Genotoxicity of synthetic amorphous silica nanoparticles in rats following short‐term exposure. Part 1: Oral route

Synthetic amorphous silica (SAS) in its nanosized form is now used in food applications although the potential risks for human health have not been evaluated. In this study, genotoxicity and oxidative DNA damage of two pyrogenic (NM‐202 and 203) and two precipitated (NM‐200 and ‐201) nanosized SAS were investigated in vivo in rats following oral exposure. Male Sprague Dawley rats were exposed to 5, 10, or 20 mg/kg b.w./day for three days by gavage. DNA strand breaks and oxidative DNA damage were investigated in seven tissues (blood, bone marrow from femur, liver, spleen, kidney, duodenum, and colon) with the alkaline and the (Fpg)‐modified comet assays, respectively. Concomitantly, chromosomal damage was investigated in bone marrow and in colon with the micronucleus assay. Additionally, malondialdehyde (MDA), a lipid peroxidation marker, was measured in plasma. When required, a histopathological examination was also conducted. The results showed neither obvious DNA strand breaks nor oxidative damage with the comet assay, irrespective of the dose and the organ investigated. Similarly, no increases in chromosome damage in bone marrow or lipid peroxidation in plasma were detected. However, although the response was not dose‐dependent, a weak increase in the percentage of micronucleated cells was observed in the colon of rats treated with the two pyrogenic SAS at the lowest dose (5 mg/kg b.w./day). Additional data are required to confirm this result, considering in particular, the role of agglomeration/aggregation of SAS NMs in their uptake by intestinal cells. Environ. Mol. Mutagen. 56:218–227, 2015. © 2014 Wiley Periodicals, Inc.     

Genetic toxicity assessment using liver cell models: past,present, and future

ABSTRACT

Genotoxic compounds may be detoxified to non-genotoxic metabolites while many pro-carcinogens require metabolic activation to exert their genotoxicity in vivo. Standard genotoxicity assays were developed and utilized for risk assessment for over 40 years. Most of these assays are conducted in metabolically incompetent rodent or human cell lines. Deficient in normal metabolism and relying on exogenous metabolic activation systems, the current in vitro genotoxicity assays often have yielded high false positive rates, which trigger unnecessary and costly in vivo studies. Metabolically active cells such as hepatocytes have been recognized as a promising cell model in predicting genotoxicity of carcinogens in vivo. In recent years, significant advances in tissue culture and biological technologies provided new opportunities for using hepatocytes in genetic toxicology. This review encompasses published studies (both in vitro and in vivo) using hepatocytes for genotoxicity assessment. Findings from both standard and newly developed genotoxicity assays are summarized. Various liver cell models used for genotoxicity assessment are described, including the potential application of advanced liver cell models such as 3D spheroids, organoids, and engineered hepatocytes. An integrated strategy, that includes the use of human-based cells with enhanced biological relevance and throughput, and applying the quantitative analysis of data, may provide an approach for future genotoxicity risk assessment.     

刺五加对环磷酰胺所致小鼠微核率影响的研究

目的　研究刺五加对环磷酰胺所致小鼠微核率的影响 ,以探讨其对突变的拮抗作用。方法　 6 0只小鼠随机分为 6组 ,连续用刺五加或蒸馏水灌胃 17d ,并在第 13d一次性腹腔注射环磷酰胺 ,之后连续用尾血涂片 5次 ,荧光显微镜观察计数微核 (MN)。结果　①刺五加无增加微核率作用 ;②环磷酰胺致微核率上升作用明显 ;③刺五加可以降低微核发生率 ,随剂量升高作用更加明显。结论　刺五加有比较明显抗突变作用 ,可开发利用到肿瘤治疗和延缓衰老等方面     

甲醛对小鼠致突变作用的研究

目的　研究甲醛对小鼠的致突变作用。方法　选择健康昆明种小鼠 5 0只 (雌雄各半 ) ,随机分为 3个剂量组 :甲醛高剂量组 (2 0 0 0mg/kg·bw)、中剂量组 (2 0 0mg/kg·bw)、低剂量组 (0 2 0mg/kg·bw) ,1个阴性对照组 (生理盐水 )和 1个阳性对照组 (环磷酰胺 5 0mg/kg) ,采用腹腔注射染毒 ,每天 1次 ,连续 5d。于第六天处死雌性小鼠进行骨髓细胞微核试验 ,于第三十五天处死雄性小鼠进行精子畸形试验 ,显微镜下观察并计数微核及畸形精子数。结果　甲醛中、高剂量组骨髓细胞微核数显著高于阴性对照组 (P <0 0 5 ;) ,同时低、中、高剂量组精子畸形率显著高于阴性对照组 (P <0 0 1)。结论　甲醛对小鼠具有致突变作用     

汽油添加剂甲基叔丁基醚的毒性研究

目的　通过研究汽油添加剂甲基叔丁基醚 (MTBE)对小鼠体内谷胱甘肽 (GSH)、谷胱甘肽过氧化物酶 (GSH -Px)活性的改变以及骨髓微核、精子畸变率的影响 ,了解汽油添加剂甲基叔丁基醚的毒性。方法　 40只健康昆明种成年小鼠 ,体重 3 3 .3± 6 .9g ,随机分为 4组。灌胃染毒 ,染毒剂量分别为1 6 0 0、40 0、1 0 0和 0mg kg。每天 1次 ,每周 5天 ,共计 40天。结果　MTBE染毒各组小鼠体重轻度降低 ,染毒组全血及肝组织匀浆中GSH在低剂量染毒时增高 ,而高剂量时表现为降低 ,与对照组比较差异有显著性 (P <0 .0 5 ) ;GSH -Px活性明显减低 ,染毒高剂量组与对照组比较差异有高度显著性 (P <0 .0 1 ) ;骨髓嗜多染红细胞微核及精子畸变率增高 ,与对照组比较明显增高 ,差异有显著性 (P <0 .0 5 )。结论　MTBE对昆明小鼠具有一定毒性 ,可降低全血及肝脏组织中GSH -Px活性 ,低剂量时可增加全血及肝脏组织中GSH含量 ,而高剂量可降低其含量。MTBE能使骨髓微核率、精子畸形率明显增高 ,提示MTBE具有潜在的遗传毒性。     

Correlation between bone marrow karyotype and the occurrence of erythroblast micronuclei and nuclear budding in patients with myelodysplastic syndromes

147 patients with myelodysplastic syndromes were investigated for the presence of micronuclei and nuclear budding in bone marrow erythroblasts. The patients were divided into subgroups on the basis of bone marrow karyotype, 31 healthy bone marrow donors constituted a control group. Patients with monosomy 7 or 7q- and patients with major karyotypic abnormalities (MAKA) had significantly more erythroblasts with micronuclei and nuclear budding than the control group. Patients with a 5q- chromosome as the sole karyotypic aberration had more micronuclei than the controls. For other patients with MDS the differences were statistically nonsignificant.     

克百威及其代谢产物的小鼠骨髓红细胞微核试验研究

[目的]利用微核试验研究克百威及其4种代谢产物的遗传毒性。[方法]分别以0．1、0．2、0．4mg/kg3个不同剂量水平的克百威及其代谢产物3-羟基呋喃丹、3-酮基呋喃丹、呋喃酚和亚硝基呋喃丹腹腔注射染毒健康小鼠，24h后以同样剂量再次注射染毒，6h后脱颈椎处死动物，制片，观察并计数嗜多染红细胞的微核率，进行统计分析。[结果]克百威、呋喃酚及3-酮基呋喃丹小鼠胸骨骨髓嗜多染红细胞微核实验为阴性结果，高剂量处理组微核率分别为1．3‰、3．25‰和3．62‰，与阴性对照组(1．83‰)差异无显著性；而高剂量组3-羟基呋喃丹(7．00‰)和三个剂量组的亚硝基呋喃丹(微核率分别为3．62‰、5．00‰、7．85‰)均有明显微核效应。[结论]克百威、呋喃酚和3-酮基呋喃丹在受试剂量下微核试验阴性，3-羟基呋哺丹和亚硝基呋喃丹微核试验阳性，提示可能对染色体具有突变效应。     

饮用水中过量铁和锰对蚕豆根尖细胞微核率的影响

目的 探讨饮用水中过量的铁和锰的致突变作用。方法 采用蚕豆根尖细胞微核技术。结果 当水中铁含量超过饮用水卫生标准3～10倍时，蚕豆根尖细胞微核率升高，且微核率与铁剂量间存在着明显的剂量-反应关系。锰对蚕豆根尖细胞微核率升高的作用不明显，只有在剂量高达卫生标准1000倍时，才会使蚕豆根尖细胞微核率有所增加。结论 过量的铁有致突变作用。     

接触金属汞的工人淋巴细胞微核率和姊妹染色单体互换率的观察

用机械法可使菜籽粕中毒性质的丙基异硫氰酸酯由０．７１％降到０．２１％，脱除率为７０．４２％，可替代猪、鸡中部分豆饼、鱼粉、降低饲料成本９．５６％－１２．６９％，县地生产性能不良影响。这种脱毒菜籽粕在体重３５－６０ｋｇ阶段猪日粮中用量不宜超过２０％；在肉仔鸡日糖中用量可为１０％或１５％。     

赤灵芝的致突变性试验

使用赤灵芝的水提取液、乙醇（３０％）提取液进行鼠伤寒沙门氏菌回复、小鼠骨髓多染红细胞微核和雄小鼠精子畸变等三种致突变试验。剂量为１０００μｇ．皿＾－１和５０００μｇ／皿＾－１的鼠伤寒沙门氏菌回复试验的结果为阴性。小鼠在服用７５００ｍｇ．ｋｇ＾－１的水提取液或２５００ｍｇ．ｋｇ＾－１的醇提取液时，微核试验和精子畸变试验结果均为阴性。