共查询到20条相似文献,搜索用时 15 毫秒
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Jeong-Sup Hong Suhyon Kim Sang Hee Lee Eunhye Jo Byungcheun Lee Junheon Yoon 《Nanotoxicology》2014,8(4):349-362
Combined repeated-dose toxicity study of citrate-capped silver nanoparticles (7.9 ± 0.95 nm) with reproduction/developmental toxicity was investigated in rats orally treated with 62.5, 125 and 250 mg/kg, once a day for 42 days for males and up to 52 days for females. The test was performed based on the Organization for Economic Cooperation and Development test guideline 422 and Good Laboratory Practice principles. No death was observed in any of the groups. Alopecia, salivation and yellow discolouration of the lung were observed in a few rats but the symptoms were not dose-dependent. Haematology, serum biochemical investigation and histopathological analysis revealed no statistically significant differences between control group and the treated groups. Toxicity endpoints of reproduction/developmental screening test including mating, fertility, implantation, delivery and foetus were measured. There was no evidence of toxicity. 相似文献
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Ling He Hua Xiang Lu‐Yong Zhang Wei‐Sheng Tian Hua‐Hong He 《Drug development research》2005,64(4):203-212
The estrogen receptor (ER) is an important drug target with allosteric characteristics that binds orthotopic hormones and other ligands. A recently developed scintillation proximity (SPA)‐based assay for high‐throughput screening (HTS) of compound libraries was used to identify novel estrogen receptor ligands that might have ER subtype selective binding activity. Radioligand binding was determined in a multi‐detector scintillation counter designed for microtitration plates. Equilibrium binding experiments and kinetic competition tests were performed with [3H]‐estradiol and human ERα and ERβ receptors. A library of 6,000 structurally diverse compounds was screened. From this, several novel ligands were identified that showed pronounced subtype‐selective differences in ligand binding for ERα and ERβ. The observed equilibrium dissociation constant (Kd) for the binding of [3H]estradiol to ERα and ERβ receptors were approximately 0.25 and 0.64 nM, respectively. When 17β‐estradiol, raloxifene and daidzein were tested for binding affinity to ERα in a competition assay, the IC50 values were 0.34, 1.31, and 75.6 nM, respectively. When tested for binding affinity to ERβ, the IC50 values were 1.05, 11.4, and 10.6 nM, respectively. The results obtained show that the methodology is valid in comparison to previously published data regarding estradiol and other standard compounds (raloxifene and daidzein) binding characteristics of estrogen receptors. The assay is also well suited to applied research as a tool in HTS of compound libraries in the search of ER ligands. Several novel active compounds were identified and selected as potent ER subtype ligands. Drug Dev Res 64:203–212, 2005. © 2005 Wiley‐Liss, Inc. 相似文献
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Takahashi M Sunaga M Hirata-Koizumi M Hirose A Kamata E Ema M 《Environmental toxicology》2009,24(1):74-81
Rats were treated by gavage once daily with 2,4-dinitrophenol (DNP) at 0 (control), 3, 10, or 30 mg/kg bw. Males were dosed for 46 days, beginning 14 days before mating, and females were dosed for 40-47 days, from 14 days before mating to day 3 of lactation. No deaths were observed in males and females of any group. A significant decrease in body weight gain and significant increase in liver weight were found in males and females at 30 mg/kg bw/day. The number of live pups on postnatal days (PNDs) 0 and 4, live birth index, and body weight of live male and female pups on PNDs 0 and 1 were significantly lowered at 30 mg/kg bw/day. External and internal examinations of pups revealed no increased incidence of malformations in DNP-treated groups. On the basis of these findings, we concluded that DNP has general and reproductive/developmental toxicity, but not teratogenicity, under the present conditions. The NOAEL of DNP is considered to be 10 mg/kg bw/day in rats. 相似文献
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In a combined repeated dose toxicity study with reproduction/developmental toxicity screening test, Crj:CD(SD)IGS rats were dosed with dinoseb, 2-sec-butyl-4,6-dinitrophenol, by gavage at 0 (vehicle), 0.78, 2.33, or 7.0 mg/kg bw/day. Six males per group were dosed for a total of 42 days beginning 14 days before mating. Twelve females per group were dosed for a total of 44-48 days beginning 14 days before mating to day 6 of lactation throughout the mating and gestation period. Recovery groups of six males per group and nonpregnant six females per group were dosed for 42 days followed by a 14-day recovery period. No deaths were observed in males of any dose group or in females of the recovery groups. At 7.0 mg/kg bw/day, eight females died and two animals were moribund during late pregnancy, and a significant decrease in body weight gain was found in both sexes. Hematocrit was significantly higher at 0.78 mg/kg bw/day and above in the main group males at the end of administration period. Reduction in extramedullary hematopoiesis in the spleen was significant at 2.33 mg/kg bw/day in the main group females. Sperm analysis revealed a decrease in sperm motility and an increase in the rates of abnormal sperm, abnormal tail, and abnormal head at 7.0 mg/kg bw/day. A number of dams delivered their pups and of dams with live pups at delivery was significantly lowered in the 7.0 mg/kg bw/day group. Based on these findings, the LOAEL for males and NOAEL for females were 0.78 mg/kg bw/day, and the NOAEL for reproductive/developmental toxicity was considered to be 2.33 mg/kg bw/day. 相似文献
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Hina Kato Sakiko Fujii Mika Takahashi Mariko Matsumoto Mutsuko Hirata‐Koizumi Atsushi Ono Akihiko Hirose 《Environmental toxicology》2015,30(11):1244-1263
Perfluoroalkyl carboxylic acids (PFCAs) are a series of environmental contaminants that have received attention because of their possible adverse effects on wildlife and human health. Although many toxicological studies have been performed on perfluorooctanoic acid with carbon chain length C8, available toxicity data on PFCAs with longer chains are still insufficient to evaluate their hazard. A combined repeated dose and reproductive/developmental toxicity screening study for perfluorododecanoic acid (PFDoA; C12) was conducted in accordance with OECD guideline 422 to fill these toxicity data gaps. PFDoA was administered by gavage to male and female rats at 0.1, 0.5, or 2.5 mg/kg/day. The administration of PFDoA at 0.5 and 2.5 mg/kg/day for 42–47 days mainly affected the liver, in which hypertrophy, necrosis, and inflammatory cholestasis were noted. Body weight gain was markedly inhibited in the 2.5 mg/kg/day group, and a decrease in hematopoiesis in the bone marrow and atrophic changes in the spleen, thymus, and adrenal gland were also observed. Regarding reproductive/developmental toxicity, various histopathological changes, including decreased spermatid and spermatozoa counts, were observed in the male reproductive organs, while continuous diestrous was observed in the females of the 2.5 mg/kg/day group. Seven of twelve females receiving 2.5 mg/kg/day died during late pregnancy while four other females in this group did not deliver live pups. No reproductive or developmental parameters changed at 0.1 or 0.5 mg/kg/day. Based on these results, the NOAELs of PFDoA were concluded to be 0.1 mg/kg/day for repeated dose toxicity and 0.5 mg/kg/day for reproductive/developmental toxicity. © 2014 Wiley Periodicals, Inc. Environ Toxicol 30: 1244–1263, 2015. 相似文献
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围绕药品非临床研究质量管理规范(GLP)体系下生殖发育毒性评价所使用仪器确认展开讨论,提供开展仪器确认所需要的关键事项:根据研究目的,选取合适种属的实验动物;动物数量应满足统计学需求;准确选取实验受试物,购入标准品或阳性药物;确定实用性强、干扰因素少的确认方法;把握实验关键点、排除其他因素对确认的干扰;建立准确度高可重现性好的评价标准;根据实验室基本情况以及研究目的,在标准作业程序(SOP)中规定不同仪器确认所需要的周期。现有生殖毒性仪器确认规范性、标准化成为实验室管理的新难点,需要努力推进其标准化规范化进程。 相似文献
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药物非临床生殖发育毒性试验中逐案原则的建议 总被引:1,自引:0,他引:1
本文围绕药物非临床生殖发育毒性试验中逐案原则展开讨论,认为:①不同的研究目的决定着不同的研究策略。②受试物的种类不同选择试验种类亦各异。③在特定的研究机构需要设立阳性对照组。④实验动物的选择需要考虑受试物的特点。⑤实验动物的给药途径需要考虑实际可行。⑥根据受试物特色增设特异性指标的检测。⑦适时开展生殖毒性伴随毒代动力学试验。⑧基于多方面实际资料综合分析得出结论。因此,既要依从药物生殖发育毒性非临床安全性评价研究的通则,又要在对受试物充分认识的基础上,遵循"具体问题具体分析"的原则,避免因循守旧和循规蹈矩,最终经仔细观测、审慎分析,综合多方面信息对试验结果进行全面分析评价,以至能准确地下达结论。 相似文献
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Evaluation of the developmental and reproductive toxicity of methoxychlor using an anuran (Xenopus tropicalis) chronic exposure model. 总被引:1,自引:0,他引:1
Douglas J Fort John H Thomas Robert L Rogers Andra Noll Clinton D Spaulding Patrick D Guiney John A Weeks 《Toxicological sciences》2004,81(2):443-453
The chronic toxicity of methoxychlor to the South African clawed frog, Xenopus (Silurana) tropicalis, was evaluated using a life cycle approach. The chronic exposure period ranged from mid-cell blastula stage [NF (Nieuwkoop and Faber, 1994) stage 8] to 90 days of exposure, during which time the organisms generally completed metamorphosis and emerged as juvenile frogs. Methoxychlor concentrations ranged from 1 to 100 micrograms/l. Methoxychlor concentrations >10 micrograms/l caused delayed development. Organisms exposed to 10 micrograms/l methoxychlor for 30 days showed enlarged thyroid glands with follicular hyperplasia. No increase in mortality or external malformation was observed at any of the test concentrations during early embryo-larval development (NF stage 8 to NF stage 46; ca. 2 days exposure). A concentration-dependent increase in external malformations and internal abnormalities of the liver and gonads were noted after 90 days of exposure, however. Skewing of the sex ratio toward the female gender decreased ovary weight and number of oocytes, and increased oocyte immaturity and necrosis were noted at methoxychlor concentrations of 100 micrograms/l. Reductions in testis weight and sperm cell count were also detected at 100 micrograms/l methoxychlor. Results from these studies suggested that methoxychlor was capable of altering the rate of larval development, but did not adversely affect early embryo-larval development (2 days of exposure) as manifested in external malformations. Internal malformations, increases in the ratio of phenotypic females, were induced by chronic methoxychlor exposure. In addition, reproductive endpoints, most notably in the female specimens, were adversely affected by methoxychlor exposure. These studies add to the standardization and validation of a useful amphibian test methods capable of evaluating both reproductive and developmental effects of potential endocrine disrupting chemicals over a life cycle exposure. 相似文献
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J L Larson T L Wallace R W Tyl M C Marr C B Myers P A Cossum 《Toxicological sciences》2000,53(2):421-429
Nyotran is a liposomally encapsulated i.v. formulation of the antifungal polyene nystatin. This drug was evaluated in a series of reproductive toxicity studies, according to the guidelines outlined by the International Conference on Harmonization (ICH). A fertility and early embryonic development study (SEG I) and a prenatal and postnatal development (SEG III) study were conducted in rats, and embryo-fetal development (SEG II) studies were conducted in rats and rabbits. Nyotran was administered iv in all studies. In SEG I and SEG III, rats were administered daily doses of 0.5, 1.5, or 3.0 mg/kg Nyotran. In both studies, parental mortality and toxicity in the 3.0 mg/kg dose group necessitated the lowering of the high dose to 2.0 mg/kg/day. Parental toxicity, in the form of decreased body weights, decreased food consumption, and piloerection were also observed at the 1.5 mg/kg/day dose level in the SEG I and SEG III studies. Despite the parentally toxic doses in the SEG I study, there was no effect of Nyotran on F0 male or female fertility or early embryonic development of F1 offspring. In the SEG III study, lactational body weights of the F1 generation were decreased at all Nyotran dose levels. There was no effect on pre-wean developmental landmarks, but post-wean development was affected by Nyotran administration at all dosage levels. Preputional separation was delayed in the 1.5 and 3.0/2.0 mg/kg/day F1 offspring, auditory startle function was decreased in F1 females at all dose levels, and motor activity was decreased in male F1 offspring at all dose levels. However, there were no treatment-related effects on the subsequent mating of the F1 generation and resulting F2 offspring. In SEG II studies, rats and rabbits were also administered 0.5, 1.5, or 3.0 mg/kg/day of Nyotran during gestation. The high dose in these SEG II studies was not lowered, as the maternal animals were able to tolerate the shorter duration of dosing. Maternal effects in rabbits were observed only in the high-dose group and were limited to decreased food consumption and decreased absolute and relative liver weight. Decreased food consumption in high-dose dams and clinical weight loss in some animals at the mid- and high-dose levels evidenced maternal toxicity in rats. Nyotran did not have any effect on Caesarian section parameters in either rats or rabbits and no effect on the incidence of fetal malformations in rabbits. A statistically significant increase in mild hydrocephaly, observed in 4 rat fetuses, was seen at the highest dose level of 3.0 mg/kg/day. The biological significance and relationship to Nyotran treatment of this finding is not clear. This finding may represent a change in the background incidence or a change in the pattern of responsiveness of this strain of rat fetus to the test chemical. Toxicokinetic data were also collected in the SEG II rabbit and rat studies for comparison to human exposures. In both species, systemic exposure to the nystatin at effective antifungal concentrations was demonstrated. The systemic exposures in rats and rabbits were, however, considerably less than have been reported in humans administered clinical doses of 2 or 4 mg/kg/day Nyotran. Thus, humans tolerate higher dosages and systemic exposures of Nyotran relative to rats and rabbits and there is no margin of safety in either dosage level or systemic exposure to drug. Given this lack of a margin of safety and the effects on postnatal development in F1 rats, caution should be exercised when using this drug in females of childbearing potential. 相似文献
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目的:以微管蛋白为靶建立高通量筛选(HTS)模型,以便有效地发现抗肿瘤化合物。方法:细胞培养与免疫荧光技术。结果:以常规的免疫组化(玻片)方法为基础优化实验条件,在96孔板上建立了以微管蛋白为靶点的高通量药物筛选模型;抗肿瘤药物紫杉醇和秋水仙碱作用于人肝癌HepG2细胞后,细胞的免疫荧光强度发生了明显的可检测的变化,间接反映药物对细胞徽管蛋白聚合/解聚作用的影响,与理论预测结果一致。结论:基于人肿瘤细胞的以徽管蛋白为靶点的高通量筛选方法可用于抗肿瘤化合物的筛选。 相似文献
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G-蛋白偶联受体的功能测定和高通量药物筛选 总被引:8,自引:2,他引:8
G 蛋白偶联受体家族是药物开发中最大的一类药物靶点 ,高通量药物筛选是开发药物早期阶段的最重要工具之一。根据G 蛋白偶联受体与配体结合及激发的信号通路 ,人们设计了各种可行的功能测试方法 ,用于G 蛋白偶联受体为药靶的高通量药物筛选 ,如 :微体积荧光数字图像测定技术 (Fluorometicmicrovolumeassaytechnology ,FMAT)、荧光偏振 (Fluoresencepolarization ,FP)、竞争性ELISA (Com petitiveenzyme linkedimmunosorbent)、闪烁邻近测定法(Scintillation proximityassay ,SPA)、载黑色素细胞测定法(Melanophoreassay)、报告基因测定法 (Reportergeneassay)和钙离子测定法等测定方法。在这些方法中 ,报告基因测定法和钙离子测定法占了主导地位。非放射性、无需底物和辅助剂的报告基因测定方法和荧光钙离子指示剂的钙离子测定方法可能是将来G 蛋白偶联受体的功能分析和高通量药物筛选的发展方向 相似文献
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Toxicological evaluation of the topoisomerase inhibitor,etoposide, in the model animal Caenorhabditis elegans and 3T3‐L1 normal murine cells
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Etoposide, a topoisomerase II inhibitor, has been widely used as a clinical anticancer drug to treat diverse cancer patients. Since not only rapidly dividing cancer cells but also the cells of normal human tissues and every living organism in environmental ecosystems have topoisomerases, it is crucial to study the toxicity of etoposide in other organisms in addition to cancer cells. In this study, we evaluated the toxicity of etoposide in both a soil nematode, Caenorhabditis elegans, and 3T3‐L1 normal murine cells. Etoposide significantly retarded the growth, egg laying, and hatching in C. elegans. Etoposide also affected the reproductive gonad tissue, decreased the number of germ cells and induced abnormally enlarged nuclei in C. elegans. In addition, etoposide inhibited 3T3‐L1 cell proliferation, with IC50 values of 37.8 ± 7.3 and 9.8 ± 1.8 μM after 24 and 48 hours of treatment, respectively, via the induction of cell cycle arrest at the G2/M phase and apoptotic cell death. Etoposide also induced nuclear enlargement in 3T3‐L1 normal murine cells. The reproductive toxicity and abnormal nuclear morphological changes seemed to correlate with the adverse effects of etoposide. We suggest that these experimental platforms, i.e., the toxicological evaluation of both nematodes and 3T3‐L1 cells, may be useful to study the mechanisms underlying the side effects of chemicals, including topoisomerase inhibitors. 相似文献
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Sarah A. Long Shan Huang Anusha Kambala Ling Ren Jennifer Wilson Michael Goetz Xiaojiang Hao Xiaosheng Yang Ekaterina I. Goncharova Libin Jia Amy LeBlanc Chand Khanna Curtis J. Henrich John A. Beutler 《Chemical biology & drug design》2021,97(1):77-86
A high‐throughput screening assay was developed and applied to a large library of natural product extract samples, in order to identify compounds which preferentially inhibited the in vitro 2D growth of a highly metastatic osteosarcoma cell line (MG63.3) compared to a cognate parental cell line (MG63) with low metastatic potential. Evaluation of differentially active natural product extracts with bioassay‐guided fractionation led to the identification of lovastatin (IC50 = 11 µm ) and the limonoid toosendanin (IC50 = 26 nm ). Other statins and limonoids were then tested, and cerivastatin was identified as a particularly potent (IC50 < 0.1 µm ) and selective agent. These compounds potently and selectively induced apoptosis in MG63.3 cells, but not MG63. Assays with other cell pairs were used to examine the generality of these results. Statins and limonoids may represent unexplored opportunities for development of modulators of osteosarcoma metastasis. As cerivastatin was previously approved for clinical use, it could be considered for repurposing in osteosarcoma, pending validation in further models. 相似文献
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Nivedita Chatterjee Hyun‐Jeong Eom Su‐Hwa Jung Joo‐Sik Kim Jinhee Choi 《Environmental toxicology》2014,29(12):1409-1419
Bio‐oils, which are multicomponent mixtures, were produced from two different biomass (rice straw (rice oil) and sawdust of oak tree (oak oil)) by using the slow pyrolysis process, and chemical compositional screening with GC‐MS detected several hazardous compounds in both bio‐oil samples. The two bio‐oils vary in their chemical compositional nature and concentrations. To know the actual hazard potentialities of these bio‐oils, toxicological assessments were carried out in a comparative approach by using in vitro (Jurkat T and HepG2 cell) as well as in vivo (Caenorhabditis elegans) systems. A dose‐dependent increase in cytotoxicity, cell death (apoptosis), and genotoxicity were observed in cultured cell systems. Similarly, the in vivo system, C. elegans also displayed a dose‐dependent decrease in survival. It was found that in comparison with rice oil, oak oil displayed higher toxicity to all models systems, and the susceptibility order of the model systems were Jurkat T > HepG2 > C. elegans. Pursuing the study further toward the underlying mechanism by exploiting the C. elegans mutants screening assay, the bio‐oils seem to mediate toxicity through oxidative stress and impairment of immunity. Taken together, bio‐oils compositions mainly depend on the feedstock used and the pyrolysis conditions which in turn modulate their toxic potentiality. © 2013 Wiley Periodicals, Inc. Environ Toxicol 29: 1409–1419, 2014. 相似文献
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Curtis J. Henrich Anuradha Budhu Zhipeng Yu Jason R. Evans Ekaterina I. Goncharova Tanya T. Ransom Xin W. Wang James B. McMahon 《Chemical biology & drug design》2013,82(2):131-139
The cancer stem cell marker, EpCAM, is an important indicator of Wnt/β‐catenin signaling activation and a functional component of hepatocellular tumor‐initiating cells. A high‐throughput screening assay was developed to identify inhibitors of EpCAM‐dependent growth of hepatocellular carcinoma (HCC) cells. EpCAM(+) and EpCAM(?) HCC cell lines were assessed for differential sensitivity to a Wnt/β‐catenin pathway inhibitor. Libraries comprising 22 668 pure compounds and 107 741 crude or partially purified natural product extracts were tested, and 12 pure compounds and 67 natural product extracts were identified for further study. Three active compounds and the positive control were further characterized in terms of effects on EpCAM expression. Treatment of EpCAM(+) Hep3B cells resulted in loss of EpCAM expression as assessed by flow cytometry. This reduction was incomplete (most cells continued to express EpCAM), but resulted in generation of cell populations expressing lower levels of EpCAM. Sublethal concentrations (~IC50) reduced median EpCAM expression to 28% of control after 1 day and 19% of control after 2 days. Reduction in EpCAM expression preceded growth inhibition suggesting that a threshold of EpCAM expression may be required for growth of EpCAM‐dependent cells. The identification of compounds with a variety of possible molecular targets suggests a likelihood of multiple mechanisms for modulation of EpCAM‐dependent cell growth. 相似文献
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Marta Walczynska Witold Jakubowski Tomasz Wasiak Kinga Kadziola Nina Bartoszek Sylwia Kotarba 《Toxicology mechanisms and methods》2018,28(6):432-439
Nematode Caenorhabditis elegans (C. elegans) was used to investigate the impact of silver nanoparticles (SNP), multiwalled carbon nanotubes (MWCNT), and polyamidoamine dendrimers (PAMAM) used in concentration of 1010 particle/mL. Population-based observations and gene expression analysis were employed in this study. SNP and PAMAM caused decrease in the number of live nematodes and their body length, but MWCNT did not affect the population of nematodes. Gene expression analysis revealed significant changes caused by the presence of all studied nanomaterials, and the results strongly suggest a specific metabolic response of the nematode organism to exposure to various nanomaterials. It was shown that C. elegans is a very sensitive organism capable to respond specifically to the exposure to some nanomaterials and therefore could be considered as a possible biosensor for early warning of presence of some nanoparticles. 相似文献
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