免疫时间毒性研究进展

免疫毒理学和时间毒理学是毒理学领域内两个较新的分支学科。时间毒理学［１］是探讨外源性有害因素与生物内源性节律相互作用及其机理的科学，而免疫毒理学则将免疫系统对环境有害因素的不良反应作为主要的研究课题。１９８８年，免疫时间毒理学（Ｉｍｍｕｎｏｃｈｒｏｎ...     

抗原与毒物的暴露时序对小鼠免疫毒性的影响

对化学物免疫毒性的检测，常常涉及到抗原和毒物的共同暴露。以小鼠血中ＩｇＧ水平为指标，观察抗原（绵羊红细胞）和毒物（氯氰菊酯）不同的处理时序对免疫毒性的影响。发现各染毒组小鼠ＩｇＧ的含量均值都有不同程度的下降，以同时免疫染毒组降低最为明显。单独免疫组小鼠ＩｇＧ含量的昼夜节律，在先染毒后免疫组和同时免疫染毒组的小鼠中消失。在不同昼夜时点染毒组中，以１４：００时染毒后毒性反应最大。这些结果提示，不同的处理顺序和时间可引起同一化学物不同的免疫毒性的表现。对氯氟菊酯而言，与抗原同时暴露以及在下午１４：００时染毒，是其产生最大免疫毒作用的时序条件。     

高顺氯氰菊酯毒性实验研究

高顺氯氟菊酯又名α-氰基-3苯氧苄基-(顺式)-3(2,2-二氯乙烯基)-2,2-二甲基环丙烷羧酸酯[α-cyano-3-phenoxybe-nzlcis-3-(2,2-dichloroviny)-2,2-dime-thylcycloprorane croboxylate],(1R顺式S和1S顺式R异构体=1:1的混合物)是新型高效、低毒、广谱及低残留含氯拟除虫菊酯杀虫剂。本文报告该杀虫剂的急性、亚急性、皮肤刺激和红细胞膜渗透脆性等毒性实验研究结果。     

烹饪油烟冷凝物对小鼠免疫功能的影响

食用油作为烹饪材料,广泛应用于我国的每一个家庭。用食用油烹调食品的过程中,随着温度的升高会产生大量的油烟和食品的热解产物。根据文献报道,烹饪油烟中存在着多种有害物质,特别是多环芳烃类及杂环胺类物质。烹饪油烟是室内主要的空气污染物,它可通过呼吸道进入人体,     

煤焦沥青烟对小鼠的免疫毒性研究

给小鼠每日皮下注射2.5、5.0和10.0μg/g的煤焦沥青烟,连续染毒10天,小鼠体重增长呈现不同程度的降低,胸腺和脾脏萎缩,外周血T淋巴细胞百分数及足跖迟发型变态反应明显降低。高剂量沥青烟可使脾抗体生成反应及血清抗体滴度降低,抑制率达69.5%。但未见对单核巨噬细胞碳粒廓清作用及肝、肾重量有明显影响。沥青烟对机体具有明显的细胞和体液免疫毒性。     

不同剂量环磷酰胺对小鼠的免疫毒性研究

采用１２,２５,３５ｍｇ／ｋｇｂｗ三个剂量环磷酰胺,经口灌胃给药,连续１８天,测定小鼠的免疫器官的脏体系数,外周血Ｔ淋巴细胞ＡＮＡＥ阳性率,以及碳粒廓清实验的廓清指数。结果表明：ＣＰ在１０ｍｇ／ｋｇｄｗ剂量时,除对ＡＮＡＥ阳性率有明显降低外,对其余两个指标的影响均不明显,而在２５ｍｇ／ｋｇｂｗ,３５ｍｇ／ｋｇｂｗ时,对所试的三个指标有明显降低。     

雷公藤甲素对大鼠肾上腺皮质毒性作用的时间节律性研究

目的观察雷公藤甲素对大鼠肾上腺皮质的毒性作用并探讨其时间节律性,为临床合理用药、降低毒副反应提供实验依据。方法♂SD大鼠30只随机分为3组,包括空白对照组;雷公藤甲素早上用药组40μg.kg-1,qd,8am;雷公藤甲素晚上用药组40μg.kg-1,qd,8pm。连续灌胃7周后断头处死,测定大鼠血浆皮质醇含量,大鼠肾上腺HE染色和透射电镜观察,从功能和形态两方面探讨较长期和不同时辰服用雷公藤甲素对大鼠肾上腺皮质分泌功能的影响、中毒病理改变及其毒性机制。结果早上用药组大鼠血浆皮质醇含量明显低于空白对照组(P<0.05);晚上用药组大鼠血浆皮质醇含量与空白对照组比较无差异,与早上用药组比较差异有显著性(P<0.05)。HE染色观察:早上用药组肾上腺皮质较空白对照组变薄、结构不清、脂质空泡减少,晚上用药组肾上腺皮质较空白对照组略微增厚,束状带增宽,脂质空泡多。电镜观察:早上用药组皮质束状带细胞质中线粒体空泡变性,脂滴少,粗面内质网扩张,周边有核糖体;晚上用药组肾上腺皮质束状带细胞质中线粒体、脂滴、核糖体均较多。结论较长期服用雷公藤甲素对大鼠肾上腺皮质具有毒性作用,且其毒性作用具有时间节律性。     

药物动力学的时间节律性

生物体本身有生物周期,一天之内有昼夜节律性变化。对此我国古籍中有“子午流注”之说,现代生物医学称之为生物时钟。药理学和时间生物学的交叉学科称为时间药理学(Chronopharmacology)。本文主要阐述药物在吸收、分布、消除过程中的时间节律性,即时     

紫茎泽兰提取物对小鼠免疫毒性的研究

目的 观察紫茎泽兰提取物对小鼠免疫功能的影响。方法 小鼠分别以75、150和300 mg/kg的剂量连续7 d经口给予紫茎泽兰提取物,7 d后无菌取其胸腺和脾脏并称重,观察紫茎泽兰提取物对胸腺及脾脏指数的影响,并取胸腺和部分脾脏甲醛固定,光学显微镜下观察胸腺及脾脏组织病理学变化。将剩余部分脾脏制成脾细胞悬液,采用流式细胞术测定脾细胞凋亡率,MTT法检测脾细胞增值活性,乳酸脱氢酶(LDH)法测定NK细胞活性。结果 紫茎泽兰提取物各组与对照组相比胸腺指数明显降低(P<0.05),胸腺及脾脏组织均有明显的病理学改变。脾细胞凋亡率明显增加(P<0.05),脾细胞增值活性明显降低(P<0.05),紫茎泽兰提取物300 mg/kg组,效-靶细胞为50∶1及25∶1浓度组NK细胞活性明显降低(P<0.05)。结论 紫茎泽兰提取物对小鼠免疫功能有一定程度的抑制作用。     

Effects of cypermethrin and methyl parathion mixtures on hormone levels and immune functions in Wistar rats

To study interaction and dose-related effects of mixed cypermethrin and methyl parathion on endocrine and immune functions, 120 Wistar rats were divided randomly into six groups of ten male and ten female rats, respectively, at the age of 2 months. All groups were force-fed every 2 days for 30 days with cypermethrin 0.0, 8.0, 0.0, 8.0, 1.8, 0.4 mg/kg bw and methyl parathion 0.0, 0.0, 0.23, 0.23, 0.0518, 0.0115 mg/kg bw. Controls received vehicle solvent only. Body weight gain and organ weights were measured. Serum or blood were used to test luteinizing hormone, follicle stimulating hormone, estradiol (E₂), testosterone, thyroid hormones (T₃, T₄, TSH), IgG, IgA, rate of neutrophil phagocytosis and of lymphocyte transformation. The effects on relative weights of ovaries and adrenals, IgA and rate of lymphocyte transformation were antagonistic interaction; the effect on estradiol was synergistic in female, whereas addictive in male rats; and the other indices indicated addictive interaction. Organ weights were similar in exposed and control animals except for adrenal (heavier in exposed rats, P<0.01). Serum levels of FSH and estradiol were higher in exposed groups than in controls (P<0.01). IgG levels were lower in exposed rats than in controls (P<0.01), and IgA levels were higher in exposed females than in controls (P<0.01). Lymphocyte transformation rates were lower (P<0.01) and neutrophil phagocytosis rates were higher (P<0.01) in exposed rats than in controls. Our results showed that exposure to low-dose mixtures of cypermethrin and methyl parathion may affect hormone levels (especially estradiol) and immune function in rats, and the NOAELs of combined compounds were located at 1/600 LD₅₀.     

Impact of cypermethrin in nephrocytes of freshwater fish Catla catla

The kidney of Catla catla, chronically exposed to sub-lethal concentrations (0.24 μg/L and 0.41 μg/L) of cypermethrin revealed a significant elevation in the activity of antioxidants superoxide dismutase (SOD), catalase (CAT), glutathione-s-transferase (GST) and reduced glutathione (GSH) after 15 days, followed by a decline of up to 45 days. Lipid peroxidation (LPO) remained elevated throughout the exposure duration. Histology presented proliferated haematopoietic tissue, tubular and glomerular degeneration. The maximum increase in the mean degree of tissue change (DTC) was observed on the 45th day of treatment. Ultra-structure study depicted cytoplasmic vacuolation, fragmented RER, the proliferation of lysosomes, mitochondrial degeneration, and degenerative changes in the epithelial lining of renal tubules. Principal component analysis (PCA) of various biomarkers generated two components PCI (SOD, GST, GSH, LPO and DTC) and PCII (CAT). These findings suggest that long term exposure to cypermethrin can lead to various pathological alterations in the fish kidney which in turn might interfere with normal renal excretory mechanism.     

Effects of selective monoaminergic reuptake blockade on activity rhythms in developing rats

Developing rats display prominent ultradian rhythms of locomotor activity when separated from the litter. A pharmacological analysis was undertaken to provide preliminary data on the role of monoaminergic neurotransmitter systems in the modulation or manifestation of this fundamental biological rhythm. Twenty-four hour activity profiles were monitored in 15-day-old rats, tested in darkness, after intraperitoneal treatment with desipramine (DMI), zimelidine (ZMI), or GBR-13069 (GBR), selective uptake inhibitors of norepinephrine, serotonin, and dopamine, respectively. Time series data were analyzed by low-resolution variance spectral analysis. DMI significantly diminished ultradian (>1 cycle per day; cpd) rhythmicity, and enhanced the circadian rhythm. Equimolar doses of ZMI had little effect on the ultradian band (7–15 cpd), but slightly reduced the circadian peak. The effects of acute GBR administration were complex, as this agent produced prominent effects on basal activity. In a second study these agents were administered continuously over a 5-day period, using subcutaneously implanted Alzet osmotic minipumps, to avoid the confounding effects of acute administration. Continuously-infused DMI virtually eliminated characteristic ultradian rhythms in the 9–15 cpd bandwidth. ZIM diminished ultradian oscillations only in the 14–15 cpd range, and GBR-12909 had little effect on ultradian rhythms throughout the usually prominent 7–16 cpd domain. All three reuptake inhibitors increased the prominence of slow ultradian rhythms with frequencies of 3–4 cpd. Continuous reuptake blockade had no significant effects on circadian amplitude or phase, as determined by cosinor analysis. Overall, these results indicate that modulation of activity rhythms in the neonatal rat are prominently affected by drugs which enhance certain central monoaminergic systems, particularly norepinephrine.     

The acute and chronic toxic effect of cypermethrin,propetamphos, and their combinations in rats

This study was aimed at determining the acute and chronic toxic effects of cypermethrin, propetamphos, and combined cypermethrin and propetamphos. Four groups, each comprising 10 animals, were established for the acute (a) and chronic (b) toxicity trials, and in total, 80 male Wistar albino rats were used. In the acute toxicity trial, the first group was maintained for control purposes, and groups 2a, 3a, and 4a were administered only once with 80 mg/kg.bw of cypermethrin, 25 mg/kg.bw of propetamphos and 80 mg/kg.bw of cypermethrin combined with 25 mg/kg.bw of propetamphos, respectively, by gavage directly into the stomach. In the chronic toxicity trial, the first group was also maintained for control purposes, while groups 2b, 3b, and 4b were administered daily with 12 mg/kg.bw of cypermethrin, 4 mg/kg.bw of propetamphos, and 12 mg/kg.bw of cypermethrin combined with 4 mg/kg.bw of propetamphos respectively, by gavage directly into the stomach for 60 days. Blood and tissue (liver, kidney, brain, spleen, and testis) samples were taken 24 h after pesticide administration in the acute toxicity trial and at the end of day 60 in the chronic toxicity trial. Oxidative stress (MDA, NO, SOD, CAT, GSH‐Px, and G6PD) parameters, serum biochemical parameters (glucose, triglyceride, cholesterol, HDL, LDL, BUN, creatinine, AST, ALT, ALP, protein, and albumin) and hepatic drug‐metabolizing parameters (CYP2E1, CYPB5, CYTC, GST, and GSH) were investigated in the samples. When administered either alone or in combination, both pesticides inhibited the antioxidant enzymes and increased MDA and NO levels. For the drug‐metabolizing parameters investigated, particularly in the chronic period, either increase (CYP2E1, CYPB5, and CYTC) or decrease (GST and GSH) was observed. Furthermore, some negative changes were detected in the serum biochemical parameters. In result, cypermethrin and propetamphos combinations and long‐term exposure to these combinations produced a greater toxic effect than the administration of these insecticides alone. © 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 1415–1429, 2016.     

Toxico-pathological effects in rats induced by concurrent exposure to aflatoxin and cypermethrin

The objective of the present study was to explore modification in toxico-pathological responses of rats toward aflatoxins in the presence of cypermethrin. A total of 120 adult male rats divided into six equal groups received AF and cypermethrin alone or in different combinations. AF was administered daily into rats with a stomach tube at dose rates of 0, 0.5 and 1.0 mg/kg AFB1. Cypermthrin was administered in the feed at dose levels of 0 and 500 mg/kg. Rats administered AF alone showed depression, decrease in feed intake, body weight and loose feces. Livers exhibited fatty change, necrosis, newly formed bile ducts and increased diameter of hepatocytes and their nuclei. Lesions in kidney included tubular necrosis and pink homogeneous tubular casts. Serum ALT and creatinine concentrations increased while those of total proteins, albumin, serum cholesterol and triglycerides decreased. Rats fed cypermethrin only had decreased feed intake and body weight. Hepatocytes showed fatty change and cellular necrosis. A concurrent administration of AF with cypermethrin indicated a potentiation of the AF toxicity reflected by increased severity of clinical signs, mortality of the rats and decreased body weights. Kidneys' relative weight also showed an equivocal interaction between the two toxicants. Other parameters studied did not show significant differences between the rats administered AF alone or concurrently with cypermethrin.     

Prenatal exposure to cypermethrin modulates rat nk cell cytotoxic functions

The synthetic pyrethroid insecticide, cypermethrin, was given during gestation to pregnant rats by gavage in corn oil. Peripheral blood and spleen cytotoxic activity of dams and their offspring were then evaluated at different times (30, 60, 90, 120 days) after birth. Pups showed a significant increase in peripheral blood natural killer (NK) and antibody-dependent (ADCC) cytotoxic activity paralleled with a similar increase in the percentage of NK-RP1⁺ cells and decreased activity in the spleen. Pregnant cypermethrin-exposed dams showed no changes in peripheral blood or spleen cytotoxic function during the postnatal period. Overall, these results suggest that immunomodulation of cytotoxic activity observed in the offspring is likely attributable to a specific effect of cypermethrin administered during the prenatal period.     

The in vitro exposure to cypermethrin does not inhibit the proliferative response of peripheral blood mononuclear cells

This study evaluated the effect of in vitro exposure to cypermethrin on peripheral blood mononuclear cells proliferative response, considering reduced peripheral blood mononuclear cells proliferative response observed in individuals occupationally exposed to pyrethroids. Peripheral blood mononuclear cells were obtained from 21 healthy subjects (28.0?±?9.0 years old). The effect of cypermethrin (at 0.5, 1.0 and 5.0?mg/ml) on cell viability was evaluated by flow cytometry using an apoptosis detection kit. Cell proliferation (PI) was evaluated by 5-(and 6)-carboxyfluorescein diacetate succinimidyl ester (CFSE) fluorescence decay using flow cytometry. Cells labeled with CFSE were exposed, in vitro, to cypermethrin (0.5, 1.0, 2.0, 2.5 and 4?μg/ml) and stimulated with phytohemagglutinin (PHA 1.0 or 5.0?μg/ml) for 5?d (37?°C, 5% CO₂). The in vitro treatment of peripheral blood mononuclear cells with cypermethrin did not induce apoptosis or necrosis after 5?d in culture. Stimulation by PHA induced cell proliferation (PI?=?1.29?±?1.09 and 2.01?±?0.62, PHA at 1.0 and 5.0?μg/ml, respectively, mean?±?SD) and in vitro exposure to cypermethrin did not alter cellular proliferative response to PHA (PI?=?1.80?±?0.50, 2.60?±?0.05 and 2.10?±?1.20 for cypermethrin at 1.0, 2.0 and 4.0?μg/ml, respectively, and PHA at 5.0?μg/ml). In vitro treatment of peripheral blood mononuclear cells with cypermethrin, at the doses tested, does not affect cell viability or proliferation. These findings suggest that the reduction of proliferation observed on lymphocytes derived from individuals occupationally exposed to pesticides may be related to other mechanisms than direct action of cypermethrin on lymphocytes.     

Evaluating the protective effects of vitamin E and selenium on hematology and liver,lung and uterus histopathology of rabbits with cypermethrin toxicity

Abstract

The objective of this study was to determine the efficacy of vitamin E and selenium as protective agents against cypermethrin (CY)-induced toxicity by evaluating hematology parameters along with liver, lung and uterus histopathology of female rabbits. Thirty female rabbits were randomly divided into five equal groups with six animals in each group (designated A, B, C, D and E). Animals in group A were control animals that did not receive CY, vitamin E, nor selenium. Animals in groups B–E were injected intraperitoneally with CY at 75?mg/kg body weight once every5 days over a 32?day period, while animals in the control group received saline. Animals in group C were also given vitamin E (150?mg/kg b.wt) orally and animals in group D were given selenium (0.45?mg/kg b.wt) orally. Group E was given both vitamin E at a dose of 150?mg/kg and selenium at a dose of 0.45?mg/kg. In group B (CY only), the values of PCV were decreased at the 12th day of gestation when compared to group A. The mean value of PCV was significantly higher in group E on the 12 and 24th day when compared to the other groups. The mean values of hemoglobin (Hb) were not significantly different among groups on the 12th and 24th day of gestation. On the 12th day of the gestation period, there were nonsignificant differences in the total number of erythrocytes among all the groups. However, on the 24thdayof the gestation period, there was a significant decrease in the total number of erythrocytes in group B compared to the control group. Total leukocytes were also increased in the animals of group B on the 12th day of gestation, whereas the total leukocytes were increased on the 24th day of gestation in all groups (A–D) compared to control. Histopathological studies of tissues of liver, lungs and uterus revealed that CY altered the normal parenchyma of these tissues and this was partially ameliorated by the vitamin E and selenium treatments. In conclusion, combined use of vitamin E and selenium partially ameliorated the toxicity of CY in female rabbits.     

新福菌素不同时间给药对大鼠免疫功能昼夜节律变化的研究

目的：探索不同时间注射新福菌素对正常大鼠免疫功能的影响是否存在昼夜节律，为临床制定新福菌素的时辰化疗方案提供必要的实验依据。方法：将60只大鼠按给药的6个时点随机分成6组，第一天用流式细胞仪记数用药前大鼠T淋巴细胞亚群，第二天按6个时点给药，第三天注射抗原。第十一天测抗体，第十二天测用药后大鼠淋巴细胞弧群及做足跖实验，24小时后观察足跖肿胀并计算足跖肿胀率。结果：不同时点用药组大鼠产生抗体的量、足跖肿胀率、淋巴细胞亚群的变化率差异均有统计学意义，且具有昼夜节律。结论：新福菌素在1天中不同时间给药对正常大鼠免疫功能的影响存在昼夜节律。     

Surface structures of gill,scale and erythrocyte of Anabas testudineus exposed to sublethal concentration of cypermethrin

The present study was undertaken to assess the toxicity of sublethal concentrations (0.015, 0.030 and 0.045 ppm) of cypermethrin on the gills, scales and erythrocytes of Anabas testudineus for 21 days. The morphological changes on the gills, scales and erythrocytes of the A. testudineus were observed using scanning electron microscope (SEM). The SEM studies on all the three treated groups revealed several kinds of gills, scales and erythrocytes alterations and modifications with abnormal morphology. Gill alterations included highly active mucous cells, epithelial hyperplasia, fusion of secondary lamellae and epithelial lifting. The scales showed damaged lepidonts. Abnormal erythrocytes (shrunken cells), oozed out cytoplasmic content and lobopodial projections were observed in the erythrocytes of fish after exposure to cypermethrin.