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1.
    
The potential for reproductive toxicity of an antisense oligonucleotide designed to inhibit ICAM-1 was evaluated as part of the safety assessment for this compound. Since antisense compounds are often specific to the species in which they are intended to work, both the human and murine active ICAM-1 inhibitors were tested (ISIS 2302 and ISIS 3082, respectively). Male and female mice were treated prior to cohabitation, through cohabitation, gestation, delivery, and weaning. Mice were treated with 0, 3, 6, and 12 mg/kg ISIS 2302 or ISIS 3082 by daily i.v. injection. Reproductive indices evaluated included estrus cycling, sperm count and motility, fertility, litter parameters, fetal development, delivery, fetal body weight, lactation, and weaning. Behavioral assessment and reproductive capacity of the F1 generation mice was assessed on selected animals. Concentrations of oligonucleotide in selected maternal target organs, placenta, fetal tissues, and expressed milk were also measured. There were no changes in reproductive performance, litter parameters, fetal development, or postnatal development in mice treated with either ISIS 2302 or ISIS 3082. Maternal liver and kidney contained dose-dependent concentrations of oligonucleotide, but there was relatively little or no oligonucleotide measured in placenta, fetal tissues, or expressed milk. Neither the human nor murine-specific antisense inhibitor of ICAM-1 produced any reproductive toxicity in mice, and exposure of fetus or pups was negligible.  相似文献   

2.
Cadmium uptake by Spirulina maxima: toxicity and mechanism   总被引:4,自引:0,他引:4  
Cadmium uptake by Spirulina maxima cells was more pronounced in living than in dead cells, with a maximum recovery of 47.63mg Cd/g cells for living cells and 37.00mg Cd/g cells for inactivated cells. When in the medium at 1.2mg/l, cadmium affected cell growth and diminished cell productivity. Cadmium was detected in the outer and inner faces of the external membrane, essentially in the lipid layer.  相似文献   

3.
吸烟作为一个社会问题受到广泛关注,目前研究认为吸烟可对生殖系统存在有害影响。从吸烟对睾丸功能、精液质量、生殖内分泌功能的影响及吸烟对生殖细胞的遗传毒作用几个方面,总结了近几年国内外有关吸烟对男性生殖与遗传毒性研究进展,为进一步研究吸烟的生殖毒性提供参考。  相似文献   

4.
    
The potential for reproductive toxicity of an antisense oligonucleotide designed to inhibit ICAM-1 was evaluated as part of the safety assessment for this compound. The human active ICAM-1 inhibitor (ISIS 2302) is not pharmacologically active in rabbits. Female rabbits were treated once daily on Day 6 through 18 of gestation. Rabbits were treated with 0, 1, 3, and 9 mg/kg ISIS 2302 by daily i.v. injection. Reproductive indices evaluated included estrus cycling, litter parameters, fetal development, and fetal body weight. Concentrations of oligonucleotide in plasma following the last dose, and in selected maternal target organs, placenta, and fetal tissues at scheduled necropsy were also measured. Maternal toxicity was evident as a decreased maternal body weight gain, decreased food consumption, and scant feces at doses > or =3 mg/kg. Increased spleen to body weight ratio and increased mononuclear cell infiltrates were indicative of a proinflammatory effect of ISIS 2302 at the 9 mg/kg dose level. Despite the maternal toxicity, there were no changes in litter parameters or fetal development in rabbits treated with ISIS 2302. The only change was a decrease in fetal body weight at the 9 mg/kg dose level, which was attributed to the maternal toxicity observed. Maternal liver and kidney contained dose-dependent concentrations of oligonucleotide, but there was relatively little or no oligonucleotide measured in placenta or fetal tissues. Thus, there was no dose-dependent exposure and maternal toxicity to ISIS 2302, but no reproductive toxicity in rabbits, and exposure of fetus or pups is negligible.  相似文献   

5.
Recently, it has been shown that the environment contains a large variety of chemical substances possessing estrogenic activity (ecoestrogens/environmental estrogens). In this connection, the problem of estrogenic effects exerted by the environment on animal ontogenesis is very important. Here, we review the available data concerning the effects of ecoestrogens on the development of the reproductive system in mammals. We discuss issues of reproductive toxicology related to the effects of these substances during prenatal and postnatal development, with special attention to the effect of ecoestrogens and modern reproductive technologies on preimplantation embryonic development.  相似文献   

6.
从铅对睾丸与附睾形态、精子生成和发育以及生殖内分泌功能等三方面的影响综述了铅对雄性生殖毒性的研究进展;并从铅对睾丸的脂质过氧化损伤,对睾丸标志酶活性的影响,对染色体、DNA及基因的影响以及对CaM、Ca2 -ATP酶活性的影响等方面探讨了铅对雄性生殖毒性作用机理。同时,提出了铅对雄性生殖毒性的研究中存在的若干问题和发展方向。  相似文献   

7.
Three rotifer species, Lecane hamataL. luna, and L. quadridentata, were submitted to acute toxicity tests to compare their susceptibility to 11 toxicants. In acute tests with 48-h exposure of neonates of less than 24 h old, copper was most toxic with LC50 values in the range of 0.06–0.33 mg l–1, while acetone was the least toxic with LC50 values in the range of 5000–7000 mg l–1. Differences in LC50 value of up to 22-fold were found in the susceptibility to lead between the three species. These data indicate large differences in toxicity among members of the same genus, and point out that it is necessary to submit several species to toxicity tests in order to assess the potential effects of toxicants to rotifers. The commonly used Brachionus calyciflorus cannot be considered representative of all freshwater rotifers in this respect.  相似文献   

8.
Animal bioassay experiments are frequently conducted to assess the toxicity of chemicals on the developing fetus. Experiments are normally conducted at dosage levels that are much higher than human exposure levels to elicit the toxic reproductive effect of the chemical in a limited number of litters. Recently there has been much discussion on the fact that some chemicals may have beneficial effects at low doses and become toxic at high doses. This concept, known as chemical hormesis, has been the focus of attention in many investigations. Here, we consider the prevalence of hormesis in developmental toxicology and show that current design of developmental toxicity testing does not accommodate the study of hormesis. If it can be proved that some developmental toxicants may have stimulatory low dose effects, then design and analysis of developmental toxicity experiments need to be revised by the scientific community and the regulatory agencies. Using a thorough analysis of an experimental data set, we further demonstrate that in order to establish the possible hormetic effects of a chemical in reproduction, often a multiple replication of the experiment may be necessary to examine such effects. Using a trend test, we illustrate that while it is possible that one replicate of a developmental toxicity experiment with a known teratogen shows strong evidence of hormesis, other replicates may show no sign of beneficial effects at low doses.  相似文献   

9.
    
Ipomoea carnea is a toxic plant that grows in tropical areas, and is readily consumed by grazing goats. The plant contains the alkaloids swainsonine and calystegines, which inhibit cellular enzymes and cause systematic cell death. This study evaluated the behavioral effects on dams and kids of prenatal ingestion of this plant. Freshly harvested leaves of I. carnea (10 g/kg body weight) were fed daily to nine pregnant goats from the fifth to the 16th week of gestation; five pregnant goats were controls. Dam and kid behavior were evaluated during 2-hr postpartum. Further evaluation of the offspring was performed using various tests after birth: (1) reaching and discriminating their dam from an alien doe (two tests at 12-hr postpartum), and (2) navigating a progressive maze (2, 4, and 6 days postpartum). Postnatal (n = 2) and fetal (n = 2) mortality were observed in the treated group. Intoxicated kids had difficulty in standing at birth, and only one was able to suckle within 2 hr of birth. Treated kids were slower than controls to arrive at their dam in the discrimination test; treated kids often (seven of nine completed tests) incorrectly chose the alien dam (controls: 0/10 tests). During some runs on days 2, 4, and 6 postpartum, treated kids were slower to leave the starting point of the maze, and were slower to arrive at the dam on all test days. This study suggests that the offspring of pregnant goats given I. carnea during gestation have significant behavioral alterations and developmental delays.  相似文献   

10.
杀菌剂丙环唑对斜纹夜蛾的毒性   总被引:2,自引:2,他引:2       下载免费PDF全文
在研究比较了11种农药对斜纹夜蛾Spodoptera litura细胞(简称SL细胞)的毒杀活性基础上,选择毒杀活性最高的杀菌剂丙环唑,对其毒理学机理进行进一步研究。结果表明,丙环唑的细胞毒力最高,在100 μg/mL浓度下处理后48 h,SL细胞的死亡率为98.08%。处理后36 h,丙环唑对SL细胞的LC50值为20.31 μg/mL。丙环唑能明显降低SL细胞的蛋白质含量。以0.5 μg/头的丙环唑注射斜纹夜蛾4龄幼虫,处理后72 h,试虫血淋巴总含量及血细胞数分别下降了26.80%和25.26%;在1.0 μg/头的剂量下,则分别下降了37.67%和36.32%。以0.5 μg/头和1.0 μg/头的丙环唑注射处理后,斜纹夜蛾幼虫体重显著降低。此外,丙环唑能降低斜纹夜蛾幼虫血淋巴含糖量及血淋巴蛋白质含量。在注射处理后96 h和120 h,丙环唑对斜纹夜蛾4龄幼虫的LD50值分别为0.59 μg/头和0.45 μg/头。丙环唑对SL细胞和斜纹夜蛾幼虫均具有较好的毒杀活性,显示出丙环唑类似物控制害虫的可能性。  相似文献   

11.
    
BACKGROUND: Parabens are widely used preservatives in cosmetics and pharmaceutical products, and approved as food additives. Parabens have been considered safe for these uses for many years. Recently, adverse effects on male reproductive parameters in rats have been reported when parabens were given orally for 8 weeks starting at three weeks of age. Our studies used two representative parabens, methyl‐ and butylparaben, to try to replicate these studies and thereby evaluate potential reproductive effects in male Wistar rats. METHODS: Diets containing 0, 100, 1000 or 10,000 ppm of either butyl‐ or methylparaben were fed to male rats for eight weeks. Rats were 22 days of age at the start of exposure. Parameters evaluated included organ weights, histopathology of reproductive tissues, sperm production, motility, morphology and reproductive hormone levels (butylparaben only). RESULTS: None of the parameters evaluated for either paraben showed compound‐ or dosage‐dependent adverse effects. Metabolism experiments of butylparaben indicate that it is rapidly metabolized by non‐specific esterases to p‐hydroxybenzoic acid and butanol, neither of which is estrogenic. CONCLUSIONS: Exposure to methyl‐ or butylparaben in the diet for eight weeks did not affect any male reproductive organs or parameters at exposures as high as 10,000 ppm, corresponding to a mean daily dose of 1,141.1±58.9 or 1,087.6±67.8 mg/kg/day for methyl‐ and butylparaben, respectively. The rapid metabolism of parabens by esterases probably explains why these weakly estrogenic substances elicit no in vivo effects when administered by relevant exposure routes (i.e., topical and oral). Birth Defects Research (Part B) 2008. 2008 Wiley‐Liss, Inc.  相似文献   

12.
  总被引:1,自引:0,他引:1  
BACKGROUND: This study was conducted to evaluate the potential adverse effects of ethylbenzene (EB) on reproductive capability from whole-body inhalation exposure of F0 and F1 parental animals. METHODS: Four groups of Crl:CD(SD)IGS BR rats (30/sex/group for F0 and 25/sex/group for F1) were exposed to 0, 25, 100, and 500 ppm EB for 6 hr/day for at least 70 consecutive days before mating. Inhalation exposure for the F0 and F1 females continued throughout mating, gestation through gestation day (GD) 20, and lactation days (LD) 5-21. On LD 1-4, females received EB in corn oil via oral gavage at dose levels of 26, 90, and 342 mg/kg/day (divided into three equal doses, approximately 2 hr apart), as calculated from a physiologically-based pharmacokinetic (PBPK) model to provide similar maternal blood area-under-concentration (AUC) as provided by inhalation. Pups were weaned on postnatal day (PND) 21 and exposure of the F1 generation started on PND 22. Estimates of internal exposure were determined by measuring EB concentrations in blood collected from F1 dams (4/group) and their culled pups 1 hr after the last gavage dose on PND 4. On PND 22, blood was collected from these same F1 dams and their weanlings for EB analysis 1 hr after a 6-hr inhalation exposure. The remainder of the F2 generation was not directly exposed. RESULTS: EB exposure did not affect survival or clinical observations. Male rats in the 500 ppm group in both generations gained weight more slowly than the controls. There were no indications of adverse effects on reproductive performance in either generation. Male and female mating and fertility indices, pre-coital intervals, spermatogenic endpoints, ovarian follicle counts, reproductive organ weights, lengths of estrous cycle and gestation, live litter size, pup weights, developmental landmarks, and postnatal survival were unaffected. No adverse exposure-related macroscopic pathology was noted at any level. CONCLUSIONS: Increased liver weights were found in the animals exposed to 500 ppm. F1 maternal whole blood EB concentrations of 0.49, 3.51, or 18.28 mg/L were found 1 hr after administration of a composite oral dose of 26, 90, or 342 mg/kg/day, respectively, but no detectable EB was found in blood samples of their F2 PND 4 culled pups. F1 maternal mean whole blood EB levels 1 hr after a 6-hr inhalation exposure on postpartum day (PPD) 22 was 0.11 mg/L (25 ppm), 0.56 mg/L (100 ppm), and 11 mg/L (500 ppm). For the offspring exposed with their dams on PND 22, F2 pup blood EB concentrations ranged from 0.017-0.039 mg/L (25 ppm), 0.165-0.465 mg/L (100 ppm), and 8.82-15.74 mg/L (500 ppm). Because decreased weight gain in the 500 ppm males was transient and no histopathological changes were associated with the increased liver weights in the 500 ppm male and female groups, these changes were not considered adverse. Therefore, for parental systemic toxicity, 100 ppm was considered a NOEL and 500 ppm a NOAEL in this study. The 500 ppm exposure concentration was considered a NOAEL for F0 and F1 reproductive toxicity and offspring developmental endpoints.  相似文献   

13.
    
Background: Ipomoea carnea (I. carnea) is a poisonous plant found in Brazil and other tropical countries that often poison livestock. The plant contains the alkaloids calystegines and mainly swainsonine, which inhibit cellular enzymes and cause systematic cell death. The objective of this study was to evaluate the perinatal effects of I. carnea in goats. Methods: Forty‐seven pregnant goats were randomly allocated into 5 treatment groups and given the following doses (g/kg BW) of I. carnea: 0 (IC0), 1.0 (IC1), 3.0 (IC3), 5.0 (IC5) and 7.5 (IC7). The treatment animals were given fresh I. carnea from day 27 of gestation to parturition. Weight gains and serum biochemistry were evaluated. Fetuses were evaluated using ultrasonographic measurements. Results: Goats from the IC7 group showed clinical signs of poisoning. Ultrasound examination revealed that I. carnea feeding in all treatment groups reduced fetal movement compared to the controls. There was an increase in the total number of birth defects (retrognathia and arthrogyposis) in the IC7 and IC5 groups compared to the controls. Conclusion: The results show that I. carnea has teratogenic potential in goats. In addition, ultrasounds were useful in evaluating fetotoxicity and teratogenicity. Birth Defects Res (Part B) 00:1–7, 2012. © 2012 Wiley Periodicals, Inc.  相似文献   

14.
    
The epididymis relies on transporters for the secretion of nucleosides and influence the disposition of nucleoside analogs (NSA). Since these compounds can cross the blood–testis barrier (BTB), it is important to understand if the epididymis reabsorbs NSA drugs. The purpose of this study is to determine the localization of nucleoside transporters expressed within rat epididymis to demonstrate the potential of epididymal reabsorption. Using immunohistochemistry, we determined that equilibrative nucleoside transporter 1 (ENT1) is localized to the basolateral membrane of epithelial cells, ENT2 is expressed in the nucleus of the epithelium and CNT2 is expressed by basal cells. The expression pattern for these transporters suggests that nucleosides are able to access the epithelial cells of the epididymal duct via the blood, but not from the lumen. We did not find any evidence for a transepithelial reabsorption pathway indicating the NSA drugs that cross the BTB remain within the epididymis.  相似文献   

15.
    
BACKGROUND : Testicular toxicity (TT) is a sporadic and challenging issue in pharmaceutical drug development. Efforts to develop TT screening assays or biomarkers have been overshadowed by consortium efforts to predict drug‐induced toxicities such as hepatic injury, which are encountered more frequently. METHODS : To gauge the current state of the field and to prioritize future TT activities, the International Life Sciences Institute‐Health and Environmental Sciences Institute Developmental and Reproductive Toxicology (DART) Technical Committee sponsored a survey to better understand the incidence and nature of TT findings encountered during drug development. RESULTS : Highlights from the 16 survey respondents include: (1) Although preclinical TT was encountered relatively infrequently, half of the participants observed repeated problems with TT during pharmaceutical development, (2) despite control measures such as use of sexually mature animals to diminish confounding effects of spurious lesions, interpretation of TT remains a challenge, (3) “traditional” evaluation tools such as hormonal monitoring and newer approaches such as ‐omics are utilized to investigate testicular changes, and (4) an understanding of the risk and relevance of TT findings is achieved through joint consideration of factors such as species specificity, potential mode of action, and safety margins. CONCLUSIONS : TT remains a relatively uncommon but persistent challenge in pharmaceutical development. Although current preclinical TT approaches appear to be effective in limiting the occurrence of pharmaceutical candidate attrition in clinical trials, improved biomarker or screening platforms would allow companies to identify TT at an earlier stage, thus decreasing the time and resources expended on safety evaluation of pharmaceutical candidates. Birth Defects Res (Part B) 92: 511–525, 2011. © 2011 Wiley Periodicals, Inc.  相似文献   

16.
Comparative toxicology of borates   总被引:3,自引:0,他引:3  
Inorganic borates, including boric acid, Na, ammonium, K, and Zn borates generally display low acute toxicity orally, dermally, and by inhalation. They are either not irritant or mild skin and eye irritants. Exceptions owing to physiochemical properties do occur. Longer-term toxicological studies have been reported mainly on boric acid or borax where the properties are generally similar on an equivalent boron (B) basis. The critical effects in several species are male reproductive toxicity and developmental toxicity. The doses that cause these effects are far higher than any levels to which the human population could be exposed. Humans would need to consume daily some 3.3 g of boric acid (or 5.0 g borax) to ingest the same dose level as the lowest animal NOAEL. No effects on fertility were seen in a population of workers exposed to borates or to a population exposed to high environmental borate levels. There is remarkable similarity in the toxicological effects of boric acid and borax across different species. Other inorganic borates that simply dissociate to boric acid are expected to display similar toxicity, whereas those that do not dissociate simply to boric acid may display a different toxicological profile.  相似文献   

17.
    
Bitopertin is a glycine type 1 (GlyT1) inhibitor intended for the treatment of psychiatric disorders. The principle adverse effect in the regulatory reproductive toxicity studies was peri‐natal pup death when rat dams were treated during parturition at a dose resulting in five‐times the human therapeutic exposure (AUC). Cessation of dosing two days before parturition prevented the pup deaths. Investigatory experiments and pharmacokinetic modelling suggested that the neonatal mortality was related to transplacental passage of bitopertin leading to high systemic levels in the newborn pups. Brain levels of bitopertin in the rat fetus and neonate were two‐fold higher than in the mother. As illustrated by knock‐out mice models, GlyT1 function is essential for neonatal pup survival in rodents, but is not necessary for normal prenatal morphological development. The glycine transport systems are immature at birth in the rat, but are functionally well‐developed in the human newborn. While the relevance to humans of the neonatal mortality seen in rats following late gestational exposure is unknown, bitopertin would not be recommended for use during late pregnancy unless the anticipated benefit for the mother outweighs the potential risk to the newborn.  相似文献   

18.
    
BACKGROUND: A variety of progestational agents have been used therapeutically and evaluated for adverse effects over the last 50 years. However, progesterone itself has come into use as a therapeutic agent only recently with the development of an orally bioavailable \"micronized\" preparation. METHODS: The current review examines progesterone adverse effects as identified in the larger literature on the toxicity of progestational agents and pharmacokinetics. RESULTS: Progesterone has cytoplasmic and membrane receptors in a variety of reproductive and nonreproductive tissues including the brain and is a potent inhibitor of GnRH. Limited information is available on progesterone receptors and actions in the fetus. Concern about exogenous progestagen effects on fetal reproductive tract development have led to considerable human research over the years, but this literature review demonstrates that contemporary developmental toxicology research on progesterone is lacking. CONCLUSIONS: Progesterone is a potent, multi-faceted endocrine agent with an expanding therapeutic profile and a minimal scientific database for evaluating safe use during pregnancy.  相似文献   

19.
黄涵年  郭江峰 《生命科学》2013,(11):1115-1120
MicroRNA(miRNA)是一类长为20~24nt的非编码单链小分子RNA,主要存在于真核生物中,具有组织特异性、无开放阅读框等特点,在转录或翻译水平调控基因表达,参与细胞增殖、分化、凋亡,并与炎症、肿瘤等疾病发生、发展密切相关。环境毒理学研究表明,当生物暴露于环境化学物质时,会引起相关miRNA表达发生变化,进而导致其靶基因表达发生改变。因此,有必要明确环境化学物质、miRNA和相关靶基因三者问的作用关系。在环境毒理学研究和环境监测中,miRNA可作为识别环境中化学物质基因毒性和致癌性的生物标记物,并可用于预测环境化学物质对生物体的毒性。  相似文献   

20.
    
Published studies for reproductive and developmental toxicity conducted with isopropanol have been conducted by the inhalation and oral gavage routes of administration. Interpretation of the data from these studies has resulted in discussions regarding NOAELs and additional benchmark dose modeling publications. Unpublished reproductive and developmental toxicity studies administered in the drinking water were also conducted by BIBRA, and the results of those studies are presented here. In addition, all of the reproductive and developmental toxicity studies conducted with isopropanol are summarized and evaluated for concordance of effects and NOAELs. Endpoints of concern for regulatory agencies were decreases in male mating index and reductions in postnatal pup survival. Original study reports were evaluated and data collated to address these two endpoints, and the data summarized. Data are presented suggesting that there were technical problems in the study that implied a decrease in male mating index, and based on the results from the drinking water studies, the weight of evidence suggests that isopropanol does not affect male mating or fertility at dose levels of up to 1000 mg/kg/day. The weight of evidence suggests that isopropanol can cause decreases in postnatal pup survival following oral gavage administration of 1000-1200 mg/kg/day to the dams. The NOAEL for this endpoint with oral gavage administration was 700 mg/kg/day. Indications of maternal toxicity were also an important predictor for decreased postnatal survival. Decreased postnatal pup survival was also noted in the drinking water studies with isopropanol with a LOAEL of 2278 mg/kg/day and a NOAEL of 1947 mg/kg/day.  相似文献   

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