甲基汞对大鼠胚胎毒性的研究

为了探讨甲基汞对大鼠胚胎毒性的影响,以Ｗｉｓｔａｒ大鼠为模型,在母鼠妊娠后６～９ｄ用双盲法进行甲基汞灌胃,分离、中、低剂量组（分别为２,０．０５,０．０１ｍｇ／ｋｇ）及对照组,进行皿基汞的胚胎毒性试验（传统致畸试验）,结果：①甲基汞对母鼠毒性、体重增长及其胚胎丢、胎窝及胎盘总重的影响不明显;②甲基汞对胎仔体重及尾长发育有明显的抑制作用（Ｐ〈０．０１）,但对外观、身长、骨化程度 脏器官组织发育的影响     

微塑料生殖和胚胎发育毒性的研究进展

目的 研究发现微塑料（粒径小于5 μm的塑料颗粒）在低等生物和哺乳动物中均可诱导生殖毒性和胚胎发育毒性。本文对微塑料在生殖和胚胎中的毒性效应和作用机制进行综述，可为预防和控制微塑料所致生殖毒性提供理论基础和科学依据。方法 以微塑料、暴露途径、毒性机制、生殖毒性、胚胎毒性为关键词在中国知网、PubMed 等数据库检索相关文献，并对国内外相关文献进行归纳与总结。结果 综述微塑料暴露途径及其转运和代谢分布、全面系统地概述微塑料生殖和胚胎发育毒性效应及毒性机制。结论 研究发现微塑料在低等生物和哺乳动物中均可诱导生殖毒性和胚胎发育毒性，但微塑料所致生殖毒性主要局限在表型研究，目前仍缺乏针对微塑料生殖毒性作用机制的系统研究，同时需在人群层面进一步研究。     

Continuous Deep Intravenous Infusion in Rat Embryotoxicity Studies: The Effects of Infusion Volume and two Different Infusion Fluids on Pregnancy

Intravenous infusion over long periods is an increasingly common method of administration for novel medicinal agents. This investigation was undertaken to evaluate the suitability of a new catheter implantation technique in the rat and to determine the effects of two different infusion fluids and volumes on litter parameters. Female Sprague-Dawley rats were anesthetized on day 1 of gestation and an indwelling catheter was implanted into the posterior vena cava by introduction into the femoral vein. A swivel joint in the roof of the cage allowed unrestricted movement of the animal. One group of rats was not treated further. Other groups were maintained on continuous infusion with physiological saline or isotonic glucose (dextrose) solution at various rates until day 15 of gestation (the test article would normally be dissolved in the infusion fluid starting from day 6 of gestation). Anesthesia and catheter implantation without infusion caused a slight transient reduction in maternal weight gain by comparison with historical data from untreated rats. This parameter then showed a clear inverse relationship to infusion volume in the infused groups. An infusion rate of 0.25 mL/h (i.e., 24 mL/kg day^?1) did not adversely affect gestation. Infusion of 1.0 mL/h of saline caused an increase in early resorption incidence and retarded fetal development. The same volume of isotonic glucose solution caused only a minor increase in resorptions with no effects on surviving fetuses.     

Maternal and developmental toxicity evaluation of Acanthus montanus leaves extract administered orally to Wistar pregnant rats during organogenesis

Acanthus montanus is a plant used in Cameroon to treat pains and threatened abortion. The aim of this study was to evaluate the influence of methanol/methylene chlorides leaves extract from Acanthus montanus on Wistar pregnant rats and identify the substance(s) essential for these actions. Dams were treated orally from days 6 to 15 of the pregnancy at the dose levels of 0, 250, 500 and 1000 mg/(kgday). They were sacrificed on day 20 or allowed to deliver and wean. Various parameters were assessed. The F(1) generation offsprings were allowed to give birth to F(2) generation and a number of parameters assessed. The results showed that there was no maternal or organs toxicity. Embryotoxicity was observed during organogenesis manifested by reduction in foetal body weight, crown-rump and tail lengths and reduced ossification of extremities bones. However after delivery, these signs of growth retardation were seen before day 5, and henceforth, the treated pups regained all their parameters to normality. All others parameters for F(1) and F(2) generations were insignificant. beta-Sitosterol was the major chemical component of the extract and its role on these results could not be ignored. The MeOH/CH(2)Cl(2) extract of this plant is embryotoxic peri-natally at high doses but this failed to manifest after 5 days of post-natal survival. beta-Sitosterol may be central in the observed effects of the extract. This extract can be tolerated by pregnant patients.     

胚胎干细胞试验预测胚胎毒性替代方法进展

小鼠胚胎干细胞试验(EST)是通过ECVAM正式验证的胚胎和发育毒性的动物试验替代方法。在新技术的推动下,多项优化的EST方法通过基因转染、利用人来源的干细胞、增加检测通量、组合检测终点、量化检测指标等方式,提高了EST方法预测胚胎毒性的科学相关性和检测效率。在整合测试策略的原则之下,经过大规模化学物质的前验证和标准化试验,新的EST方法可单独或作为组合试验的一部分可以应用于先导药物的研发和化学品的胚胎毒性预测及机制研究。     

Modifying Effect of Folinic Acid on Methotrexate-induced Embryotoxicity in Rats

Abstract Embryotoxicity of methotrexate (MTX) and modification of its effect by folinic acid (FA) were evaluated in rats. MTX was administered intraperitoneally to pregnant rats on day 9 of gestation (vaginal plug = day 0), and was followed by an intraperitoneal injection of FA after various time intervals (0-8 hours). Two dose combinations were used; 0.3 mg/kg of MTX and 1.0 mg/kg of FA, and 3.0 mg/kg of MTX and 10.0 mg/kg of FA. The dams were sacrificed on day 20 of gestation, and the fetuses were examined for visceral and skeletal development. The results are as follows: 1) A single dose of 0.3 mg/kg of MTX resulted in high embryolethality and growth retardation in all live fetuses and a single dose of 3.0 mg/kg of MTX showed 100% embryolethality. 2) A single dose of 1.0 or 10.0 mg/kg of FA showed no embryotoxicity. 3) The mitigating effect of FA on MTX-induced embryotoxicity was observed when FA was administered simultaneously with MTX, but was rapidly decreased as the time interval between MTX and FA dosings became longer. 4) Some live fetuses which escaped from MTX embryolethality showed growth retardation and dilation of the cerebral ventricles. The dilation of the cerebral ventricles was found even in the simultaneously treated groups, though the incidences were much lower than the belatedly treated groups.     

槟榔碱对生殖与泌尿系统的影响

近年来,对槟榔的研究已不局限其对口腔的危害及对癌症的诱发,而逐渐扩展到其对人体其他主要器官及系统的影响。研究表明,槟榔果的主要成分槟榔碱可对男（雄）性的泌尿生殖系统以及女（雌）性泌尿生殖系统和妊娠造成损伤。对男（雄）性生殖系统,槟榔碱可导致活性氧簇增高并引起氧化应激反应。槟榔碱还可上调肿瘤坏死因子α水平及诱导环氧合酶2（COX-2）高表达,影响免疫系统进而对精子造成损伤。另外,槟榔碱通过多种途径刺激睾丸Leydig细胞分泌合成过量睾酮。对女（雌）性泌尿生殖系统及妊娠,槟榔碱可造成卵细胞损伤。孕妇长期咀嚼槟榔会影响新生儿出生结局,如低出生体质量和婴幼儿死亡。动物胚胎模型研究结果显示,槟榔碱可产生胚胎毒性,影响胚胎发育。对两性泌尿系统,槟榔碱诱导慢性肾病（CKD）的发生并致使膀胱癌进一步恶化。阐述槟榔碱对生殖和泌尿系统的损伤作用可进一步了解此类生物成分的危害,并能及时且有效地建立疾病的预防机制。     

Anti-inflammatory activity of Lychnophora passerina, Asteraceae (Brazilian "Arnica")

Aim of the study

Boehmeria nivea (L.) Gaud. was commonly used to treat miscarriages clinically. The aim of this study was to examine its safety for embryonic development.

Materials and methods

Pregnant mice were randomly assigned into 5 groups, i.e. mice were oral-treated with distilled water (G1), with Boehmeria nivea extract of 2, 8 or 32 g/kg/day (G2, G3 or G4), and with 3 doses of vitamin A of 200,000 IU/kg as positive controls (G5). Meanwhile, IC₅₀ values for both embryonic stem cells (ESCs) and 3T3 cells were detected by cytotoxicity assays.

Results

(1) The resorptions and malformed fetuses in G5 were significantly higher than G1 (P < 0.001), whereas the maternal body-weight and uterus-weight were lower than G1 (P < 0.05); (2) there was no difference in the fetal body-weight, maternal relative body-weight gain, liver-, kidney- or heart-weight, relative organ-weight, and histological examination among five groups; (3) there was no difference in IC₅₀ values between ESCs and 3T3 cells, but high concentration of Boehmeria nivea extract might significantly lower ESCs’ viability (P < 0.05).

Conclusion

Boehmeria nivea extract at 32 g/kg/day did not cause significant embryotoxicity or maternal toxicity in mice, although it might cause cytotoxicity in cultured ESCs at a high dose.     

Prednisone reduces ketoconazole-induced skeletal defects in rat fetuses

Ketoconazole (KT) is a broad-spectrum antifungal agent whose pharmacological activity is based on the capability to interfere with steroid biosynthesis through an interaction with fungal cytochrome P-450 enzymes and thereby avoiding the formation of fungal walls. As the inhibition of fungal cytochrome P-450 by KT is not specific, the mammalian cytochrome P-450 species, which play an important role in the biosynthesis of steroidogenesis, are also affected. The reproductive and developmental toxicity of KT have been assessed. This antimycotic agent has been reported as embryotoxic and teratogenic when administered in high doses (80 mg/kg) to pregnant rats. The mechanisms by which KT exert teratogenic effects remains to be elucidated. When considering the potential inhibitory effect of KT on mammalian steroid biosynthesis as a possible responsible for the skeletal anomalies induced by this drug, this study aimed at determining whether steroid maternal supplementation may prevent the skeletal anomalies induced by KT. To test this hypothesis, maternal supplementation with prednisone (PRED) (0.1, 0.2 or 0.4 mg/kg) and 80 mg/kg of KT were administered to pregnant Wistar rats (n = 10) during organogenesis period. On gestational day 21, the dams were euthanized and examined for standard parameters of reproductive outcome. In summary, the results showed that PRED supplementation therapy may cause reductions in the incidence of KT-induced cranial and appendicular skeletal anomalies as well as cleft palate in the rat, being these results more consistent with 0.4 mg/kg of this drug. These results suggest an important role for glucocorticoids in KT-induced teratogenesis     

Studies on the prenatal toxicity of toluene in rabbits following inhalation exposure and proposal of a pregnancy guidance value

Prenatal toxicity of toluene was determined in two separate studies by inhalation exposure of Himalayan rabbits. In the first study 15 artificially inseminated females per group were exposed to 30, 100, or 300 ppm and in the second study 20 artificially inseminated females per group inhaled 100 or 500 ppm. In each case the rabbits were exposed for 6 hours per day from day 6 post-insemination (p. i.) to day 18 p. i. The respective controls inhaled conditioned clean air under the same exposure conditions. No signs of maternal toxicity were observed. All data obtained on gestational parameters were found to be within the variation range reported for this rabbit strain. The fetal external, soft tissue and skeletal findings were seen in toluene exposed fetuses in a frequency similar to the corresponding and/or historical controls. Differences observed between the groups were not concentration dependent and were considered incidental rather than compound related. Therefore, toluene was not embryotoxic, fetotoxic, or teratogenic for rabbits exposed during the period of organogenesis. The highest concentration tested under these conditions (500 ppm) was found to be a no-observable-adverse-effect level (NOAEL) for both the adult and the fetal Himalayan rabbit. Based on these and previous results of animal studies of prenatal toxicity, a safety or uncertainty factor approach is considered for setting limits of exposure for women at workplaces. A pregnancy guidance value of 20 ppm is proposed.The present studies were sponsored by the Berufsgenossenschaft der Chemischen Industrie, W-6900 Heidelberg, FRG