM can result in behavioral consequences subtle enough to require unmasking of the effects with psychotropic drugs. Additionally, periods may exist during development when the embryo or fetus is most susceptible to behavioral or functional teratogenic effects of exposure to chemical insult. The testing procedures used in these experiments were objective, automatic and amenable for use with relatively large sample sizes compared with other operant behavior analytical methods. They also lend themselves to appropriate parametric statistical analyses, a staunch requirement for behavioral toxicological and teratological studies.     

Postnatal behavioral effects in mice after prenatal exposure to methylmercury

CFW mice were injected with methylmercury hydroxide (1, 2, 3, 5 or 10 mg/kg as mercury) on Day 8 of gestation. Mice treated with 3, 5 or 10 mg/kg averaged $\text{1}\text{3}$ fewer pups than controls. Pups from these treated animals weighed less than controls and the weight differences persisted through weaning but were no longer significant at 56 days of age. Mice exposed to methylmercury in utero showed significant differences from controls in their behavior in a 2-way active avoidance shuttle box and in a punishment situation but not when tested in an open field, a water escape runway or a conditioned suppression paradigm. Neither the mothers nor progency of the mice exposed prenatally to methylmercury showed behavioral deficits.     

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.     

Effects of in utero and lactational exposure to SbV on rat neurobehavioral development and fertility

Meglumine antimoniate (MA) is a pentavalent antimony drug used to treat leishmaniases. We investigated the neurobehavioral development, sexual maturation and fertility of the offspring of MA-treated rats. Dams were administered MA (0, 75, 150, 300 mg Sb^V/kg body wt/d, sc) from gestation day 0, throughout parturition and lactation, until weaning. At the highest dose, MA reduced the birth weight and the number of viable newborns. In the male offspring, MA did not impair development (somatic, reflex maturation, weight gain, puberty onset, open field test), sperm count, or reproductive performance. Except for a minor effect on body weight gain and vertical exploration in the open field, MA also did not affect the development of female offspring. Measurements of the Sb levels (ICP-MS) in the blood of MA-treated female rats and their offspring demonstrated that Sb is transferred to the fetuses via the placenta and to the suckling pups via milk.     

Comparative study of the sensitivity of virgin and pregnant rats to methylmercury

Pregnant and virgin female rats were dosed by gastric lavage 10 times or 5 times with 5 mg/kg mercury as methylmercury. Treatment of pregnant animals started on day 3 of gestation and ended on day 14 of gestation with two days break between the 5th and the 6th doses. In Group B, treatment lasted from day 10 to day 14 of gestation. Pregnant and virgin rats responded identically to methylmercury in terms of body weight changes, coordination disorders, and cerebellar histological changes. Furthermore, the brain, liver and kidney concentrations and the rates of methylmercury elimination in the post-treatment period were identical. Thus the results indicate no difference in sensitivity of pregnant versus non-pregnant animals.     

Effects of postnatal exposure to methylmercury on spatial learning and memory and brain NMDA receptor mRNA expression in rats

The extreme vulnerability of developing nervous system to methylmercury (MeHg) is well documented. Still unclear is the consequence of different postnatal period exposure to MeHg. We investigated the critical postnatal phase when MeHg induced neurotoxicity in rats and the underlying mechanism. Rats were given 5 mg/(kg day) methylmercury chloride (MMC) orally on postnatal day (PND) 7, PND14, PND28, and PND60 for consecutive 7 days. A control group was treated with 0.9% sodium chloride solution 5 ml/(kg day) instead. On PND69, spatial learning and memory was evaluated by Morris water maze test. Behavior deficits were found in MMC-treated rats of PND7 and PND14 groups (p < 0.01). N-methyl-d-aspartate (NMDA) receptor 2 subunits mRNA expressions were evaluated 3 days after the last administration. In hippocampus, the mRNA expression of NR2A and NR2B decreased, but the NR2C expression increased in PND14 group following MMC-treatment (p < 0.01). In cerebral cortex, mRNA expression of NR2A decreased, with NR2C expression elevating in PND14 group following MMC-treatment (p < 0.05). These observations suggest that the postnatal exposure to MeHg during PND7–20 could cause neurobehavioral deficits which extend to adulthood. Furthermore, the abnormal expression of NMDAR 2 subunits might associate with the impairment.     

Behavioral teratogenicity of valproic acid: selective effects on behavior after prenatal exposure to rats

Pregnant Sprague-Dawley rats were treated with 0, 150 or 200 mg/kg valproic acid by gavage (VPA) on days 7–18 of gestation. These doses produced no maternal toxicity, reproductive effects or effects on offspring growth and survival. Maternal plasma VPA peak levels averaged 99 and 134 g/ml 1 h after the last treatment, values approximating human therapeutic levels. VPA offspring tested after weaning exhibited reduced open-field central, but not peripheral, activity and reduced hole-board horizontal, but not vertical, activity. No activity differences were found in a figure-8 test or on a preweaning activity test. The VPA offspring also showed lengthened straight channel swimming times, increased swimming maze errors, but only among the females, while producing no differences in maze times. VPA offspring exhibited reduced spontaneous alternation frequency and reduced startle responding to both auditory and tactile (air-puff) stimuli. The effects of VPA were dose dependent in some cases (straight channel swimming and water maze errors), or the effect was seen only in the high-dose group (open-field, hole-board, spontaneous alternation, startle). The conclusion was reached that prenatal VPA is behaviorally teratogenic in rats at relevant maternal blood concentrations and at non-malforming doses.     

Effects of perinatal coexposure to methylmercury and polychlorinated biphenyls on neurobehavioral development in mice

Methylmercury (MeHg) and polychlorinated biphenyls (PCBs) are environmental pollutants that cause neurobehavioral deficits in humans. Because exposures to MeHg and PCBs occur through fish consumption, it is necessary to clarify the effects of the interaction of the two pollutants. Therefore, we investigated the effects of perinatal exposure to MeHg and PCBs on the neurobehavioral development in mice. Female mice (C57BL/6Cr) were divided into four groups according to the type of exposure: (1) vehicle control, (2) MeHg alone, (3) PCBs alone, and (4) MeHg + PCBs. The MeHg-exposed groups were fed with a diet containing 5 ppm MeHg (as Hg), from 4 weeks before mating, throughout pregnancy, and lactation. The PCB-exposed groups were given a commercial mixture of PCBs, Aroclor 1,254, at 18 mg/kg body weight in corn oil by gavage every 3 days from day 5 after breeding and continued until postnatal day (PND) 20. Before weaning, an assessment of eye opening showed the interactive effects between MeHg and PCBs on PND 12: The coexposure group showed a similar response to the control group, whereas the MeHg- and PCB-exposed groups showed a high response than the former two groups. We also observed delay in development of grasp reflex by MeHg exposure on PNDs 12 and 14. When the offspring mice were 8 weeks old, the group exposed to PCBs alone showed increases in the frequencies of excrement defecation and urine traces in an open-field test. Analysis of the latency revealed the antagonistic interaction between the MeHg and PCBs: The latency increased by either MeHg or PCB exposure was decreased by coexposure. Treatment with MeHg decreased the distance walked by the mice, and MeHg interacted with PCBs. Moris' water maze test showed that the MeHg-treated mice took a long time to reach the submerged platform; however, this MeHg exposure showed no interaction with PCB exposure. The spontaneous locomotion activity of the mice was not affected by the chemical exposure at 9 weeks of age. These behavioral changes were not accompanied by any histopathological changes at the levels of the frontal cortex-caudoputamen, hippocampus-amygdala, brainstem and cerebellum. These results show that perinatal coexposure to MeHg and PCBs produces no additive or synergistic effects. This phenomenon needs to be further investigated.     

Time dependent effects produced in chicks after prenatal injection of methylmercury

Methylmercury dicyandiamide (0.05 to 10 mg/kg egg) injected into the yolk sac of fertilized chicken eggs prior to incubation produced a dose related decrease in the percentage of chicks hatched (90-57% of control). With dosage fixed at 0.5 or 5.0 mg/kg egg and injections made on Days 0, 7 or 14 of incubation, hatches were 90, 68 and 75%, respectively, for the low dose and 63, 13 and 18% for the high dose. In contrast to results obtained from chicks hatched from eggs injected on Day 0 of incubation, chicks hatched from eggs injected with 0.5 or 5.0 mg MMD/kg on Day 7 or 14 were not different from controls in a detour learning situation. Administration of 14-C methylmercury revealed maximal brain radiolabel in embryos injected on Day 0 to be 10% that seen with eggs injected on Day 7 but twice that seen with eggs injected on Day 14. We tentatively conclude that a period of maximal sensitivity to the behavior effects exists prior to Day 7 and that the mechanisms of embryolethality is different from that producing the functional deficits.