母鼠低剂量甲基汞染毒致亲、仔代肝脏的氧化损伤

[目的]ICR母鼠通过饮水染毒低剂量氯化甲基汞（MeHgCl），观察MeHgCl对子代生长发育以及亲、仔代氧化损伤的影响。[方法]ICR孕鼠随机分为对照组、低剂量组和高剂量组，各组于怀孕第6天起分别自由饮用蒸馏水和MeHgCl含量分别为0．01、0．1mg／L（相当于饮用水汞含量标准的8倍和80倍剂量）的蒸馏水直至哺乳期结束。研究指标包括母鼠孕期和仔鼠出生后的体重增长及母鼠、仔鼠肝脏中汞含量、脂质过氧化产物丙二醛（MDA）含量及总抗氧化活力（T-AOC）的水平。[结果]在0．01和0．1mg／L剂量下，亲仔两代体重增长各剂量组无差异，也未出现明显的毒性反应，但均有明显的体内汞蓄积。表现为对照组、低剂量组和高剂量组母鼠肝脏汞含量分别为3．703、11．516、100．821ng／g组织湿重，仔鼠肝脏汞含量分别为2．664、5．454、38．846ng／g组织湿重。对照组、低剂量组和高剂量组母鼠总抗氧化活力和MDA含量分别为2．833、2．517、1．974U／mg蛋白和0．849、1．883、2．219nmol／mg蛋白，与对照组相比，甲基汞可使母鼠肝脏总抗氧化活力降低，肝脏中MDA含量增加（P〈0．05）；对照组、低剂量组和高剂量组仔鼠总抗氧化活力和MDA含量分别为1．860、2．361、2．945U／mg蛋白和0．506、0．702、0．617nmol／mg蛋白，甲基汞使仔鼠总抗氧化活力升高（P〈0．05），使低剂量组MDA含量明显高于对照组（P〈0．05），但MDA含量高剂量组和对照组相比变化不显著（P〉0．05）。[结论]在相当于饮用水汞卫生标准8倍和80倍剂量水平上，低剂量甲基汞虽未引起仔代明显发育障碍，但是可通过母体在仔代体内蓄积，并对亲、仔代肝脏产生不同的氧化损伤。     

甲基汞在脑组织中的积累和脂质过氧化作用

[目的]通过对SD大鼠进行腹腔注射氯化甲基汞,研究不同时间、不同剂量氯化甲基汞在大鼠脑组织中的积累情况和对大鼠脑组织的脂质过氧化作用及两者之间可能存在的关系.[方法]将SD大鼠在不同剂量(0,0.05,0.5,5mg/kg)下分别暴露20min和24h.处死后测定脑组织汞含量、谷胱甘肽过氧化物酶(GSH-Px)、超氧化物歧化酶(SOD)活性和丙二醛(MDA)含量.[结果]20min时,0.5mg/kg剂量下脑组织汞含量为(0.0173±0.0230)μg/g,表明甲基汞已到达脑组织;20min时,各剂量下各脂质过氧化指标与对照组相比均未见显著差异.24h时,5mg/kg剂量下,GSH-Px活性为(19.13±4.49)U/mgprot,SOD活性为(89.09±13.55)U/ml,MDA含量为(3.53±0.70)nmol/ml,与对照相比差异显著,表明已有脂质过氧化发生.[结论]甲基汞对脑组织有极大的亲合性,在0.5mg/kg剂量下,20min即可迅速穿过血脑屏障进入脑组织并逐渐积累.脂质过氧化作用是在甲基汞积累到一定程度后发生,可能与组织中汞的含量有一定关系.     

乐果染毒28天对大鼠脑组织及外周血淋巴细胞M受体mRNA水平的影响

目的研究低剂量乐果预处理诱导大鼠产生耐受及再暴露于高剂量乐果时其脑组织与外周血淋巴细胞毒草碱型乙酰胆碱受体(M受体)变化情况，探索耐受产生的机制。方法大鼠分两个阶段染毒：连续28d皮下注射25mg／kg乐果后，分别再给以生理盐水及50、100mg／kg乐果激发。记录大鼠的中毒症状，测其全血乙酰胆碱酯酶(ACHE)活力。激发后24h，测大鼠脑AChE活力和M1、M2受体亚型密度和受体mRNA水平；测大鼠外周血淋巴细胞M3受体mRNA基础水平和诱导水平。结果乐果28d染毒过程中，大鼠全血AChE活力持续下降，第13天达最低，乐果激发染毒使其活力进一步下降；乐果预处理组大鼠脑组织AChE活力远低于对照组，且随激发剂量升高而下降。对照组、25mg／kg乐果预处理组和预处理后50、100mg／kg乐果激发组大鼠脑组织M1受体密度分别为979．15、856．54、539．46、539．14fmoL／mgpro，M1受体mRNA水平相对数值分别为2．59、2．47、2．20和1．81，同M1受体密度变化基本一致，但激发剂量增加，其水平继续下降；M2受体密度分别为507．38、611．11、548．42、337．47fmoL／mgpro，预处理对之影响不明显，但随激发剂量升高，其密度下降，M2受体mRNA水平则变化不明显。这4组外周血淋巴细胞M3受体mRNA基础水平差异不明显，而诱导水平随乐果激发剂量升高而下降。结论低剂量乐果可以诱导动物产生对乐果毒性的耐受，M受体密度的下降是其可能机制。M受体密度的下降可能由其mRNA水平下降引起。外周血淋巴细胞M3受体mRNA的诱导水平同脑组织M1受体mRNA水平一致。     

牛磺酸对急性甲基汞致大鼠脑氧化损伤的影响

目的观察牛磺酸对甲基汞致大鼠脑氧化损伤的影响。方法24只大鼠,分成3组,每组8只。第1组为对照组,第2组单纯染甲基汞组,第3组为牛磺酸预处理组。第1、2组皮下注射0．9％氯化钠溶液,第3组皮下注射2mmol／kg的牛磺酸。2h后,第1组腹腔注射0．9％氯化钠溶液,第2、3组腹腔注射25μmol／kg的氯化甲基汞溶液。染毒后24h处死大鼠,切取大脑皮质,测定大鼠大脑皮质汞含量,谷胱甘肽（GSH）和丙二醛（MDA）含量,谷胱甘肽过氧化物酶（GSH—Px）和超氧化物歧化酶（SOD）活力。结果染甲基汞24h后,与对照组比较,单纯染甲基汞组大鼠大脑皮质汞含量显著升高（P〈0．01）,GSH含量显著降低（P〈0．01）,MDA含量明显升高（P〈0．05）,而GSH—Px和SOD活力均明显下降（P〈0．05）;与单纯染甲基汞组比较,牛磺酸干预组大鼠大脑皮质汞含量差异无统计学意义（P〉0．05）,GSH含量明显升高（P〈0．05）和MDA含量明显下降（P〈0．05）,而GSH—Px活力显著回升（P〈0．01）和SOD活力明显回升（P〈0．05）。结论牛磺酸对急性甲基汞致大鼠脑氧化损伤有一定拮抗作用。     

甲基汞急性暴露下大鼠脑c-fos mRNA表达

目的探讨即刻早期基因c fos在甲基汞神经毒性分子机制中的作用。方法应用RT PCR方法研究大鼠注射甲基汞急性暴露后,中枢神经系统c fosmRNA表达。结果甲基汞在剂量为0.05mg/(kg·d)暴露60min和剂量为0.5mg/(kg·d)暴露20min就能够显著诱导大鼠脑即刻早期基因c fos表达;c fosmRNA表达量与汞的浓度没有明显正比关系。结论甲基汞能够显著诱导大鼠脑c fosmRNA表达,c fosmRNA表达变化在甲基汞神经毒性分子机制中具有重要作用,即刻早期基因c fos参与了甲基汞对中枢神经系统损害的毒性过程。     

牛磺酸对镉致大鼠脑损伤组织中单胺类递质的影响

目的研究牛磺酸对镉致大鼠脑损伤组织中单胺类递质的影响。方法将40只大鼠按体重随机分为4组：正常对照组、模型组、高剂量组、低剂量组,每组10只。除正常对照组外,其余各组每周2次腹腔注射氯化镉（CdCl2）2．0ms／kg,正常对照组每周2次腹腔注射生理盐水（相同体积）。同时,高剂量组、低剂量组每日分别灌胃牛磺酸1000和750mg／kg,正常对照组和模型组每日灌胃蒸馏水。实验持续4周后处死动物,测定脑组织中乙酰胆碱酯酶（AchE）、胆碱乙酰转移酶（ChAT）活力及对脑组织病理形态学进行观察。结果牛磺酸高剂量组脑组织中AchE活力与模型组比较明显降低（P〈0．05）,ChAT活力明显增高（P〈0．05）;脑组织病理形态观察显示,模型对照组出现明显细胞核固缩,神经细胞数目减少,细胞排列层次减少;高剂量组海马神经细胞核固缩明显减少。结论牛磺酸可调节大鼠单胺类神经递质的释放水平,可显著改善镉致大鼠脑组织损伤。     

α-硫辛酸对甲基汞致大鼠脑谷氨酸代谢转运障碍的拮抗作用

[目的]探讨出硫辛酸（alpha—lipoicacid,α-LA）对甲基汞所致大鼠脑谷氨酸代谢转运障碍的拮抗作用。[方法]清洁级Wistar大鼠24只,按体重随机分为4组,分别为对照组,低、高甲基汞染毒组和α-LA干预组,每组6只,雌雄各半。对照组和低、高甲基汞染毒组先皮下注射0．9％氯化钠溶液,α-LA干预组皮下注射35gmol／kgct-LA;2h后,对照组腹腔注射0．9％氯化钠溶液,低、高甲基汞染毒组和α-LA干预组分别腹腔注射氯化甲基汞4、12和12lamol／kg。α-LA预处理隔日1次;染毒组每日1次,每周5次;连续处理4周。最后1次染毒24h后,分离大鼠大脑皮质,制备5％、10％的组织匀浆,测定大脑皮质汞（Hg）、谷氨酸（Glu）、谷氨酰胺（Gin）含量,及谷氨酰胺酶（PAG）、谷氨酰胺合成酶（GS）、Na＋-K＋ATPase、Ca2＋．ATPase活力。[结果]甲基汞高剂量染毒组大鼠脑汞为（17．72±1．36）μg,／g组织、Glu含量为（71．57±10．87）μmol／g白、PAG活力为（31．26±4．38）μmol／（min·g蛋白）,均高于对照组（P〈0．01）;CAn含量及Gs活力分别为（0．155±0．04）μmol／g蛋白及（23．89±3．60）u儋蛋白,Na＋-K＋-ATPase及Ca2＋-ATPase活力分别为（4．03±0．57）μmol／（mg蛋白·h）及（2．21±0．62）μmol／（mgg蛋白·h）,均低于对照组（P〈0．01）;与甲基汞高剂量染毒组比较,α-LA干预组大鼠脑汞含量未见明显变化;Glu含量（63．02±3．33）μmol／g蛋白及PAG活力（26．03±3．88）μmol/（min·g蛋白）均降低（P〈0．01或P〈0．05）,Gin含量（0．20±0．05）μmol／g蛋白、GS活力（34．05士4．23）U／g蛋白、Na＋-K＋-ATPase活力为（5．52±1．16）μmol／（h·mg蛋白）及Ca2＋-ATPase活力为（3．27±0．60）μmol／（h·mg蛋白）,均升高（P〈0．01或P〈0．05）。[结论]a-LA对甲基汞所致大鼠脑谷氨酸代谢紊乱有一定的拮抗作用。     

丙烯腈对大鼠神经行为和脑组织中生化指标的影响

目的探讨丙烯腈(acrylonitrile,ACN)对大鼠的神经行为及脑组织生化指标的影响,为ACN神经毒性的研究提供线索。方法将40只SPF级SD大鼠按体重随机分为4组:3个ACN染毒组(12.5、25、50 mg/kg)、对照组(玉米油)灌胃染毒,1次/d,6天/周,连续13周。末次染毒后,使用Video Track动物行为分析系统对其自主活动度进行检测,同时检测大鼠脑组织中乙酰胆碱酯酶(ACh E)活力、乳酸和葡萄糖含量及血糖含量。结果染毒6周后,高剂量组出现明显流涎。各组之间脑组织脏器系数比较,差异均无统计学意义(P0.05)。大鼠脑组织中ACh E活力低、中、高剂量组与对照组相比降低(P0.05);乳酸含量中、高剂量组与对照组和低剂量组相比降低(P0.05);葡萄糖含量各组间比较,差异均无统计学意义(P0.05)。大鼠血糖含量高剂量组明显低于对照组、低和中剂量组(P0.05)。平面翻正和断崖回避试验中,染毒前和染毒后各组大鼠结果均为阳性。Openfield试验中各组大鼠在每个时间段的运动距离比较,差异均无统计学意义(P0.05)。结论在该试验条件下ACN能够引起脑组织ACh E活力、乳酸含量及血糖含量的变化,但未引起大鼠自主活动功能和活动量的变化。     

急性氯化甲基汞染毒大鼠脑某些抗氧化指标的变化

目的 对SD大鼠经腹腔注射氯化甲基汞(MeH必)的急性染毒方式，观察其对大鼠脑组织和血清某些抗氧化指标的变化。方法 用甲基汞对大鼠染毒24h后，断头处死，取血清和脑组织检测谷胱甘肽过氧化物酶(GSH—Px)和超氧化物歧化酶(SOD)活性及丙二醛(MDA)含量。结果 染毒24h后，5．00mg／kg和10．00mg／kg剂量的大鼠脑组织匀浆和血清中的GSH—Px活性和S0D活性下降，MDA含量上升。结论 甲基汞染毒24h后，GSH—Px和SOD活性下降，MDA含量上升，表明这种作用对MeHgCl引起的神经毒性有一定的敏感性。MeHgCl可使脑组织和血清中某些抗氧化指标发生变化。     

地卓西平马来酸盐和牛磺酸对甲基汞致大鼠脑谷氨酸代谢的影响

目的研究地卓西平马来酸盐(dizocilpine maleate,MK-801)和牛磺酸对大鼠甲基汞中毒所致的谷氨酸代谢紊乱的影响。方法将健康清洁级Wistar大鼠40只按体重随机分为对照组、低剂量甲基汞染毒组、高剂量甲基汞染毒组、MK-801+甲基汞染毒组和牛磺酸+甲基汞染毒组。,每组8只。对照组和低、高剂量甲基汞染毒组皮下注射生理盐水,MK-801+甲基汞染毒组和牛磺酸+甲基汞染毒组分别皮下注射0.3μmol/kgMK-801和1mmol/kg牛磺酸。注射2h后,对照组腹腔注射0.9%生理盐水,低剂量甲基汞染毒组腹腔注射4μmol/kg氯化甲基汞,高剂量甲基汞染毒组、MK-801+甲基汞染毒组和牛磺酸+甲基汞染毒组腹腔注射12μmol/kg氯化甲基汞。连续进行4周,每周5天,每天染毒氯化甲基汞1次,每周一、三、五注射MK-801和牛磺酸。测定各组大鼠大脑皮质汞含量、谷氨酸(Glu)和谷氨酰胺(Gln)含量以及谷氨酰胺合成酶(GS)和谷氨酰胺酶(PAG)活力。结果与对照组比较,高、低剂量甲基汞染毒组和MK-801+甲基汞染毒组、牛磺酸+甲基汞染毒组大鼠大脑皮质中汞含量均升高;高剂量甲基汞染毒组大鼠大脑皮质中Glu含量较高,GS活力较低;高、低剂量甲基汞染毒组大鼠大脑皮质中Gln含量较低,PAG活力较高,差异有统计学意义(P0.01)。与高剂量甲基汞染毒组比较,MK-801+甲基汞染毒组和牛磺酸+甲基汞染毒组大鼠大脑皮质中汞含量无明显差异,Glu含量和PAG活力较低,Gln含量和GS活力较高,差异有统计学意义(P0.01)。结论MK-801和牛磺酸对甲基汞所致大鼠谷氨酸代谢紊乱有一定的拮抗作用。     

Repeated malathion exposure induces behavioral impairment and AChE activity inhibition in brains of rat pups

The present study evaluated if repeated malathion administration would cause behavioral impairment in rat pups. Na⁺ K⁺ ATPase and acetylcholinesterase (AChE) activities were investigated in brains of rat pups. Malathion was administered (100 or 200 mg/kg) orally (p.o.), once a day for four consecutive days. Rat pups were submitted to behavioral tests on the 5th day, 24 h after the last malathion administration. Malathion at the dose of 200 mg/kg caused a significant increase in the negative geotaxis latency and a decrease in the rotarod latency of rat pups. Rat pups exposed to malathion at both doses showed a significant decrease in the forelimb support latency and an inhibition of brain AChE activity. Repeated exposure of rat pups to malathion caused a decrease in motor coordination, vestibular function and muscular strength/coordination. The brain activity of AChE is involved in the behavioral alterations caused by malathion in rat pups.     

Benefit of nanocarrier of magnetic magnesium in rat malathion-induced toxicity and cardiac failure using non-invasive monitoring of electrocardiogram and blood pressure

Medical management in acute organophosphate (OP) poisoning is not always successful because of tissue hypoxia which results in a reduction of heart contractility and cell damage. This study reports improvement of malathion (MAL)-induced cardiac failure by a nanocarrier of magnetic isotope of Mg (PMC16). A rat model of acute MAL poisoning was set up. PMC16 nanoparticle at doses of 0.05, 0.1, 0.2 LD50 = 896 mg/kg) were administered intravenously (iv) 30 minutes after a single intraperitoneal (ip) injection of MAL (0.25 LD50= 207 mg/kg). Atropine (AT; 40 mg/kg, ip) plus pralidoxime (PAM; 40 mg/kg, ip) and magnesium sulfate (MgSO?; 600 mg/kg, iv) were used as standard therapy or controls. Anesthetized animals were monitored for heart rate, electrocardiogram, blood pressure, and blood oxidative stress biomarkers like cellular lipid peroxidation, total thiol molecules, antioxidant power, gamma glutamil transpeptidase, and acetylcholinesterase (AChE) as a marker of OP toxicity. Results indicated that after MAL administration, heart rate and BP decreased and R-R duration increased. PMC16 markedly restored BP at all doses as compared with MgSO?. PMC16 at the dose of 0.05 LD50 significantly increased BP in comparison to AT + PAM. PMC16 restored heart rate at dose of 0.2 LD50 and reduced lipid peroxidation at dose of 0.05 LD50 as compared to MgSO?. PMC16 also improved total antioxidant power at all doses when compared to AT + PAM and reduced GGT activity at dose of 0.2 LD50 but did not affect total thiol molecules. MgSO? could improve MAL-induced reduction of total antioxidant power. After 24 h, PMC16 significantly improved MAL-suppressed AChE activity at doses of 0.05 and 0.1 LD50. PMC16 at all doses significantly recovered MAL-induced arrhythmia when compared to standard therapies. It is concluded that PMC16 is able to control OP-induced cardiac failure and toxicity.     

乐果90 d染毒对大鼠大脑皮质GABA系统的影响

[目的]研究乐果[O,O-二甲基-S-(N-甲基氨基甲酰甲基)二硫化磷酸酯]90d染毒对大鼠大脑皮质γ-氨基丁酸(GABA)系统的影响。[方法]48只健康雄性SD大鼠分成4组,剂量分别为O(生理盐水)、5、10、20mg/kg,灌胃给药,每周染毒5d(次),实验周期90d,每天称重1次,每3天记录动物饲料消耗量,定期测定全血乙酰胆碱酯酶(AChE)活性,实验结束时全部动物断头处死,测定延髓AChE活性,反相高效液相色谱荧光法测定大脑皮质GABA含量,放射性配体受体结合法测定大脑皮质GABA_A受体的活性。[结果]实验期间,各染毒组动物全血AChE活性明显抑制,实验后期有所恢复。实验结束时,低、中、高染毒组延髓AChE活性分别约为对照组的78%、63%、42%。与对照组相比,中、高剂量组大脑皮质GABA含量明显降低(P<0.01);GABA_A受体的最大结合容量(maximum binding capacity,Bmax)低剂量组升高(P<0.05),中剂量组降低(P<0.05);各剂量组GABA_A受体的平衡解离常数(equilibrium dissociation constant,Kd)比对照组均有降低,但仅低、中剂量组差异有统计学意义(P<0.05)。[结论]乐果90d染毒过程中大脑皮质GABA含量、GABA_A受体功能都有所改变,可能参与了乐果慢性中毒过程中的非胆碱能机制。     

Brain microdialysis study of the effects of hazardous chemicals on the central nervous system 2. Toluene exposure and cerebral acetylcholine

The microdialysis technique was applied to detect the changes in the activity of acetylcholine (ACh) neurons in the rat brain. The effects of intraperitoneal (i.p.) injection of toluene on the amount of ACh release from the nerve terminals of the brain cholinergic neurons were investigated in freely moving rats. In the striatum, injection of toluene decreased the extracellular concentration of ACh in a dose dependent manner in the range 200 to 2,000 mg/kg. Similar effects of toluene on ACh release were observed in the hippocampus after i.p. administration. The increases in ACh content in brain homogenate after i.p. injection of toluene seemed to be caused by the decreased release of ACh from cholinergic nerve endings. Injection of toluene at doses higher than 200 mg/kg decreased ACh release and a similar decrease was suggested to occur in 8-h inhalation exposure to toluene at 1,000 ppm or higher concentrations.     

胚胎期暴露于甲基汞大鼠的迷宫测试

为研究胚胎期甲基汞暴露对大鼠迷宫学习与记忆能力的影响 ,用不同剂量甲基汞 [0、0 .0 1、0 .0 5和 2 .0 0 mg/ (kg· d) ]于大鼠孕 6～ 9天连续灌胃染毒 ,仔鼠出生 7周时进行 Y型迷宫测试。学习记忆成绩以平均错误次数、到达安全区平均时间和主动回避率表示。整个实验采用双盲法。结果与对照组相比 ,各暴露组大鼠的平均错误次数和到达安全区平均时间显著增高 ,主动回避率显著降低 (P<0 .0 5或 P<0 .0 1) ;各组大鼠学习记忆能力无性别差异。提示甲基汞可通过胎盘屏障和乳汁进入仔鼠体内 ,影响仔鼠神经系统的发育 ,使其学习记忆能力受到明显损害     

宫内接触氯化甲基汞对发育阶段小鼠学习记忆能力和海马神经元超微结构的影响

目的　研究宫内接触氯化甲基汞对发育阶段小鼠学习记忆能力及海马神经元超微结构的影响.方法　对妊娠7～10天的小鼠每天灌胃给予0和4mg kgbw氯化甲基汞。以出生6周龄仔鼠进行学习记忆能力测试及透射电镜技术观察宫内接触氯化甲基汞对发育阶段小鼠学习记忆能力及海马神经元超微结构的影响。结果　氯化甲基汞暴露组学习记忆能力显著低于对照组(P <0 . 0 5 )。超微结构显示海马神经元细胞膜结构不清,部分核膜消失,核膜皱缩,核孔不清,染色质淡染;线粒体肿胀变大、粗面内质网扩张、空泡变性,核糖体减少;轴突环出现分层;有髓神经纤维脱髓鞘、板状分离。结论　甲基汞可致小鼠学习记忆障碍和海马神经元超微结构改变;宫内接触氯化甲基汞引起海马神经元超微结构的改变与小鼠学习记忆障碍密切相关。     

巴豆醛致雄性大鼠神经毒性作用的研究

目的探讨巴豆醛暴露致雄性大鼠神经毒性作用,分析其可能的作用机制。方法于2019年7至10月,将24只SPF级雄性Wistar大鼠随机分为对照组和2.5、4.5、8.5 mg/kg染毒组,每组6只,分别经口给予0.0、2.5、4.5、8.5 mg/kg体重巴豆醛溶液,每周5次,连续染毒90 d。染毒结束后,测量大鼠体重,麻醉解剖取大鼠大脑组织和肝组织。测定大脑组织乙酰胆碱酯酶(AChE)活力及肝组织乙酰胆碱(ACh)水平;检测大脑组织中超氧化物歧化酶(SOD)、谷胱甘肽过氧化物酶(GSH-Px)活力以及丙二醛(MDA)和还原型谷胱甘肽(GSH)水平;酶联免疫吸附测定(ELISA)法检测大脑组织中白细胞介素6(IL-6)、白细胞介素1β(IL-1β)、肿瘤坏死因子α(TNF-α)水平。结果与对照组比较,2.5、4.5、8.5 mg/kg染毒组大鼠大脑组织中AChE活力明显降低,8.5 mg/kg染毒组大鼠肝组织中ACh水平明显升高,差异均有统计学意义(P<0.05);与对照组比较,4.5、8.5 mg/kg染毒组大鼠大脑组织中MDA水平明显升高,GSH水平和SOD、GSH-Px活力明显降低,差异均有统计学意义(P<0.05);与对照组比较,2.5、4.5、8.5 mg/kg染毒组大鼠大脑组织中TNF-α、IL-6水平明显升高,4.5、8.5 mg/kg染毒组IL-1β水平明显升高,差异均有统计学意义(P<0.05)。结论巴豆醛暴露可致大鼠神经系统损伤,可能与氧化平衡状态改变及上调大脑组织炎性因子表达等作用有关。     

甲醛致扩张性简单串联重复序列突变小鼠子代对四氯化碳和苯暴露易感性研究

目的 探讨甲醛染毒致基因组扩张性简单串联重复序列(ESTR)突变小鼠的子代对外源性化学物的易感性.方法 选择经甲醛染毒小鼠繁殖的有ESTR突变的F1子代小鼠(H组)与对照组小鼠(C组),在洁净环境中饲养传代至F10代.以F5和F10代小鼠分别建立四氯化碳(CCl4)致小鼠肝脏损伤模型(CCl4处理组腹腔注射含有CCl4的橄榄油10 ml/kg,CCl4浓度分别为0.05%、0.50%和5.00%)和苯致小鼠血液毒性模型(腹腔注射苯染毒剂量分别为500、1000 mg/kg).分别测定小鼠血清中丙氨酸转氨酶(ALT)、天冬氨酸转氨酶(AST)活力及肝脏组织中超氧化物歧化酶(SOD)活力、丙二醛(MDA)含量,观察肝脏组织病理学变化以评价肝氧化损伤程度;检测小鼠胸骨骨髓嗜多染红细胞微核率以评价苯的血液毒性.结果 C组F5代0.50%、5.00%CCl4染毒剂量组小鼠血清中ALT、AST活力,F10代3个CCl4染毒剂量组ALT活力和0.50%、5.00%CCl4染毒剂量组AST活力,H组F5、F10代3个CCl4染毒剂量组ALT活力和0.50%、5.00%CCl4染毒剂量组AST活力均明显高于溶剂对照组,差异均有统计学意义(P<0.05,P<0.01).与溶剂对照组比较,C组F5、F10代0.50%、5.00%CCl4染毒剂量组小鼠肝匀浆中SOD活力明显降低,F10代0.50%、5.00%CCl4染毒剂量组小鼠肝匀浆中MDA含量明显升高,差异有统计学意义(P<0.05);H组F5代0.50%、5.00%CCl4染毒剂量组,F10代5.00%CCl4染毒剂量组小鼠肝匀浆中SOD活力明显降低,F5代3个CCl4染毒剂量组,F10代0.50%、5.00%CCl4染毒剂量组小鼠肝匀浆中MDA含量明显升高,差异均有统计学意义(P<0.05).甲醛染毒后基因组ESTR突变的F5代小鼠对CCl4的相对易感性比对照组相应子代明显增加,而F10代小鼠对CCl4的相对易感性明显降低.CCl4染毒后小鼠肝脏细胞坏死和脂肪变性均呈现剂量-效应关系,而且在H组明显较C组严重.C组及H组苯染毒小鼠骨髓细胞微核率(C组500 mg/kg苯染毒组:F5代为5.88‰±4.55‰,F10代为8.25‰±2.06‰;C组1000 mg/kg苯染毒组:F5代为7.50‰±6.99‰,F10代为10.67‰±1.16‰;H组500 mg/kg苯染毒组:F5代为7.88‰±3.09‰,F10代为9.20‰±1.30‰;H组1000 mg/kg苯染毒组:F5代为9.63‰±4.34‰,F10代为13.33‰±2.08‰)随苯剂量的增加而增加,与溶剂对照组(C组F5代为1.13‰±0.35‰,F10代为1.20‰±0.82‰;H组F5代为1.25‰±0.46‰,F10代为1.33‰±1.03‰)的差异均有统计学意义(P<0.05,P<0.01).结论 甲醛暴露引起的基因组ESTR突变可改变子代小鼠对CCl4和苯的易感性.ESTR突变可能是影响机体对化学物易感性的生物学标志,其分子机制有待进一步阐明.

Abstract：

Objective To investigate the susceptibility to carbon tetrachloride and benzene in offspring of expanded simple tandem repeats (ESTR) mutation mice exposed to formaldehyde (FA). Methods F5 and F10 offspring (200 mg/m3 ×2 hours) served as H group and ICR mice were used as control group(group C). The F5 and F10 offspring were exposed to 10 ml/kg carbon tetrachloride at the doses of 0.05%, 0.50% or 5.00% for 24 hours, respectively or 500 or 1000 mg/kg benzene for 24 hours, respectively by intraperitoneal injection. Serum alanine transaminase (ALT), aspartate transaminase (AST) and the hepatic superoxide dismutase (SOD) or malondialdehyde (MDA) were detected; also the hepatic pathological changes were observed under light microscope; the micronucleus in sternum bone marrow cells as the biomarker of benzene blood toxicity were measured. Results ALT and AST activities in group C of F5 mice exposed to 0.50% and 5.00% CCl4, ALT in groups C and H of F10 mice exposed to 0.05%, 0.50%, 5.00% CCl4, AST in groups C and H of F10 mice exposed to 0.50% and 5.00% CCl4 were significantly higher than those in controls, respectively (P<0.05); as compared to the control, hepatic SOD activities in group C of F5 and F10 mice exposed to 0.50% and 5.00% CCl4, in group H of F5 mice exposed to 0.50% and 5.00% CCl4, and F10 mice exposed to 5.00% CCl4 were significantly reduced, respectively (P<0.05); however, MDA contents in group C of F10 mice exposed to 0.50% and 5.00% CCl4, in group H of F5 mice exposed to 0.05% and 0.50%, 5.00% CCl4 and F10 mice exposed to 0.50% and 5.00% CCl4 were significantly increased than those in control group, respectively (P<0.05). The susceptibility to CCl4 in ESTR mutation F5 mice exposed to FA was significantly higher than that in control F5 mice, but the susceptibility to CCl4 in ESTR mutation F10 mice exposed to FA was significantly lower than that in control F10 mice. The histopathological examination showed that the injury of hepatocytes in C and H groups significantly increased CCl4 doses, and the injury of hepatocytes in H group was higher than that in C group. The micronuclear rates in C and H group mice exposed to benzene (500 mg/kg C group, F5 and F10 mice; 1000 mg/kg C group, F5 and F10 mice; 500 mg/kg H group, F5 and F10 mice; 1000 mg/kg C group, F5 and F10 mice) were 5.88‰±4.55‰, 8.25‰±2.06‰, 7.50‰±6.99‰, 10.67‰±1.16‰, 7.88v±3.09‰, 9.20‰±1.30‰, 9.63‰±4.34‰ and 13.33‰±2.08‰, respectively, which were significantly higher than those (1.13‰±0.35‰, 1.20‰±0.82‰, 1.25‰±0.46‰, 1.33‰±1.03‰) in the solvent control group(P<0.05 or P<0.01). Conclusion FA could result in the change of susceptibility to CCl4 and benzene in offspring of ESTR mutation mice. ESTR mutation may be a biomarker of the susceptibility to chemicals, but the molecular mechanisms should be investigated in the future.     

Low-dose pharmacokinetics and oral bioavailability of dichloroacetate in naive and GST-zeta-depleted rats

We studied the pharmacokinetics of dichloroacetate (DCA) in naive rats and rats depleted of glutathione S-transferase-zeta (GST-zeta), at doses approaching human daily exposure levels. We also compared in vitro metabolism of DCA by rat and human liver cytosol. Jugular vein-cannulated male Fischer-344 rats received graded doses of DCA ranging from 0.05 to 20 mg/kg (intravenously or by gavage), and we collected time-course blood samples from the cannulas. GST-zeta activity was depleted by exposing rats to 0.2 g/L DCA in drinking water for 7 days before initiation of pharmacokinetic studies. Elimination of DCA by naive rats was so rapid that only 1-20 mg/kg intravenous and 5 and 20 mg/kg gavage doses provided plasma concentrations above the method detection limit of 6 ng/mL. GST-zeta depletion slowed DCA elimination from plasma, allowing kinetic analysis of doses as low as 0.05 mg/kg. DCA elimination was strongly dose dependent in the naive rats, with total body clearance declining with increasing dose. In the GST-zeta-depleted rats, the pharmacokinetics became linear at doses less than or equal to 1 mg/kg. Virtually all of the dose was eliminated through metabolic clearance; the rate of urinary elimination was < 1 mL/hr/kg. At higher oral doses (less than or equal to 5 mg/kg in GST-zeta-depleted and 20 mg/kg in naive rats), secondary peaks in the plasma concentration appeared long after the completion of the initial absorption phase. Oral bioavailability of DCA was 0-13% in naive and 14-75% in GST-zeta- depleted rats. Oral bioavailability of DCA in humans through consumption of drinking water was predicted to be very low and < 1%. The use of the GST-zeta-depleted rat as a model for assessing the kinetics of DCA in humans is supported by the similarity in pharmacokinetic parameter estimates and rate of in vitro metabolism of DCA by human and GST-zeta-depleted rat liver cytosol.     

THE EFFECTS OF THE NITRIC OXIDE SYNTHASE INHIBITOR 7-NITROINDAZOLE ON ETHANOL PHARMACOKINETICS IN RATS AFTER ACUTE AND CHRONIC ETHANOL ADMINISTRATION

The aim of this work was to study the effects of the nitricoxide synthase (NOS) inhibitors 7-n,troindazole (7-NI) and N^G-nitro-L-arginine(L-NOARG) on the effects and pharmacokinetics of ethanol inrats. Ethanol at a dose of 4 g/kg, i.p. induced sleep in rats(sleep time: 117.2 ± 30.7 min). Administration of theNOS inhibitors 7-NI (20 mg/kg, i.p.) and L-NOARG (20 mg/kg,i.p.) 30 min before ethanol significantly increased the durationof ethanol-induced sleep. L-NOARG also significantly increasedthe toxicity of ethanol as evidenced by increased post-experimentallethality Ethanol at a dose of 2 g/kg (i.p.) did not inducesleep in vehicle-treated rats; however, the combined administrationof ethanol (2 g/kg) and 7-NI at doses of 40, 80, and 120 mg/kgcaused sleep, for 49.4 ± 3.7, 204.0 ± 13.3, and447.5 ± 62.8 min, respectively. L-NOARG (20 mg/kg) hadno effect on ethanol concentrations in blood after acute ethanoladministration (4 g/kg). 7-NI in lower doses (20 and 40 mg/kg)had no effect and in higher doses (80 and 120 mg/kg) significantlyslowed ethanol clearance during the 12 h after ethanol administration.The effect of 7-NI (20 mg/kg) on ethanol pharmacokinetics afterchronic ethanol administration (inhalation for 18 days) wasalso studied. The administration of 7-NI immediately after theend of ethanol exposure had a pronounced effect on ethanol pharmacokinetics;in 7-NI-treated rats the fall in ethanol concentrations wassignificantly slower as compared with vehicle-treated rats.In 7-NI- treated rats, blood-ethanol levels were higher at 3,6, 9, and 12 h after the end of ethanol exposure.