反义LeETR1转基因番茄的生殖发育毒性及外源基因转移试验

目的 评价反义LeETR1转基因番茄(ETR1)向动物肠道菌群和子代动物转移外源基因的能力及对小鼠生殖发育的影响.方法 SD大鼠和ICR小鼠连续饲喂ETR1、非转基因番茄(B1)和蒸馏水30 d后,分别进行大鼠盲肠菌群培养物的抗生素耐药性试验及小鼠生殖毒性试验,提取耐药阳性菌、亲代和子代小鼠的基因组进行外源基因特异性聚合酶链式反应法(PCR).结果 肠道菌的耐药性和小鼠生殖发育情况无明显改变,在耐药菌和两代小鼠体内均未发现由受试物引入的外源基因.结论 ETR1对小鼠无生殖毒性,其携带的外源基因不能向动物体细胞、肠道菌及子代动物转移.     

孕期外源化合物暴露影响子代下丘脑-垂体-肾上腺轴功能的研究进展

作为机体最重要的神经内分泌轴,下丘脑-垂体-肾上腺(HPA)轴在机体应激反应中具有重要作用。宫内暴露于外源物可通过多种途径影响胎儿的发育,包括损伤母体或胎盘,也可直接对胎儿产生毒性作用,造成胎儿HPA轴的发育编程改变,出生后对应激的敏感性增加,成年后对抑郁症、焦虑症等精神性疾病以及糖尿病等代谢性疾病的易感性增加。其发生机制可能与通过损伤胎盘间接影响胎儿和直接改变胎儿基因的表观遗传学修饰有关。本文以生活中常见的外源物为对象,综述了近年来有关不良宫内环境所致子代HPA轴功能异常及成年疾病易感的研究进展。     

小资料

比较毒理学 (comparativetoxicology)它以比较解剖学、比较生理学和比较生物化学等为基础 ,研究外源化学物对不同种系动物 (有时包括植物 )的毒性、效应、中间代谢和作用机制 ,并进行比较分析 ,揭示有关规律 ,更深层次地了解外源化学物对生物体的有害作用小资料@顾祖维     

铁叶绿酸钠对小鼠行为发育毒性的实验研究

铁叶绿酸钠为叶绿素衍生物,研究表明铁叶绿酸钠治疗妊娠期缺铁性贫血,疗效显著。由于妊娠期用药可能对子代产生行为发育毒性,因此本文重点针对铁叶绿酸钠在动物围产期用药后,可能对子代动物的神经行为发育产生的毒性进行了测试,试验结果表明在高、中、低三种剂量下其对子代小鼠无明显行为发育毒性。     

应用Epi Info软件建立发育毒物体外筛选试验数据库的研究

应用 EpiInfo软件包建立了发有毒性体外测试方法数据库,并对该数据中的15种方法及其检测的化学物进行了分析,结果提示不同方法检测的化学物的种类和数量都相差很大．有的相同化学物却有着不同名称,在EpiInfo软件的支持下建立的数据库、对发育毒性体外筛选方法进行了比较和分析．并就有关问题提出了解决办法。随着体外方法不断增多．该数据库将进一步完善。     

药物胚胎毒性新方法与技术研究进展

正胚胎毒性研究是一门研究外源化学物对胚胎和胎儿造成损伤的学科。胚胎对某些外源化学物较为敏感,因此妊娠期用药不当可能会对胚胎-胎儿造成严重的危害,包括胚胎死亡、生长迟缓、畸形和功能缺陷等。而且有毒物质引起的胚胎的损伤往往不可逆,伴随胎儿终生存在,影响以后生命各个阶段的生长、发育和生理特征~([1])。这就决定了妊娠期用药的特殊性,上世纪五十年代的"反应停"事件,引发了人类对药物胚胎毒性研究的广泛关注,对药物进行上市前的非临床     

盐酸西部曲明对小鼠生殖力和着床前后胚胎发育的影响

目的　评价减肥新药盐酸西部曲明对♀亲代动物的生殖毒性和受精卵着床前的发育毒性。方法　持续饮水内给药 ,♂小鼠交配前给药 8周并持续给药至交配成功处死之前 ;♀小鼠交配前给药 2周并持续给药至妊娠d6。设 32、2 83、0 .2 5mg·kg-1·d-13个剂量组及 1个阴性对照组 ,观察亲代动物的一般状况、交配、受孕和妊娠 ,胎仔的着床、存活、体长、体重、外观、内脏和骨骼畸形等检测指标。结果　除相当于人预期摄入量 12 8倍的高剂量引起了亲代雄鼠体重减轻外 ,亲代和子代小鼠均未见其他毒性反应。结论　未见盐酸西部曲明对亲代有生殖毒性和对子代有发育毒性。     

外源物致宫内发育迟缓的胎肾上腺内分泌功能干预机制

已知孕期接触外源物可影响胎儿体格、神经系统的正常发育,造成宫内发育迟缓(IUGR)。IUGR发病率为3%~10%。IUGR胎儿不仅表现为出生时低体重,还伴有系列近期及远期并发症。已证实能诱发IUGR发生的外源物包括一些生活消耗品、环境毒物和药物。外源物的胚胎毒性机制错综复杂,目前国     

健脾生血颗粒对围产期大鼠的毒性研究

目的:考察健脾生血颗粒对围产期大鼠的毒性作用。方法:将受孕大鼠按体质量随机分为阴性对照组和健脾生血颗粒低、中、高剂量组(0.77、2.31、6.93 g/kg),每组21只,从妊娠第15天开始至分娩后第21天止每天ig相应药物1次。观察健脾生血颗粒对母代大鼠一般毒性和生育能力的影响,对F1代仔鼠运动能力、学习记忆能力、生育能力以及对F2代仔鼠早期发育能力的影响。结果:对母代的毒性作用方面,健脾生血颗粒高剂量组母代大鼠妊娠天数较阴性对照组显著延长(P<0.05),给药初期体质量显著降低(P<0.01)。对子代的毒性作用方面,健脾生血颗粒高剂量组F1代仔鼠初生体质量较阴性对照组显著降低(P<0.05),第4、5次发现水下平台时间较阴性对照组显著缩短(P<0.01);对F1代仔鼠生育能力及F2代仔鼠早期发育能力均未见明显影响(P>0.05)。健脾生血颗粒中、低剂量组子代大鼠各指标均未见受到明显影响。结论:健脾生血颗粒对母代及子代大鼠均未见毒性反应的剂量为2.31 g/kg。     

自噬与宫内发育迟缓

宫内发育迟缓(intrauterine growth retardation,IUGR)是最常见的发育毒性结局,可导致子代围产期发病率和死亡率增加,且其危害会延续至出生后引起成年多种慢性疾病易感。自噬,作为胚胎发育的重要调节者,参与了多脏器发育过程。自噬增强或减弱可通过调控细胞增殖、分化等生命活动,参与胎盘及胎儿多种脏器发育,最终导致IUGR。该文主要综述了自噬的发生机制及其与IUGR的关系,为自噬在IUGR相关疾病中的研究提供理论依据。     

Developmental toxicity and programming alterations of multiple organs in offspring induced by medication during pregnancy

Medication during pregnancy is widespread, but there are few reports on its fetal safety.Recent studies suggest that medication during pregnancy can affect fetal morphological and functional development through multiple pathways, multiple organs, and multiple targets. Its mechanisms involve direct ways such as oxidative stress, epigenetic modification, and metabolic activation, and it may also be indirectly caused by placental dysfunction. Further studies have found that medication during pregna...     

A perspective on the significance of maternally mediated developmental toxicity

The significance of maternally mediated developmental toxicity has been controversial from both a biological and a regulatory point of view. The open literature has at times been interpreted to mean that a number of the effects seen in fetuses from dams exposed to maternally toxic doses of chemicals were secondary consequences of maternal toxicity rather than direct effects on the conceptus. Recent experimental studies, however, indicate that although certain relatively species-specific manifestations of developmental toxicity may at times be maternally mediated, most are not. On occasion, even severe maternal toxicity can apparently occur without causing readily discernible effects on the embryo/fetus. The most important concern of a regulatory agency with regard to developmental toxicity is the possibility of the causation of significant, irreversible harm to the offspring. In practical terms, the margin of safety for exposure to a developmental toxicant is of much more importance than whether or not the agent's effects are maternally mediated. For protection of the unborn, it is obviously the end result that matters, regardless of the mechanism. Safeguarding the conceptus from specific developmental toxicants (i.e., agents with relatively high A/D ratios) requires the use of safety factors based on the developmental toxicity NOEL. Protecting the conceptus against agents with A/D ratios near unity could be based on the maternal toxicity NOEL, however, as the true NOEL for developmental toxicity may be near that for the mother, but the adult NOEL is likely to be more readily determinable.     

Combined effects of perfluorooctane sulfonate (PFOS) and maternal restraint stress on hypothalamus adrenal axis (HPA) function in the offspring of mice

Although it is known that prenatal exposure to perfluorooctane sulfonate (PFOS) can cause developmental adverse effects in mammals, the disruptive effects of this compound on hormonal systems are still controversial. Information concerning the effects of PFOS on hypothalamus adrenal (HPA) axis response to stress and corticosterone levels is not currently available. On the other hand, it is well established that stress can enhance the developmental toxicity of some chemicals. In the present study, we assessed the combined effects of maternal restraint stress and PFOS on HPA axis function in the offspring of mice. Twenty plug-positive female mice were divided in two groups. Animals were given by gavage 0 and 6 mg PFOS/kg/day on gestation days 12-18. One half of the animals in each group were also subjected to restraint stress (30 min/session, 3 sessions/day) during the same period. Five plug-positive females were also included as non-manipulated controls. At 3 months of age, activity in an open-field and the stress response were evaluated in male and female mice by exposing them to 30 min of restraint stress. Male and female offspring were subsequently sacrificed and blood samples were collected to measure changes in corticosterone levels at four different moments related to stress exposure conditions: before stress exposure, immediately after 30 min of stress exposure, and recuperation levels at 60 and 90 min after stress exposure. Results indicate corticosterone levels were lower in mice prenatally exposed to restraint. In general terms, PFOS exposure decreased corticosterone levels, although this effect was only significant in females. The recuperation pattern of corticosterone was mainly affected by prenatal stress. Interactive effects between PFOS and maternal stress were sex dependent. The current results suggest that prenatal PFOS exposure induced long-lasting effects in mice.     

Restraint stress does not enhance the uranium-induced developmental and behavioral effects in the offspring of uranium-exposed male rats

The influence of stress on postnatal development and behavior was assessed in the offspring of male rats exposed to uranium (U). Eight groups of adult animals received uranyl acetate dihydrate (UAD) in the drinking water at doses of 0, 10, 20 and 40 mg/kg/day during 3 months. One half of rats in each group were concurrently subjected to restraint stress during 2 h per day throughout the study. At the end of the experimental period, male rats were mated with untreated females (1:2). On gestation day 14, one half of pregnant rats were euthanized in order to evaluate maternal toxicity and gestational parameters. The remaining dams were allowed to deliver and wean their offspring. Pups were evaluated for physical development, neuromotor maturation, as well as for behavioral effects. Restraint significantly increased the gravid uterine weight at 40 mg/kg/day. However, no significant interactions between restraint and U could be established in the remaining parameters of maternal toxicity. In the offspring, no remarkable effects of U, restraint or their combination were noted on developmental landmarks, or in the passive avoidance and water maze test. It is concluded that at the current U doses, restraint stress did not enhance the few uranium-induced physical, neuromotor and behavioral changes in the offspring of UAD-exposed male rats.     

On the impact of second generation mating and offspring in multi-generation reproductive toxicity studies on classification and labelling of substances in Europe

The possible impact on classification and labelling decisions of effects observed in second generation parental (P1) and offspring (F2) parameters in multi-generation studies was investigated. This was done for 50 substances classified as reproductive toxicants in Europe, for which a multi-generation study was available. The P1 and F2 effects were compared to parental (P0) and first generation offspring (F1) effects with regard to type of effect as well as incidence, magnitude and severity (IMS), at any dose level. For every study with unique P1/F2 effects, or differences in IMS, the influence of the P1/F2 findings on the classification decision was investigated. Unique P1/F2 generation findings did not play a crucial role in the classification decision of any of the 50 classified substances, except for fenarimol. This substance however provided abundant alerts on the basis of its endocrine activity and developmental neurotoxicity and would therefore also be expected to be identified as a developmental neurotoxicant in an Extended One Generation Reproductive Toxicity Study (EOGRTS). These findings, in addition to the increased number of parameters analysed, increased statistical power and reduced animal use, provide strong further support for replacement of the classical two-generation reproductive toxicity study by the EOGRTS in regulatory reproductive toxicity assessment.     

An experimental protocol for maternal pulmonary exposure in developmental toxicology

To establish a protocol for studying effects of pulmonary exposure in developmental toxicity studies, the effects of intratracheal sham instillation under short-term isoflurane anaesthesia were evaluated with a protocol including multiple instillations during gestation. Twelve time-mated mice (C57BL/6BomTac) were anaesthetized with isoflurane and intratracheally instilled with saline containing 10% bronchoalveolar lavage (BAL) on gestation days 8, 11, 15 and 18. In addition, the early effects of the procedure were assessed in naive female mice. Control animals were not handled. Dams were followed until weaning, and the offspring were observed from birth to sexual maturation. The cell composition of BAL was examined in the females early after treatment (3 days) and in the dams at weaning (25 days). DNA damage in BAL and liver cells was determined by the comet assay. The procedure did not affect gestation or viability, growth and sexual maturation of the offspring. Lung markers of inflammation and DNA damage were comparable in control and treated dams. Livers of the anaesthetized and instilled females, dams and their offspring displayed no induction of DNA damage. Intratracheal instillation under isoflurane anaesthesia did not induce observable effects in pregnant mice or their offspring. We suggest that this procedure can be used as a means of exposure through the airways in studies of developmental toxicity.     

Alterations in glucocorticoid negative feedback following maternal Pb, prenatal stress and the combination: a potential biological unifying mechanism for their corresponding disease profiles

Combined exposures to maternal lead (Pb) and prenatal stress (PS) can act synergistically to enhance behavioral and neurochemical toxicity in offspring. Maternal Pb itself causes permanent dysfunction of the body's major stress system, the hypothalamic pituitary adrenal (HPA) axis. The current study sought to determine the potential involvement of altered negative glucocorticoid feedback as a mechanistic basis of the effects in rats of maternal Pb (0, 50 or 150 ppm in drinking water beginning 2 mo prior to breeding), prenatal stress (PS; restraint on gestational days 16-17) and combined maternal Pb + PS in 8 mo old male and female offspring. Corticosterone changes were measured over 24 h following an i.p. injection stress containing vehicle or 100 or 300 μg/kg (females) or 100 or 150 μg/kg (males) dexamethasone (DEX). Both Pb and PS prolonged the time course of corticosterone reduction following vehicle injection stress. Pb effects were non-monotonic, with a greater impact at 50 vs. 150 ppm, particularly in males, where further enhancement occurred with PS. In accord with these findings, the efficacy of DEX in suppressing corticosterone was reduced by Pb and Pb + PS in both genders, with Pb efficacy enhanced by PS in females, over the first 6 h post-administration. A marked prolongation of DEX effects was found in males. Thus, Pb, PS and Pb + PS, sometimes additively, produced hypercortisolism in both genders, followed by hypocortisolism in males, consistent with HPA axis dysfunction. These findings may provide a plausible unifying biological mechanism for the reported links between Pb exposure and stress-associated diseases and disorders mediated via the HPA axis, including obesity, hypertension, diabetes, anxiety, schizophrenia and depression. They also suggest broadening of Pb screening programs to pregnant women in high stress environments.     

A retrospective analysis of developmental toxicity studies in rat and rabbit: What is the added value of the rabbit as an additional test species?

In contrast to most toxicological tests, developmental studies are usually required in both a rodent and a non-rodent species. This study retrospectively assessed the added value of the rabbit developmental test when a rat developmental test is available. In contrast with previous reviews, we looked at developmental toxicity instead of teratogenicity, and took into account maternal toxicity in the evaluation of developmental toxicity. We analyzed data for 54 substances classified for developmental toxicity and 73 substances considered to be teratogenic in the rabbit and not in the rat in two previous reviews. On average, the rat and the rabbit developmental toxicity studies were similarly sensitive: the average ratio of the NOAELs between the two species was about one, and for most compounds there were no differences between rat and rabbit studies in terms of classification for developmental toxicity. For certain substances the developmental study in either one of the two species appeared to be more sensitive than in the other species. However, these differences are partly due to differences between studies other than the test species used. Overall, our analysis does not clearly indicate that the evaluation of developmental toxicity, as opposed to other types of toxicity, would specifically require the rabbit as an additional test species. The discrimination between direct and indirect (i.e., as a consequence of maternal toxicity) developmental effects was often doubtful, and is one of the factors that could explain the apparent differences between the two species. A more accurate assessment of maternal toxicity might improve the reliability of the results from a single developmental toxicity study. More knowledge about the interaction between maternal and developmental effects is required before decisions on omitting the requirement for the developmental toxicity testing in a second species can be considered.     

Combinative effects of hexachlorobenzene and crowding on rat adrenal cell mitochondria.

The effects of social stress (crowding) on hexachlorobenzene (HCB) toxicity in male rats was evaluated by a morphometrical analysis of adrenal cortex mitochondria. The social stress was produced by transferring singly-housed rats from cages of ample size (1000 cm2 floor space) into small cages (100 cm2 floor space) each containing four rats. Differences in cage design as well as size may have contributed to the overall stress experienced by the rats. The food of the treated rats was supplemented with 250 ppm HCB. Structural changes in mitochondrial volume, surface area, or cristae area were not significant in HCB-treated or in crowded animals when compared with those of the controls. However, increases in mitochondrial volume and diameter were significant in those animals simultaneously challenged by HCB and crowding. The results strongly suggest that even a relatively mild social stress may adversely affect the ability of an animal to resist the effects of some exogenous chemicals.     

Epigenetic Mechanisms for the Early Environmental Regulation of Hippocampal Glucocorticoid Receptor Gene Expression in Rodents and Humans

Parental care influences development across mammals. In humans such influences include effects on phenotypes, such as stress reactivity, which determine individual differences in the vulnerability for affective disorders. Thus, the adult offspring of rat mothers that show an increased frequency of pup licking/grooming (ie, high LG mothers) show increased hippocampal glucocorticoid receptor (GR) expression and more modest hypothalamic–pituitary–adrenal responses to stress compared with the offspring of low LG mothers. In humans, childhood maltreatment associates decreased hippocampal GR expression and increased stress responses in adulthood. We review the evidence suggesting that such effects are mediated by epigenetic mechanisms, including DNA methylation and hydroxymethylation across GR promoter regions. We also present new findings revealing associated histone post-translational modifications of a critical GR promoter in rat hippocampus. Taken together these existing evidences are consistent with the idea that parental influences establish stable phenotypic variation in the offspring through effects on intracellular signaling pathways that regulate the epigenetic state and function of specific regions of the genome.