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ABSTRACT: Epidemiological investigations have indicated that aluminum (Al), as an important environmental neurotoxicant, could cause damage to the cognitive function which was closely related with neurodegenerative diseases. Long-term potentiation (LTP) is one form of synaptic plasticity in association with cognitive function. Previous studies have demonstrated that Al impaired early phase long-term potentiation (E-LTP) in vivo and in vitro. However, Al-induced damage to late phase long-term potentiation (L-LTP) has poorly been studied. The present study was designed to observe the effects of subchronic Al exposure on the spatial memory, hippocampus ultrastructure and L-LTP in rats. Pregnant Wistar rats were assigned to four groups. Neonatal rats were exposed to Al by parental lactation from parturition to weaning for 3 weeks and then fed with the distilled water containing 0, 0.2%, 0.4% and 0.6% aluminum chloride (AlCl3) respectively from weaning to postnatal 3 months. The levels of Al in blood and hippocampus were quantitated by atomic absorption spectrophotometer. Morris water maze test was performed to study spatial memory. The induction and maintenance of L-LTP in area of Schaffer collateral- CA1 synapse was recorded by extracellular microelectrode recording technology in hippocampus of experimental rats. Hippocampus was collected for transmission electron microscopy observation. The results showed that the Al concentrations in blood and hippocampus of Al-exposed rats were higher than those of the control rats. Al could impair spatial memory ability of rats. Neuronal and synaptic ultrastructure from Al-exposed rats presented pathological changes; the incidence of L-LTP has a decrease trend while population spike (PS) amplitude was much smaller significantly stimulated by high-frequency stimulation (HFS) in Al-exposed rats. Our findings showed that Al exposure caused spatial memory damage, under which the neuronal and synaptic ultrastructure changes maybe were their morphological basis and the impaired L-LTP of hippocampus could be their electrophysiological basis.
The Journal of Toxicological Sciences 01/2013; 38(2):255-268. · 1.52 Impact Factor
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Xiaobo Lu,
Yanhua Liu,
Tao Yu,
Sha Xiao,
Xiaoyan Bao,
Liang Pan,
Guolian Zhu,
Yuan Cai,
Qiufang Liu, Cuihong Jin,
Jinghua Yang,
Shengwen Wu,
Li An,
Tahar van der Straaten
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ABSTRACT: Benzo[a]pyrene(B[a]P), and its ultimate metabolite Benzo[a]pyrene 7,8-diol 9,10-epoxide (BPDE), are classic DNA damaging carcinogens. DNA damage caused by BPDE is normally repaired by Nucleotide Excision Repair (NER), of which ERCC1 and ERCC2/XPD exert an indispensable role. Genetic variations in ERCC1 and ERCC2 have been related to DNA repair efficiency. In this study we used lymphocytes from healthy individuals to show that polymorphisms in ERCC1 and ERCC2 are directly associated with decreased DNA repair efficiency.
ERCC1 (rs3212986 and rs11615) and ERCC2 (rs13181, rs1799793 and rs238406) were genotyped in 818 healthy Han individuals from the northeast of China. BPDE induced DNA adducts in lymphocytes were assessed by high performance liquid chromatography (HPLC) in 282 randomly selected participants. The effect of ERCC1 rs3212986 and ERCC2 rs238406 on DNA damage caused by B[a]P was assessed with a modified comet assay.
We found that the variant genotypes of ERCC1 rs3212986 and ERCC2 rs238406 were associated with the high levels of BPDE-DNA adducts. Especially ERCC1 rs3212986 A-allele variant was significantly associated with the high BPDE-DNA adducts. Haplotype analysis showed that the ERCC1 haplotype AC (OR = 2.36, 95% CI = 1.84-2.97), ERCC2 haplotype AGA (OR = 1.51, 95% CI = 1.06-2.15) and haplotype block AGAAC (OR = 5.28, 95% CI = 2.95-9.43), AGCAC (OR = 1.35 95% CI = 1.13-1.60) were linked with high BPDE-DNA adducts. In addition, we found that the combined minor alleles of ERCC1 rs3212986 and ERCC2 rs238406 were associated with a reduced DNA repair capacity.
Our results suggest that the variant genotypes of ERCC1 rs3212986 and ERCC2 rs238406 are associated with decreased repair efficiency of BPDE induced DNA damage, and may be predictive for an individual's DNA repair capacity in response to environmental carcinogens.
PLoS ONE 01/2013; 8(4):e60006. · 4.09 Impact Factor
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ABSTRACT: To evaluate the association between DNA damage repair capacity induced by environment carcinogen benzo[a] pyrene (B [a] P) and ERCC2/XPD single nucleotide polymorphisms(SNP).
8 ml peripheral bloods of 282 healthy ethnic Han people from Liao-ning province were collected, isolated lymphocytes and extracted DNA. The genotypes of ERCC2/XPD Lys751 Gln (rs13181), Asp312Asn (rs1799793), Arg156Arg (rs238406) were detected by Taqman real time PCR; BPDE-DNA adduct in vitro induced by B[a]P and S9 mixture in lymphocyte were detected by high performance liquid chromatography (HPLC).
The BPDE-DNA adduct levels of ERCC2/XPD Arg156Arg AA genotype were significantly higher than CC genotype. Compared with < or = 30 years, people at age of 50 - 70 years and > or = 70 years have higher BPDE-DNA adduct level (P < 0.05). Multiple covariates analysis showed SNP of ERCC2/XPD Arg156Arg (rs238406) and age have been related to BPDE-DNA adduct levels closely among all covariates (P < 0.05).
ERCC2/XPD Arg156Arg rs238406 polymorphisms may be associated with DNA repair capacity in excising BPDE-DNA adduct and A allele may increase the risks of cancer susceptibility.
Wei sheng yan jiu = Journal of hygiene research 01/2013; 42(1):49-54.
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Tao Yu,
Yanhua Liu,
Xiaobo Lu,
Sha Xiao,
Yuan Cai, Cuihong Jin,
Qiufang Liu,
Jinghua Yang,
Shengwen Wu,
Xiaoyan Bao,
Liang Pan,
Tahar van der Straaten
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ABSTRACT: Benzo[a]pyrene-7,8-dihydrodiol-9,10-epoxide (BPDE), a metabolite of Benzo[a]pyrene (B[a]P), is a high-risk factor for development of a number of cancers. DNA damage caused by BPDE is normally repaired by Nucleotide Excision Repair system of which ERCC1 exerts an important role. We investigated whether two single nucleotide polymorphisms in ERCC1 (C19007T; rs11615 and C8092A; rs3213986) affected the repair efficacy of BPDE-DNA adducts. We collected peripheral blood of 780 healthy individuals from the northeast of China and detected the genotypes of rs11615 and rs3213986. The amount of induced BPDE-DNA adducts in lymphocytes from 117 randomly selected participants was assessed by HPLC. Presence of BPDE-DNA adducts in nucleus of lymphocytes was visualized using the modified comet assay. ERCC1 and CAST (3' adjacent gene of ERCC1) mRNA expression levels were quantified after in vitro exposure to BPDE. We found that the minor A allele in rs3212986 was related to higher levels of BPDE-DNA adducts and holistic marking DNA damage (P < 0.01). Haplotype CA (rs11615 and rs3213986) was also associated with an elevated risk of high BPDE-DNA adduct levels (OR = 1.801, 95 % CI of OR 1.191-2.724). Interestingly, in participants with AA genotype for rs3213986, CAST mRNA level was decreased compared to individuals with the homozygous CC genotype. Our findings suggests that ERCC1 C8092A (rs3213986) is associated with a diminished capacity of repairing BPDE-DNA adducts and may be used as a valid biomarker to predict an individual's risk to develop cancer upon exposure to environmental carcinogens.
Archive für Toxikologie 12/2012; · 4.67 Impact Factor
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ABSTRACT: DNA damage induced by benzene and its metabolites is thought of as an important mechanism underlying benzene genotoxicity in chronic benzene poisoning (CBP). Therefore, genetic variation in DNA repair genes may contribute to susceptibility to CBP in the exposed population. Since benzene-induced DNA damages include DNA adducts, we hypothesized that the polymorphisms of ERCC1 (Excision repair cross complementation group 1) and ERCC2/XPD (Excision repair cross complementation group 2/xeroderma pigmentosum group D) are associated with the risk of CBP. A case-control study involving 102 benzene-poisoned patients and 204 none-benzene-poisoned controls occupationally exposed to benzene was carried out in the Northeast region of China. The polymorphisms of codon 118 (rs11615) and C8092A (rs3212986) of ERCC1, codon 751 (rs13181), 312 (rs1799793) and 156 (rs238406) of ERCC2/XPD were genotyped by TaqMan® Real-time PCR. The results showed that individuals carrying the ERCC1 codon 118 TT genotype had an increased risk of CBP (OR(adj)=3.390; 95%CI: 1.393∼8.253; P=0.007) comparing with its CC genotype. After stratified by smoking, gender and exposure duration we found that the increased risk of CBP associated with the ERCC1 codon 118 TT genotype confined to nonsmokers (OR=3.214; 95% CI: 1.359∼7.601; P=0.006), female (OR=3.049; 95% CI: 1.235∼7.529; P=0.013) and exposure duration> 12 years (OR=3.750; 95% CI: 1.041∼13.513; P=0.035). Since ERCC1 and ERCC2/XPD are both located on chromosome 19q13.3, haplotype analysis of all 5 SNPs was also conducted. However no correlations between the risks of CBP and other genotypes or haplotypes were found. Therefore, our findings suggest an important role of ERCC1 codon 118 polymorphisms for a biomarker to CBP in the Chinese occupational population.
Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis 11/2012; · 2.85 Impact Factor
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ABSTRACT: Oxidative stress and apoptosis facilitation in the developing central nervous system (CNS) have been inferred as two mechanisms related to lead's neurotoxicity, and excessive reactive oxygen species (ROS) can promote oxidative stress and apoptosis facilitation. Few studies systematically investigated the potential relationship among oxidative stress, ROS generation, and apoptosis facilitation after lead exposure in earlier life as a whole. To better understand the adverse effect on the developing central nervous system (CNS) after lead exposure during pregnancy and lactation, the indexes of oxidative stress, apoptosis status, and Bax and Bcl-2 expression of offspring rats' hippocampus were determined. Pregnant rats were randomly divided into four groups and given free access to drinking water which contained 0 %, 0.05 %, 0.1 %, and 0.2 % Pb(AC)(2) respectively from gestation day 0 to postnatal day 21 (PND21). Results showed that ROS and malondialdehyde level of either PND7 or PND21 pups' hippocampus were significantly raised; reduced glutathione level and superoxide dismutase activity were obviously decreased following the increase of blood and brain lead level. Similar to apoptotic indexes, Bax/Bcl-2 ratio increased after 0.1 % and 0.2 % Pb(AC)(2) exposure, especially for the pups on PND7. Comparing with cortex, the hippocampus seemed much more sensitive to damage induced by lead. We concluded that the disruption of pro-oxidant and antioxidant balance and apoptosis facilitation could be associated with the mechanisms of neurotoxicity after lead exposure in earlier life.
Biological trace element research 10/2012; · 1.92 Impact Factor
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ABSTRACT: Chemical-induced bystander effects have been known for several years, but the underlying mechanism is still seldom investigated. Previous researchers have found that mitomycin C and phleomycin induced micronuclei in bystander cells the same as in exposed cells. We previously demonstrated the ability of actinomycin D (ACTD) to induce bystander effects in normal Chinese hamster fibroblast V79 cells and found that conditioned medium (CM) obtained from ACTD-exposed apoptotic cells induced apoptosis in bystander cells. The present study further explores the probable mechanism of apoptosis in bystander cells. The main findings of this study are: (1) ACTD-treated CM induced apoptosis in bystander cells in a time-dependent manner, which was confirmed with morphological changes. (2) ACTD-treated CM increased the mRNA and protein levels of pro-apoptotic p53 and Bax, whereas it decreased those of anti-apoptotic Bcl-2 in bystander cells; these were all time-dependent effects. Reactive oxygen species (ROS) were also involved in apoptosis of bystander cells. (3) ACTD-treated CM reduced mitochondria membrane potential and induced cytochrome c release. (4) ACTD-treated CM induced G1 cell phase arrest, which may be another response in bystander cells when cultured with CM. These results suggest that chemical-treated CM induces p53-Bcl-2/Bax-cytochrome c signaling (i.e., mitochondria pathway)-dependent apoptosis in bystander cells, which is a kinetic response.
Toxicology Letters 03/2012; 211(1):45-53. · 3.23 Impact Factor
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ABSTRACT: Bystander effect (BE) can be induced by ionizing radiation and chemicals, including alkylating agents. Ionizing radiation mostly induces the bystander effect by causing double-strand DNA breakage in the exposed cells. However, the chemical-induced bystander effect is poorly studied. Here we chose actinomycin D (ACTD), a genotoxic chemotherapeutic drug, to investigate whether it could cause bystander effect in Chinese hamster V79 cells. Results are that (1) ACTD induced apoptosis in V79 cells and an optimal apoptosis model in V79 cells was established with ACTD (4 mg/L, 1h); (2) using apoptosis rate, chromosome aberration, and ultrastructure changes as endpoints of bystander effect, ACTD could induce bystander effect in V79 cells; (3) as in the exposed cells, ACTD mainly induced apoptosis in bystander V79 cells cultured in different period conditioned medium; (4) the strongest bystander effect was induced by 4 h conditioned medium collected from cells treated with ACTD. It suggests that ACTD could cause BE through the medium soluble factors excreted from exposed cells during apoptosis and ACTD-induced BE was a novel quantitative and kinetic response.
Toxicology Letters 02/2011; 202(3):178-85. · 3.23 Impact Factor
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ABSTRACT: To study the effect of DEHP on testis development and the related gene expression in prepubertal male rats after 28 days exposure in order to explore the mechanism of genital toxicity.
The prepubertal Wistar rats were lavaged consecutively for 28 days with the DEHP dose of 10,100 and 1000 mg x kg(-1) x d(-1). The change of body weight and status were observed dynamically. After decapitation 28 days later,the organ coefficient of testis was measured. Meanwhile the morphological changes of testis and epididymis were observed by HE staining under optical microscopes. The total RNA of testis was extracted and cDNA synthesis was followed as the manual instruction of RT-PCR kit. The effect of DEHP on gene expression of StAR, CYP19a1 and CYP11a1 was compared to each other in different DEHP group.
The body weight growth of rats in 1000 mg/kg DEHP group was restricted compared with the control (F = 3. 54, P < 0.05). Both the weight and the organ coefficient of testis were also degraded, and there were statistical significance between the 1000 mg/kg DEHP group and the control (F = 105.545, P < 0.05). The serious morphological changes of testis and epididymis were shown in 100, 1000 mg/kg DEHP group. In addition, the distinct difference in the gene expression of StAR wasn't shown in the study. On the other hand, CYP19a1 and CYP11a1 showed significant changes compared with the control due to the DEHP treatment.
DEHP could influence the expression of aromatized enzyme such as CYP19a1 and CYP11a1, and then induce genital toxicity in male rats during the developmental phase.
Wei sheng yan jiu = Journal of hygiene research 05/2010; 39(3):263-7.
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ABSTRACT: To explore the effect of aluminium on neural behavior and the expressions of apoptosis genes in weaning rats in order to make out the mechanism of damage of CNS development.
Weaning Wistar rats were randomly divided into three groups. Aluminium chloride was administrated by water at the doses of 0.2%, 0.4% (m/v) for 12 weeks. Aluminium concentrations in blood were determined by atomic absorption spectrophotometry. Platform experiment was used to detect the activities of neural behavior including learning and memory. Evaluation of apoptosis parameters in hippocampus Fas and Bcl-2 protein expressions were estimated by an immunohistochemical study. Light microscope was used to observe the morphological changes of hippocampus through HE and nissle stain.
The brain coefficient in high-dose exposed group was remarkably lower than the control group. The blood aluminium and brain aluminium concentrations increased significantly with the increase of doses (P < 0.05, P < 0.01). The incubation shortened and mistake times increased significantly related with the dose of aluminium (P < 0.01). The decreases of expression of Bcl-2 protein and the increases of expression of Fas protein in hippocampus were related with the doses of aluminium (P < 0.01). Changes of the morphological structure of hippocampus under light microscope were not found in exposed groups.
Aluminium could influence the activities of learning and memory and could reduce the expression of Bcl-2 and promote the expression of Fas.
Wei sheng yan jiu = Journal of hygiene research 01/2009; 38(1):1-3.
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ABSTRACT: To compare the changes of oxidative damage in rats inhaled by nano-sized and micro-sized silicon dioxide.
36 male rats were randomly divided into two control groups and four experimental groups which was inhaled by nano-sized and micro-sized silicon dioxide respectively at the concentration of 300 mg/m3 for 2 hours and the activities of SOD, CAT and GSH-Px and the contents of H2O2, GSH and MDA of the liver, kidney, brain were determinated 24h and 48h after inhalation.
The contents of H2O2 in all organs in nano-sized groups increased significantly while increased in micro-size groups only in liver and kidney at 24h and in brain at 48h. On the contrary, the activities of CAT in nano-sized group were lower than those in micro-sized group. Superoxide anion contents increased only in the brain of nano-sized group. The activities of SOD decreased significantly in nano-sized groups in kidney at 24h and brain but not in micro-sized groups. The content of GSH decreased only in liver at 24h. The activities of GSH-PX decreased significantly in nano-sized compared with control group and were lower significantly in brain than those in micro-sized group. The contents of MDA increased in all nano-sized groups but only in liver and brain in micro-sized group. The total anti-oxygen activities decreased in all nano-sized groups, but only in kidney at 24h and brain in micro-sized group, especially more significantly in brain at 48h in nano-sized than micro-sized group. While the activity in kidney in nano-sized group increased at 48h comparing to at 24h.
Nano-sized silicon dioxide could induce oxidative damage more easily than micro-sized silicon dioxide. Through comparing different interval, it was found that the degree of oxidative damage at 48h after inhalation inferior to that at 24h after inhalation, which could be associated with the repair of the body against the oxidative damage.
Wei sheng yan jiu = Journal of hygiene research 02/2008; 37(1):16-8, 36.
