Publications by authors named "Shengwen Wu"

47 Publications

Benzo[a]pyrene diol epoxide-induced transformed cells identify the significance of hsa_circ_0051488, a ERCC1-derived circular RNA in pulmonary squamous cell carcinoma.

Mol Carcinog 2021 10 28;60(10):684-701. Epub 2021 Jul 28.

Department of Toxicology, School of Public Health, China Medical University, Shenyang, Liaoning, China.

ERCC1 is a gene for repairing DNA damage whose function is related to carcinogenic-induced tumorigenesis and the effectiveness of platinum therapies. Circular RNAs (circRNAs) are products of posttranscriptional regulation with pleiotropic effects on the pathogenesis of lung cancer. We aim to identify that specific circRNAs derived from ERCC1 can regulate key biological processes involved in the development of lung cancer. We performed bioinformatics analysis, in vitro experiments, and analyzed clinical samples, to determine the biological features of a certain ERCC1-derived circRNA termed as hsa_circ_0051488 in benzo[a]pyrene diol epoxide-induced malignant transformed cell and lung cancer cell. The well-established model of transformed cells provided an ideal platform for analyzing the molecular characteristics of this circRNA in the malignant transformation of lung epithelial cell, which supports that hsa_circ_0051488 functions in the onset and growth of lung squamous cell carcinoma (LUSC). Further analysis indicates that the absence of hsa_circ_0051488 promoted the proliferation of cells with the malignant phenotype. Extensive experiments confirm that hsa_circ_0051488 is present in the cytoplasm and functioned as a competing endogenous RNA. In particular, hsa_circ_0051488 binds to mir-6717-5p, thereby modulating the expression of SATB2 gene, a lung cancer suppressor. Furthermore, our in silico experiments indicate that SATB2 can inhibit multiple tumor pathways and its expression positively correlated with the tumor suppressor gene CRMP1. These findings suggest a possible regulatory mechanism of hsa_circ_0051488 in LUSC, and that the newly discovered hsa_circ_0051488/miR-6717-5p/SATB2 axis may be a potential route for therapeutic intervention of LUSC.
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http://dx.doi.org/10.1002/mc.23335DOI Listing
October 2021

Co-exposure to BPA and DEHP enhances susceptibility of mammary tumors via up-regulating Esr1/HDAC6 pathway in female rats.

Ecotoxicol Environ Saf 2021 Sep 26;221:112453. Epub 2021 Jun 26.

Department of Toxicology, School of Public Health, China Medical University, No. 77 Puhe Road, Shenyang North New District, Shenyang 110122, Liaoning Province, PR China. Electronic address:

Breast cancer (BrCa) as one of the major malignancies threatening women's health worldwide occurs due to the genetic and environmental interactions. Epidemiological studies have suggested that exposure to endocrine disrupting chemicals (EDCs) can elevate the risk of breast cancer. Di-(2-ethylhexyl)-phthalate (DEHP) and bisphenol A (BPA) are known as two typical EDCs. Although several studies have implied that there appear to have adverse effects of exposure to BPA or DEHP alone on breast development, no study to date has demonstrated the exact toxic effect of combined exposure to DEHP and BPA on breast tumorigenesis. In the present study, we performed an in vivo experiment including 160 female Sprague-Dawley (SD) rats, in which 80 rats were randomly allocated to 4 groups including control group given to normal diet, DEHP (150 mg/kg body weight/day), BPA (20 mg/kg body weight/day), and DEHP (150 mg/kg body weight/day) combined with BPA (20 mg/kg body weight/day) by gavage for 30 weeks. Additionally, a DEN/MNU/DHPN (DMD)-induced carcinogenesis animal model was also established to assess their effect on tumor promotion. Namely, the other 80 SD rats were separated into another 4 groups: in addition to DMD initiation each group treated with vehicle, DEHP, BPA and the combination of BPA and DEHP respectively. Our data demonstrated that BPA alone or in combination with DEHP may induce hyperplasia of mammary glands, including the proliferation of ductal epithelial cells and an increase in the number of lobules and acinus after a 30-week exposure. Notably, co-exposure to DEHP and BPA increased the incidence and reduced the latency of mammary tumor, which seemed to enhance the susceptibility of carcinogens-induced tumor. Mechanistically, our results supported the hypothesis that exposure to BPA and DEHP might promote breast cancer dependent on Esr1 and HDAC6 as pivotal factors, and further lead to the activation of oncogene c-Myc. Our study suggested that BPA combined with DEHP facilitate the occurrence of mammary tumors, which contributed to advance our understanding in the complex effects of compound exposure to endocrine disrupting chemicals.
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http://dx.doi.org/10.1016/j.ecoenv.2021.112453DOI Listing
September 2021

Lanthanum chloride causes blood-brain barrier disruption through intracellular calcium-mediated RhoA/Rho kinase signaling and myosin light chain kinase.

Metallomics 2020 12;12(12):2075-2083

Department of Occupational and Environmental Health, School of Public Health, Jinzhou Medical University, #40 Section Three Songpo Road, Jinzhou 121001, P. R. China.

Rare earth elements (REEs) have caused bioaccumulation and adverse health effects attributed to extensive application. The penetrability of REEs across the blood-brain barrier (BBB) contributes to their neurotoxicity process, but potential mechanisms affecting BBB integrity are still obscure. The present study was designed to investigate the effects of lanthanum on BBB adheren junctions and the actin cytoskeleton in vitro using bEnd.3 cells. After lanthanum chloride (LaCl3, 0.125, 0.25 and 0.5 mM) treatment, cytotoxicity against bEnd.3 cells was observed accompanied by increased intracellular Ca2+. Higher paracellular permeability presented as decreased TEER (transendothelial electrical resistance) and increased HRP (horse radish peroxidase) permeation, and simultaneously reduced VE-cadherin expression and F-actin stress fiber formation caused by LaCl3 were reversed by inhibition of ROCK (Rho-kinase) and MLCK (myosin light chain kinase) using inhibitor Y27632 (10 μM) and ML-7 (10 μM). Moreover, chelating overloaded intracellular Ca2+ by BAPTA-AM (25 μM) remarkably abrogated RhoA/ROCK and MLCK activation and downstream phosphorylation of MYPT1 (myosin phosphatase target subunit 1) and MLC2 (myosin light chain 2), therefore alleviating LaCl3-induced BBB disruption and dysfunction. In conclusion, this study indicated that lanthanum caused endothelial barrier hyperpermeability accompanied by loss of VE-cadherin and rearrangement of the actin cytoskeleton though intracellular Ca2+-mediated RhoA/ROCK and MLCK pathways.
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http://dx.doi.org/10.1039/d0mt00187bDOI Listing
December 2020

Lanthanum chloride impairs spatial learning and memory by inducing [Ca] overload, mitochondrial fission-fusion disorder and excessive mitophagy in hippocampal nerve cells of rats.

Metallomics 2020 04 12;12(4):592-606. Epub 2020 Mar 12.

Department of Toxicology, School of Public Health, China Medical University, No. 77 Puhe road, Shenyang North New Area, Shenyang 110112, Liaoning Province, People's Republic of China.

Lanthanum (La) is a kind of rare earth element (REE) widely found in nature. La has neurotoxicity and can impair learning and memory, but the underlying mechanism is still not completely clear. The mitochondrial calcium uniporter (MCU) complex can cause the uptake of cytoplasmic calcium ([Ca]) into mitochondria and thereby resist [Ca] overload. However, the abnormal increase of calcium in the mitochondrial matrix ([Ca]) can also disturb the mitochondrial fission-fusion balance, and then induce excessive mitophagy, and disrupt mitochondrial quality control (MQC). It is unclear whether La can interfere with the function of nerve cells through the above-mentioned mechanism and thus impair learning and memory. In this study, four groups of Wistar rats were treated with 0%, 0.25%, 0.5% and 1.0% (w/v) lanthanum chloride (LaCl) from the embryonic phase to 1 month after weaning. The results showed that La could impair the spatial learning and memory of rats, promote the uptake of [Ca] by MCU, induce the abnormal increase of [Ca], up-regulate p-Drp1 Ser616 expression and inhibit Mfn1/2 expression, enhance mitochondrial fission and lead to mitochondrial fission-fusion disturbance in hippocampal nerve cells. Meanwhile, La could also activate the PINK1-Parkin signaling pathway, up-regulate LC3B-II expression and decrease p62 expression, and thereby induce excessive mitophagy. These results suggested that learning and memory impairment caused by La may be related to MQC disturbance. The present data provide some novel clues for elucidating the neurotoxic effect mechanism of La.
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http://dx.doi.org/10.1039/c9mt00291jDOI Listing
April 2020

Association of T Stage and Serum CEA Levels in Determining Survival of Rectal Cancer.

Front Med (Lausanne) 2019 10;6:270. Epub 2020 Jan 10.

Department of Medical Oncology, The Affiliated Jianhu Hospital of Nantong University, Jianhu People's Hospital, Jianhu, China.

To investigate the association of T stage and serum carcinoembryonic antigen (CEA) levels in determining oncologic outcomes of rectal cancer. Patients diagnosed with stage I-II rectal cancer patients were identified from the Surveillance, Epidemiology, and End Results database. In stage T1N0M0 disease, elevated level of serum CEA (C1) was associated with 227.6% increased risk of mortality compared to normal level of serum CEA (C0; hazard ratio = 3.276, 95% confidence interval = 2.781-3.858, < 0.001). Stage T1N0M0 rectal cancer, when involved in preoperative serum CEA elevation, may be a surrogate of biologically aggressive disease and correlate with unfavorable oncologic outcomes. Moreover, this subgroup of rectal cancer deserves more clinical attention of oncologists.
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http://dx.doi.org/10.3389/fmed.2019.00270DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6965058PMC
January 2020

Lanthanum Chloride Impairs Learning and Memory and Induces Dendritic Spine Abnormality by Down-Regulating Rac1/PAK Signaling Pathway in Hippocampus of Offspring Rats.

Cell Mol Neurobiol 2020 Apr 27;40(3):459-475. Epub 2019 Nov 27.

Department of Toxicology, School of Public Health, China Medical University, NO.77 Puhe Road, Shenyang North New Area, Shenyang, 110122, Liaoning, People's Republic of China.

Lanthanum (La) is a natural rare earth element. It has neurotoxic effects which can impair learning and memory in humans. However, its mechanism of neurotoxicity is unclear. Learning and memory are coordinated by dendritic spines which form tiny protruding structures on the dendritic branches of neurons. This study investigated the effect of LaCl exposure to pregnant and lactating rats on the offspring rats' learning and memory ability. In this study, rats were divided into 4 groups and given distilled water solution containing 0%, 0.125%, 0.25%, 0.5% LaCl, respectively, and this was done from conception to the end of the location. The effects of LaCl on spatial learning and memory ability in offspring rats and in the development of dendritic spines in CA1 pyramidal cells were investigated. The results showed that LaCl impaired spatial learning and memory ability in offspring rats, and decreased dendritic spine density during development. In addition, LaCl can affect the expression of CaMKII, miRNA132, p250GAP, Tiam1, PARD3, and down-regulated the activation of Rac1 which led to a decrease in the expression of Rac1/PAK signaling pathway and downstream regulatory proteins Cortactin and actin-related protein 2/3 complex (Arp2/3 complex). This study indicated that the learning and memory impairment and the decrease of dendritic spine density in the offspring of LaCl exposure may be related to the down-regulation of the Rac1/PAK signaling pathway regulated by Tiam1 and p250GAP.
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http://dx.doi.org/10.1007/s10571-019-00748-7DOI Listing
April 2020

Activation of Nrf2 by lead sulfide nanoparticles induces impairment of learning and memory.

Metallomics 2020 01;12(1):34-41

Department of Toxicology, School of Public Health, China Medical University, Shenyang 110001, China.

Lead sulfide nanoparticles (PbS NPs) are semiconductor materials that have been widely applied to light-emitting diodes (LEDs), biological fluorescent probes, infrared detection, solar receivers, ion-selective electrodes, and ion-sensitive materials. However, the effects of PbS NPs on the central nervous system are still unclear. Thus, this study aimed to determine, using rats, the mechanism of action of PbS NPs, exposure to which results in persistent alterations in nervous system function. The results of the Morris water maze test showed that PbS NPs significantly impaired learning and memory. Compared with that in the control group, the lead content in the hippocampal tissue was significantly elevated after PbS NP exposure. Exposure to PbS NPs led to increased oxidative damage in blood and hippocampal tissues, and significantly inhibited the activities of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and catalase (CAT) while increasing the serum malondialdehyde (MDA) content. In addition, reactive oxygen species triggered the activation of Nrf2 and the antioxidant system, including HO-1, r-GCS, and GSH-Px. Moreover, we observed significant apoptosis in the hippocampi of the rats using the TUNEL assay and transmission electron microscopy. The MOD values from the TUNEL assay of the hippocampi were all significantly higher than those of the control group, which increased as the concentration of the PbS NPs increased. There were also changes in the ultrastructure of the hippocampal neurons and synapses in the PbS-treated rats, including a shorter synaptic active zone, smaller curvature of the synaptic interface, and thicker postsynaptic density. Therefore, PbS NP exposure could lead to increased brain lead content, oxidative damage, and apoptosis.
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http://dx.doi.org/10.1039/c9mt00151dDOI Listing
January 2020

AC138128.1 an Intronic lncRNA originating from ERCC1 Implies a Potential Application in Lung Cancer Treatment.

J Cancer 2019 9;10(16):3608-3617. Epub 2019 Jun 9.

Dept. of Toxicology, School of Public Health, China Medical University, Shenyang, P.R. China.

Lung cancer is one of the most devastating tumors with a high incidence and mortality worldwide. Polymorphisms and expression of commonly predicted the occurrence and prognosis of lung cancer. However, few studies have focused on long non-coding RNAs related to though some studies reminded the importance of its post-transcriptional regulation. In the present study, an intronic lncRNA AC138128.1 originated from was firstly identified in microarray chip and database, and its possibility as a novel biomarker to predict lung cancer treatment was further discussed. Firstly, the qRT-PCR data showed that AC138128.1 expression was much lower in lung cancer comparing with its para-cancer tissues, which further analyzed by ROC curve. Similarly, the difference was also verified in 16HBE, A549 and LK cells. Then AC138128.1 expression was found to have an increasing trend in a dose or time-dependent manner after cisplatin treatment. Finally, the subcellular distribution of AC138128.1 reminded that AC138128.1 was mainly expressed in the nucleus. Interestingly a positive relationship between AC138128.1 and expression was only found in cancer tissues, which reminded AC138128.1 may be involved in the regulation of ERCC1. Therefore, as a preliminary exploration of the lncRNA originated from , the present study suggested AC138128.1 is of potential value in predicting platinum analogue benefit in lung cancer.
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http://dx.doi.org/10.7150/jca.31832DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6636308PMC
June 2019

Epidemic Situation of Brucellosis in Jinzhou City of China and Prediction Using the ARIMA Model.

Can J Infect Dis Med Microbiol 2019 13;2019:1429462. Epub 2019 Jun 13.

Department of Toxicology, School of Public Health, China Medical University, Shenyang 110122, China.

Objective: This study aimed to investigate the specific epidemiological characteristics and epidemic situation of brucellosis in Jinzhou City of China so as to establish a suitable prediction model potentially applied as a decision-supportive tool for reasonably assigning health interventions and health delivery.

Methods: Monthly morbidity data from 2004 to 2013 were selected to construct the autoregressive integrated moving average (ARIMA) model using SPSS 13.0 software. Moreover, stability analysis and sequence tranquilization, model recognition, parameter test, and model diagnostic were also carried out. Finally, the fitting and prediction accuracy of the ARIMA model were evaluated using the monthly morbidity data in 2014.

Results: A total of 3078 cases affected by brucellosis were reported from January 1998 to December 2015 in Jinzhou City. The incidence of brucellosis had shown a fluctuating growth gradually. Moreover, the ARIMA(1,1,1)(0,1,1) model was finally selected among quite a few plausible ARIMA models based upon the parameter test, correlation analysis, and Box-Ljung test. Notably, the incidence from 2005 to 2014 forecasted using this ARIMA model fitted well with the actual incidence data. Notably, the actual morbidity in 2014 fell within the scope of 95% confidence limit of values predicted by the ARIMA(1,1,1)(0,1,1) model, with the absolute error between the predicted and the actual values in 2014 ranging from 0.02 to 0.74. Meanwhile, the MAPE was 19.83%.

Conclusion: It is suitable to predict the incidence of brucellosis in Jinzhou City of China using the ARIMA(1,1,1)(0,1,1) model.
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http://dx.doi.org/10.1155/2019/1429462DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6595367PMC
June 2019

Lanthanum chloride induces neuron damage by activating the nuclear factor-kappa B signaling pathway in activated microglia.

Metallomics 2019 07;11(7):1277-1287

Department of Toxicology, School of Public Health, China Medical University, No. 77, Puhe Road, Shenyang North New Area, Shenyang 110122, Liaoning Province, People's Republic of China.

Lanthanum is a rare earth element which can have adverse effects on the central nervous system (CNS). However, the mechanisms of these effects are not fully understood. The activated microglia plays an important role in the pathogenesis of neurodegenerative diseases and thus could be involved in mediating the toxic effects of lanthanum on the CNS. Nuclear factor-kappa B (NF-κB) is a critical nuclear factor which regulates the expression of inflammatory mediators in the activated microglia. This study investigated the effects of lanthanum chloride (LaCl3) on the NF-κB signaling pathway and explored the relationship between the microglia activation and neuron damage induced by La in vitro. The results showed that BV2 microglial cells treated with 0, 0.05, 0.1 or 0.2 mM LaCl3 could up-regulate the expression of Iba1 protein, a marker of microglia activation, and of p-IKKαβ and p-IκBα in a dose-dependent manner. La could also increase the translocation of the NF-κB p65 subunit from the cytosol into the nucleus, and then elevate the production of NO, TNF-α, IL-1β, IL-6 and MCP-1 by BV2 microglial cells. In a neuron-microglia co-culture system, BV2 microglia treated with LaCl3 resulted in a significant increase of the rates of neuron apoptosis. Conversely, the pre-treatment with PDTC (an inhibitor of the NF-κB signaling pathway) could inhibit the release of inflammatory cytokines and reduce the number of apoptotic neurons caused by La. These findings suggested that the neuron injury induced by LaCl3 might be related to the abnormal activation of microglia, which could remarkably increase the expression and release of pro-inflammatory cytokines via activating the NF-κB signaling pathway.
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http://dx.doi.org/10.1039/c9mt00108eDOI Listing
July 2019

Lanthanum chloride induces autophagy in rat hippocampus through ROS-mediated JNK and AKT/mTOR signaling pathways.

Metallomics 2019 02;11(2):439-453

Department of Toxicology, School of Public Health, China Medical University, No. 77 Puhe road, Shenyang North New Area, Shenyang 110122, Liaoning Province, People's Republic of China.

Lanthanum (La) can cause central nervous system damage in rats and lead to learning and memory impairment, but the relevant mechanisms have not been fully elucidated. Autophagy is the self-balancing and self-renewal process of cells that degrades damaged macromolecules and organelles through the lysosomal pathway. It is an important mechanism to resist harmful stress, but excessive autophagy leads to type II programmed cell death. A variety of chemicals can induce oxidative stress, and a large number of reactive oxygen species (ROS) can regulate the level of autophagy through multiple signaling pathways. Our previous studies showed that La could cause oxidative stress, inhibit Nrf2/ARE signaling pathway and impair learning and memory, but it is unclear whether the mechanism is related to autophagic disorders of neurons. In this study, Wistar rats were exposed to 0% (w/v), 0.25%, 0.5% and 1.0% lanthanum chloride (LaCl3) through their mother and drinking water from the embryonic phase to 1 month after weaning, and then the subsequent experiments were performed. The results showed that LaCl3 impaired spatial learning and memory and avoidance conditioning in rats and induced an increase in ROS levels in hippocampal nerve cells, which up-regulated p-JNK, p-c-Jun, p-FoxO1, p-FoxO3a, Beclin1 and LC3B-II expression and down-regulated p-AKT, p-mTOR and p62 expression. Meanwhile, the number of autophagosomes in hippocampal neurons in the 1.0% LaCl3-treated group was significantly increased. These results indicate that La can activate the JNK/c-Jun and JNK/FoxOs signaling pathways, inhibit the AKT/mTOR signaling pathway by inducing oxidative stress, and enhance autophagy in the hippocampus. This study suggests that the mechanism of learning and memory impairment induced by LaCl3 may be related to excessive autophagy.
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http://dx.doi.org/10.1039/c8mt00295aDOI Listing
February 2019

An Antagonism Joint Action of Lead and Di-2-Ethylhexyl Phthalate Explains an Improved Ability of Learning and Memory after Combined Exposure in Weaning Rats.

Biol Trace Elem Res 2019 Sep 6;191(1):126-134. Epub 2018 Dec 6.

Department of Toxicology, School of Public Health, China Medical University, No.77 Puhe Road, Shenyang North New Area, Shenyang, 110122, Liaoning Province, People's Republic of China.

Lead and di-2-ethylhexyl phthalate (DEHP) are widely distributed in the environment, and their neurotoxicity has caused a widespread concern. The complexity of environmental exposure provides the possibility of their combined exposure. The present study aims to describe a joint neurotoxicity and clarify the potential mechanism after combined exposure to lead and DEHP. A 2 × 3 factorial design was used to analyze either single effects or their interaction by a subchronic lead and DEHP exposure model of the male weaning rats. Similar to the previous study, lead or DEHP single exposure showed an increased neurotoxicity. Interestingly, our neurobehavioral test showed the rats in the combined exposure groups had a better ability of learning and memory compared with the single-exposure ones. It seemed to reflect an antagonism joint action in neurotoxicity after combined exposure. The content of dehydroepiandrosterone (DHEA) in serum and the mRNA level of brain-derived neurotrophic factor (Bdnf) in the hippocampus showed a similar trend to the ability of learning and memory. However, there was insufficient evidence to support the joint action on some indexes of oxidative stress such as malondialdehyde (MDA), the ratio of reduced glutathione(GSH) to oxidized glutathione(GSSG), γglutamylcysteine synthetase (γ-GCS), glutathione-s transferase (GST), and nuclear factor E2-related factor 2 (Nrf2) mRNA expression in the hippocampus. In a word, our current study reminded a unique antagonism joint action of neurotoxicity after combined exposure to lead and DEHP, which may contribute to understanding some shallow mechanism of the joint toxicity due to the complexity of environmental pollutant exposure.
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http://dx.doi.org/10.1007/s12011-018-1586-5DOI Listing
September 2019

Rs3212986 polymorphism, a possible biomarker to predict smoking-related lung cancer, alters DNA repair capacity via regulating ERCC1 expression.

Cancer Med 2018 12 19;7(12):6317-6330. Epub 2018 Nov 19.

Department of Toxicology, School of Public Health, China Medical University, Shenyang, China.

Single nucleotide polymorphisms (SNPs) in 3'UTR of key DNA repair enzyme genes are associated with inter-individual differences of DNA repair capacity (DRC) and susceptibility to a variety of human malignancies such as lung cancer. In this study, seven candidate SNPs in 3'UTR of DRC-related genes including ERCC1 (rs3212986, rs2336219, and rs735482), OGG1 (rs1052133), MLH3 (rs108621), CD3EAP (rs1007616), and PPP1R13L (rs6966) were analyzed in 300 lung cancer patients and controls from the northeast of China. Furthermore, we introduced ERCC1 (CDS+3'UTR) or CD3EAP (CDS) cDNA clone to transfect HEK293T and 16HBE cells. Cell viability between different genotypes of transfected cells exposed to BPDE was detected by CCK-8 assay, while DNA damage was visualized using γH2AX immunofluorescence and the modified comet assay. We found that minor A-allele of rs3212986 could reflect a linkage with increasing risk of NSCLC. Compared with CC genotype, AA genotype of ERCC1 rs3212986 was a high-risk factor for NSCLC (OR = 3.246; 95%CI: 1.375-7.663). Particularly stratified by smoking status in cases and controls, A allele of ERCC1 rs3212986 also exhibited an enhanced risk to develop lung cancer in smokers only (P < 0.05). Interestingly, reduced repair efficiency of DNA damage was observed in 293T ERCC1(AA) and 16HBE ERCC1(AA), while no significant difference was appeared in two genotypes of CD3EAP (3' adjacent gene of ERCC1) overexpressed cells. Our findings suggest that rs3212986 polymorphism in 3'UTR of ERCC1 overlapped with CD3EAP may affect the repair of the damage induced by BPDE mainly via regulating ERCC1 expression and become a potential biomarker to predict smoking-related lung cancer.
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http://dx.doi.org/10.1002/cam4.1842DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6308093PMC
December 2018

Conditioned medium from overly excitatory primary astrocytes induced by La increases apoptosis in primary neurons via upregulating the expression of NMDA receptors.

Metallomics 2018 07;10(7):1016-1028

Department of Toxicology, School of Public Health, China Medical University, No. 77 Puhe road, Shenyang North New Area, Shenyang 110122, Liaoning Province, People's Republic of China.

Lanthanum (La) can accumulate in the brain and impair learning and memory. However, the underlying mechanism of La-induced neurotoxicity has remained elusive. Under physiological conditions, it has been reported that moderately excitatory astrocytes play an important role in the regulation of neuronal signals and synaptic plasticity. However, under pathological conditions, overly excitatory astrocytes can release excess excitatory transmitters, such as glutamate (Glu) and d-serine, and induce the over-activation of NMDA receptors (NMDAR) in neurons, ultimately leading to neuronal excitotoxicity. To date, limited work has been performed with respect to whether La can induce neuronal excitotoxicity by inducing astrocytes to become overexcited. In this study, in vitro models of primary culture rat cortical astrocytes and neurons were established. First, the astrocytes were treated with 0.125 mM, 0.25 mM and 0.5 mM lanthanum chloride (LaCl3) for 24 h, and the supernatants were collected as a conditioned medium (CM) which is denoted as CM (La3+); then, the neurons were treated with CM (La3+) for 48 h. The results illustrate that LaCl3 treatment significantly upregulated the mRNA and protein expression levels of metabotropic glutamate receptor 5 (mGLUR5), phospholipase C (PLC), connexin 43 (Cx43) and Cx30, increased the concentrations of inositol trisphosphate (IP3) and [Ca2+]i, and promoted the synthesis and release of Glu and d-serine in astrocytes. Moreover, the CM (La3+) could increase the mRNA and protein expression levels of NMDAR subunits (NR1, NR2A, NR2B), the concentration of [Ca2+]i and the rate of apoptosis in neurons. Furthermore, after removal of La, CM (La-free) had a similar effect on neurons which could be antagonized by MK-801, DCKA and DAAO. These results suggest that the neuron apoptosis induced by La is closely related to the excessive release of Glu and d-serine from overly excitatory astrocytes.
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http://dx.doi.org/10.1039/c8mt00056eDOI Listing
July 2018

Lanthanum Chloride Impairs the Blood-Brain Barrier Integrity by Reduction of Junctional Proteins and Upregulation of MMP-9 in Rats.

Biol Trace Elem Res 2019 Feb 6;187(2):482-491. Epub 2018 Jun 6.

Department of Toxicology, School of Public Health, China Medical University, #77 Puhe Road, Shenyang, 110122, People's Republic of China.

Lanthanum could cause cognitive impairment in children and rodent animals. The normal blood-brain barrier (BBB) integrity is essential for protecting the brain from systemic toxins and maintaining the homeostasis for proper neuronal function. BBB dysfunction has been implicated as a potential mechanism of heavy metal-induced neurotoxicity. The present study was aimed to investigate effects of lanthanum on BBB integrity and endothelial junctional complexes in the cerebral cortex of young rats. Animals were exposed to lanthanum chloride (LaCl) through drinking water under 0, 0.25, 0.5, and 1.0% concentrations from postnatal day 0 until 30 days after weaning. LaCl-exposure increased BBB permeability, caused ultrastructure changes in cerebral capillaries, and reduced protein expression of claudin-5, occludin, and VE-cadherin. Due to the critical role of matrix metalloproteinases (MMPs) in BBB integrity, we further examined alterations in MMPs activity and expression. Enhanced gelatinase activity and upregulated MMP-9 expression were observed after LaCl-exposure, concurrently with decreased expression of endogenous inhibitor tissue inhibitors of metalloproteinase (TIMP)-1. Taken together, this study demonstrated that postnatal lanthanum exposure caused leakage of BBB in young rats, partially attributed to upregulation of MMP-9 and reduction of junctional proteins expression.
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http://dx.doi.org/10.1007/s12011-018-1402-2DOI Listing
February 2019

Different splicing isoforms of ERCC1 affect the expression of its overlapping genes CD3EAP and PPP1R13L, and indicate a potential application in non-small cell lung cancer treatment.

Int J Oncol 2018 Jun 29;52(6):2155-2165. Epub 2018 Mar 29.

Department of Toxicology, School of Public Health, China Medical University, Shenyang, Liaoning 110122, P.R. China.

Numerous genes are arranged in complex overlapping and interlaced patterns, and such arrangements potentially contribute to the regulation of gene expression. Previous studies have demonstrated that a region in chromosome 19q13.2-3 encompassing the overlapping genes excision repair cross-complementation group 1 (ERCC1), CD3e molecule associated protein (CD3EAP) and protein phosphatase 1 regulatory subunit 13 like (PPP1R13L) was found to be associated with the risk and prognosis of non-small cell lung cancer (NSCLC). The present study confirmed the hypothesis that there are co-expression patterns among these overlapping genes. The suggestive bioinformatic evidence of The Cancer Genome Atlas was verified by quantitative polymerase chain reaction (qPCR) analysis of NSCLC tissue samples. In addition, a cisplatin-induced DNA damage cell model was assessed by microarray analysis, qPCR and 3' rapid amplification of cDNA ends (3'RACE) to verify and quantify the expression levels of co-expressed alternative splicing isoforms in the NSCLC tissues, as well as in cancer A549 and normal 16HBE cells. The expression of CD3EAP exon 1 was demonstrated to be significantly associated with PPP1R13L exon 1, while CD3EAP exon 3 was significantly associated with ERCC1 exon 11 in normal and NSCLC tissues. It was observed that short transcripts of ERCC1, CD3EAP and PPP1R13L are co-expressed in A549 cells and full-length transcripts are co-expressed in 16HBE cells. Furthermore, a novel transcriptional regulation pattern was described based on the positional associations of overlapping genes. The region encompassing the overlapping genes ERCC1, CD3EAP and PPP1R13L may be involved in linking the upstream and downstream genes, while the different splicing isoforms of ERCC1 affect the expression of its overlapping genes, suggesting potential application in cisplatin resistance in NSCLC treatment.
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http://dx.doi.org/10.3892/ijo.2018.4347DOI Listing
June 2018

The polymorphisms of miRNA-binding site in MLH3 and ERCC1 were linked to the risk of colorectal cancer in a case-control study.

Cancer Med 2018 04 8;7(4):1264-1274. Epub 2018 Mar 8.

Department of Toxicology, School of Public Health, China Medical University, Shenyang, China.

Colorectal cancer (CRC), as a malignant tumor of lower digestive tract, has been found to have an increasing morbidity and mortality in China. It was particularly important to find some earlier biomarkers to predict the risk and prognosis. In this study, several polymorphisms on 3'UTR of three DNA repair genes including MLH3 rs10862, ERCC1 rs3212986, ERCC1 rs735482, ERCC1 rs2336219, and OGG1 rs1052133 were chosen by bioinformatics exploration, and then, a case-control study of 200 CRC cases and controls was performed. Furthermore, a dual-luciferase assay was also carried out to certify whether the candidate miRNA can regulate its target gene and the selected SNPs have a valid effect on the target miRNA. Finally, both of ERCC1 rs3212986 and MLH3 rs108621 were shown to be associated with the risk of CRC. Comparing with rs3212986 CC genotype, AA was at a higher risk (OR = 3.079, 95% CI: 1.192-7.952). For MLH3 rs108621, comparing with TT genotype, CC and TC were at a higher risk of CRC in male (OR = 5.171, 95% CI: 1.009-26.494; OR = 1.904, 95% CI: 1.049-3.455). Interestingly, an analysis combining both ERCC1 rs3212986 and MLH3 rs108621 also showed an increased risk of CRC. In addition, a dual-luciferase assay showed that miR-193a-3p could regulate MLH3, and the polymorphism rs108621 could alter the miR-193a-3p binding to MLH3. Therefore, MLH3 rs108621 may be associated with the risk of CRC due to the effect of miR-193a-3p on MLH3, which reminded the possibility as potential susceptibility biomarkers to predict the risk of CRC.
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http://dx.doi.org/10.1002/cam4.1319DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5911615PMC
April 2018

Lanthanum chloride impairs memory in rats by disturbing the glutamate-glutamine cycle and over-activating NMDA receptors.

Food Chem Toxicol 2018 Mar 17;113:1-13. Epub 2018 Jan 17.

Department of Hygiene Toxicology, School of Public Health, China Medical University, Shenyang, Liaoning, PR China. Electronic address:

Studies have reported that lanthanum chloride (LaCl) can across the blood-brain barrier, accumulate in the brain and affect the spatial learning and memory abilities. However, the potential mechanism that LaCl-induced neurotoxic effects has not yet been defined. Glutamate (Glu) is a vital excitatory neurotransmitter, and the excessive Glu accumulation in extracellular space can induce excitatory neurotoxicity. This study was designed to research the influence of LaCl on the spatial learning and memory abilities of rats and to discuss the possible mechanism underlying this effect regarding the extracellular Glu concentration, the Glu-glutamine (Gln) cycle and the N-methyl-D-aspartate (NMDA) receptors. Four groups of Wistar rats were exposed to 0%, 0.125%, 0.25% or 0.5% LaCl via the drinking water from the day of conception to 1 month after weaning. These results showed that LaCl exposure damaged spatial learning and memory, long-term potentiation, and neuronal ultrastructure, generated an excessive accumulation of glutamate, significantly decreased the expression of glutamate/aspartate transporter (GLAST), glutamate transporter-1 (GLT-1), glutamine synthetase (GS) and phosphate-activated glutaminase (PAG), and increased the expression of GluN1, GluN2A and GluN2B. This study showed that LaCl impaired the rats' spatial learning and memory abilities by disturbing the Glu-Gln cycle and over-activating NMDA receptors thereby inducing excitotoxicity.
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http://dx.doi.org/10.1016/j.fct.2018.01.023DOI Listing
March 2018

Lanthanum chloride reduces lactate production in primary culture rat cortical astrocytes and suppresses primary co-culture rat cortical astrocyte-neuron lactate transport.

Arch Toxicol 2018 Apr 20;92(4):1407-1419. Epub 2017 Dec 20.

Department of Toxicology, School of Public Health, China Medical University, No.77Puhe road, Shenyang North New Area, Shenyang, 110122, Liaoning Province, People's Republic of China.

Lanthanum (La) can impair learning memory and induce behavioral abnormalities in animals. However, the mechanism underlying these adverse effects of La is still elusive. It has been demonstrated that lactate derived from astrocytes is the major energy source for neurons during long-term memory (LTM) formation and the deficiency of lactate supply can result in LTM damage. However, little work has been done with respect to the impact of La on the lactate production in astrocytes and astrocyte-neuron lactate transport (ANLT). Herein, experiments were undertaken to explore if there was such an adverse effect of La. Primary culture rat cortical astrocytes and primary co-culture rat cortical astrocyte-neuron were treated with (0.125, 0.25 and 0.5 mM) lanthanum chloride (LaCl) for 24 h. The results showed that LaCl treatment significantly downregulated the mRNA and protein expression of glucose transporter 1 (GLUT1), glycogen synthase (GS), glycogen phosphorylase (GP), lactate dehydrogenase A (LDHA), and monocarboxylate transporter 1, 2 and 4 (MCT 1 2 and 4); upregulated the mRNA and protein expression of lactate dehydrogenase B (LDHB); and decreased the glycogen level, total LDH and GP activity, GS/p-GS ratio and lactate contents. Moreover, rolipram (20, 40 μM) or forskolin (20, 40 μM) could increase the lactate content by upregulating GP expression and the GS/p-GS ratio, as well as antagonize the effects of La. These results suggested that La-induced learning-memory damage was probably related to its suppression of lactate production in astrocytes and ANLT. This study provides some novel clues for clarifying the mechanism underlying the neurotoxicity of La.
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http://dx.doi.org/10.1007/s00204-017-2148-xDOI Listing
April 2018

Lanthanum damages learning and memory and suppresses astrocyte-neuron lactate shuttle in rat hippocampus.

Exp Brain Res 2017 12 9;235(12):3817-3832. Epub 2017 Oct 9.

Department of Toxicology, School of Public Health, China Medical University, No.77 Puhe Road, Shenyang North New Area, Shenyang, 110122, People's Republic of China.

Rare-earth elements (REEs) are applied in various fields by virtue of their superior physical and chemical properties. Surveys have reported that REEs can impair learning and memory in children and induce neurobehavioral abnormalities in animals. However, the mechanism underlying this neurotoxicity is still unclear. Lanthanum (La) is often chosen to study the effects of REEs. Here, we investigated the role of astrocyte-neuron lactate shuttle (ANLS) in spatial learning and memory impairment induced by LaCl in hippocampus, an important spatial memory-related brain region. Pregnant Wistar rats were exposed to 0, 0.125, 0.25, 0.5, or 1% LaCl in drinking water during pregnancy and lactation. After weaning, young rats continued to receive 0, 0.125, 0.25, 0.5, and 1% LaCl in the drinking water for 1 month. The results showed that LaCl exposure impaired the spatial learning and memory of rats in Morris water maze test, significantly reduced the mRNA and protein levels of glycogen synthetase, glycogen phosphorylase, lactate dehydrogenase A, monocarboxylate transporter 4, MCT-1, and MCT-2, and decreased total LDH activity and lactate contents in rat hippocampus. These results indicate that LaCl impairs spatial learning and memory in rats probably by suppressing ANLS in rat hippocampus. The study provides a novel clue of energy supply for neurons to clarify the neurotoxicity of REEs.
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http://dx.doi.org/10.1007/s00221-017-5102-5DOI Listing
December 2017

Activation of Nrf2/ARE signaling pathway attenuates lanthanum chloride induced injuries in primary rat astrocytes.

Metallomics 2017 08;9(8):1120-1131

Department of Toxicology, School of Public Health, China Medical University, No. 77 Puhe Road, Shenyang North New Area, Shenyang 110122, Liaoning Province, People's Republic of China.

Lanthanum (La) exposure can lead to learning and memory disorder in animals; however, the underlying mechanism of La induced neurotoxicity is still unknown. It has been demonstrated that Nrf2 activation by tert-butylhydroquinone (tBHQ) results in neuroprotection against brain injuries. However, little study has been done with respect to its effect on La induced neurotoxicity. Herein, experiments are undertaken to determine if there is a correlation between La damaged astrocytes and the Nrf2/ARE signalling pathway. Primary rat astrocytes are exposed to 0 mmol L, 0.125 mmol L, 0.25 mmol L and 0.5 mmol L lanthanum chloride (LaCl) for 24 hours. The results reveal that LaCl increases the apoptosis/necrosis rate of astrocytes, decreases the glutathione (GSH) content, increases reactive oxygen species (ROS) levels and significantly down-regulates Nrf2 as well as the mRNA and protein expression of Nrf2-regulated genes, including NADP(H): dehydrogenase quinone 1 (NQO1), hemeoxygenase-1 (HO-1), superoxide dismutase 2 (SOD), glutathione peroxidase 1 (GSH-Px), glutathione-s-transferase (GST) and γ-glutamine cysteine synthase (γ-GCS) in astrocytes. In addition, it is found that tBHQ displays an antagonistic effect on astrocytes damaged by LaCl. Therefore, La damaged astrocytes are possibly related to the down-regulated Nrf2/ARE pathway, and treatment with tBHQ clearly activates the Nrf2/ARE signalling pathway, which exerts protection against oxidative stress.
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http://dx.doi.org/10.1039/c7mt00182gDOI Listing
August 2017

Effects of Aluminium on Long-Term Memory in Rats and on SIRT1 Mediating the Transcription of CREB-Dependent Gene in Hippocampus.

Basic Clin Pharmacol Toxicol 2017 Oct 19;121(4):342-352. Epub 2017 Jun 19.

Department of Toxicology, School of Public Health, China Medical University, Shenyang, China.

Epidemiological investigations have shown that aluminium (Al) is an important neurotoxicant which can be absorbed by organisms via various routes. Previous studies have confirmed that exposure to Al could cause neurodegenerative diseases, decline CREB phosphorylation and then down-regulate the transcription and protein expression of its target genes including BDNF. However, recent studies revealed that CREB activation alone was far from enough to activate the expression of long-term memory (LTM)-related genes; there might be other regulatory factors involved in this process. Several studies showed that TORC1 might be involved in regulating the transcription of downstream target genes as well. Also, TORC1 could be mediated by SIRT1 during the formation of LTM. However, the role of CREB regulating system in Al-induced LTM impairment was still not utterly elucidated till now. This study was designed to establish the rat model of subchronic Al exposure to observe the neuroethology, regulatory factor levels and molecular biological alterations in hippocampal cells. The results showed that, with the increasing AlCl dose, blood Al content increased gradually; morphology of the hippocampus and neuronal ultrastructure were aberrant; in the Morris water maze test, the escape latency and distance travelled became longer, swimming traces turned more complicated in the place navigation test; intracellular Ca , cAMP levels declined significantly in AlCl -treated rats, followed by abated nuclear translocation of TORC1 and decreased SIRT1, TORC1 and pCREB levels. These results indicate that SIRT1 and TORC1 might play an important mediating role in Al-induced LTM impairment.
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http://dx.doi.org/10.1111/bcpt.12798DOI Listing
October 2017

High expression of matrix metalloproteinases 16 is associated with the aggressive malignant behavior and poor survival outcome in colorectal carcinoma.

Sci Rep 2017 04 19;7:46531. Epub 2017 Apr 19.

Department of Interventional Radiology, The Affiliated Yancheng Hospital of Southeast University Medical College, Yancheng Third People's Hospital, Yancheng, Jiangsu Province, 224001, China.

Recent evidence suggested an important role of matrix metalloproteinases 16 (MMP16) in the progression of several cancers. However, the contribution of MMP16 to colorectal cancer (CRC) remains elusive. In this study, we combined analyzed the MMP16 expression in The Cancer Genome Atlas (TCGA), GSE39582 database and in-house database. In TCGA and GSE39584 database, the log-rank test demonstrated that overall survival (OS) for patients with low MMP16 expression in tumor tissues was significantly higher than those with high expression (P < 0.05). In the validation cohort, high MMP16 expression was significantly correlated with N stage (P = 0.008) and lymphovascular invasion (P = 0.002). The 5-year OS and disease free survival (DFS) in high and low MMP16 expression groups were 66.0% and 80.6%, 54.3% and 72.8%, respectively. Univariate and multivariate analysis showed that high MMP16 expression was an independently prognosis factor for both OS and DFS (P < 0.05). Functional study found that silencing MMP16 expression could inhibit migration and invasion of colon cancer cells. In conclusion, high expression of MMP16 is associated with the aggressive malignant behavior and poor survival outcome of CRC patients. MMP16 can serve as an indicator of prognosis as well as a potential novel target for treatment of CRC patients.
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http://dx.doi.org/10.1038/srep46531DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5396192PMC
April 2017

ERCC2/XPD Lys751Gln alter DNA repair efficiency of platinum-induced DNA damage through P53 pathway.

Chem Biol Interact 2017 Feb 24;263:55-65. Epub 2016 Dec 24.

Dept. of Toxicology, School of Public Health, China Medical University, Shenyang, PR China. Electronic address:

Platinum-based treatment causes Pt-DNA adducts which lead to cell death. The platinum-induced DNA damage is recognized and repaired by the nucleotide excision repair (NER) system of which ERCC2/XPD is a critical enzyme. Single nucleotide polymorphisms in ERCC2/XPD have been found to be associated with platinum resistance. The aim of the present study was to investigate whether ERCC2/XPD Lys751Gln (rs13181) polymorphism is causally related to DNA repair capacity of platinum-induced DNA damage. First, cDNA clones expressing different genotypes of the polymorphism was transfected to an ERCC2/XPD defective CHO cell line (UV5). Second, all cells were treated with cisplatin. Cellular survival rate were investigated by MTT growth inhibition assay, DNA damage levels were investigated by comet assay and RAD51 staining. The distribution of cell cycle and the change of apoptosis rates were detected by a flow cytometric method (FCM). Finally, P53mRNA and phospho-P53 protein levels were further investigated in order to explore a possible explanation. As expected, there was a significantly increased in viability of UV5 as compared to UV5 after cisplatin treatment. The DNA damage level of UV5 was significant decreased compared to UV5 at 24 h of treatment. Mutation of ERCC2rs13181 AA to CC causes a prolonged S phase in cell cycle. UV5 alleviated the apoptosis compared to UV5, meanwhile P53mRNA levels in UV was also lower when compared UV5. It co-incides with a prolonged high expression of phospho-P53, which is relevant for cell cycle regulation, apoptosis, and the DNA damage response (DDR). We concluded that ERCC2/XPD rs13181 polymorphism is possibly related to the DNA repair capacity of platinum-induced DNA damage. This functional study provides some clues to clarify the relationship between cisplatin resistance and ERCC2/XPDrs13181 polymorphism.
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http://dx.doi.org/10.1016/j.cbi.2016.12.015DOI Listing
February 2017

Genetic polymorphisms in 19q13.3 genes associated with alteration of repair capacity to BPDE-DNA adducts in primary cultured lymphocytes.

Mutat Res 2016 Dec 29;812:39-47. Epub 2016 Oct 29.

Dept. of Toxicology, School of Public Health, China Medical University, Shenyang, PR China. Electronic address:

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 in cells caused by BPDE is normally repaired by Nucleotide Excision Repair (NER) and Base Excision Repair (BER). Genetic variations in NER and BER can change individual DNA repair capacity to DNA damage induced by BPDE. In the present study we determined the number of in vitro induced BPDE-DNA adducts in lymphocytes, to reflect individual susceptibility to Polycyclic aromatic hydrocarbons (PAHs)-induced carcinogenesis. The BPDE-DNA adduct level in lymphocytes were assessed by high performance liquid chromatography (HPLC) in 281 randomly selected participants. We genotyped for 9 single nucleotide polymorphisms (SNPs) in genes involved in NER (XPB rs4150441, XPC rs2228001, rs2279017 and XPF rs4781560), BER (XRCC1 rs25487, rs25489 and rs1799782) and genes located on chromosome 19q13.2-3 (PPP1R13L rs1005165 and CAST rs967591). We found that 3 polymorphisms in chromosome 19q13.2-3 were associated with lower levels of BPDE-DNA adducts (MinorT allele in XRCC1 rs1799782, minor T allele in PPP1R13L rs1005165 and minor A allele in CAST rs967571). In addition, a modified comet assay was performed to further confirm the above conclusions. We found both minor T allele in PPP1R13L rs1005165 and minor A allele in CAST rs967571 were associated with the lower levels of BPDE-adducts. Our data suggested that the variant genotypes of genes in chromosome 19q13.2-3 are associated with the alteration of repair efficiency to DNA damage caused by Benzo[a]pyrene, and may contribute to enhance predictive value for individual's DNA repair capacity in response to environmental carcinogens.
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http://dx.doi.org/10.1016/j.mrgentox.2016.10.004DOI Listing
December 2016

The effect of nuclear factor erythroid 2-related factor/antioxidant response element signalling pathway in the lanthanum chloride-induced impairment of learning and memory in rats.

J Neurochem 2017 02 11;140(3):463-475. Epub 2017 Jan 11.

Department of Toxicology, School of Public Health, China Medical University, Shenyang, Liaoning, China.

Lanthanum exerts adverse effects on the central nervous system. However, the mechanism underlying these adverse effects has not been clarified. It is known that oxidative stress plays an important role in neurological injuries induced by harmful factors. Nuclear factor erythroid 2-related factor (Nrf2) is very important in the response to oxidative stress in tissues and cells. The purpose of this study was to explore the effect of lanthanum chloride (LaCl ) on the spatial learning and memory of rats and to determine whether the Nrf2/antioxidant response element pathway acts in the hippocampus. Four groups of Wistar rats were exposed to 0 mM, 9 mM, 18 mM or 36 mM LaCl through their drinking water from the day of birth to 2 months after weaning. The results showed that LaCl impaired the spatial learning and memory of the rats, damaged the neuronal ultrastructure, increased reactive oxygen species levels and significantly down-regulated Nrf2 as well as the mRNA and protein expression of Nrf2-regulated genes, including NADP(H): dehydrogenase quinone 1, haeme oxygenase-1, superoxide dismutase 2, glutathione peroxidase 1, glutathione-S-transferase, γ-glutamine cysteine synthase and glutathione reductase, in the hippocampus. This study suggests that LaCl can impair the spatial learning and memory of rats, possibly by perturbing the Nrf2/antioxidant response element signalling pathway.
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http://dx.doi.org/10.1111/jnc.13895DOI Listing
February 2017

The ERCC2/XPD Lys751Gln polymorphism affects DNA repair of benzo[a]pyrene induced damage, tested in an in vitro model.

Toxicol In Vitro 2016 Aug 29;34:300-308. Epub 2016 Apr 29.

Dept. Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, The Netherlands.

Nucleotide excision repair (NER) is an important defense mechanism of the body to exogenous carcinogens and mutagens, such as benzo[a]pyrene (B[a]P). Genetic polymorphisms in ERCC2/XPD, a critical element in NER, are thought to be associated with individual's cancer susceptibility. Although ERCC2/XPD Lys751Gln (rs13181) is the most studied polymorphism, the impact of this polymorphism on DNA repair capacity to carcinogen remains unclear. In the present study, cDNA clones carrying different genotypes of ERCC2/XPD (Lys751Gln) were introduced into an ERCC2/XPD deficient cell line (UV5) in a well-controlled biological system. After B[a]P treatment, cell growth inhibition rates and DNA damage levels in all cells were detected respectively. As expected, we found that the DNA repair capacity in UV5 cells was restored to levels similar to wildtype parent AA8 cells upon introduction of the cDNA clone of ERCC2/XPD (Lys751). Interestingly, after B[a]P treatment, transfected cells expressing variant ERCC2/XPD (751Gln) showed an enhanced cellular sensitivity and a diminished DNA repair capacity. The wildtype genotype AA (Lys) was found to be associated with a higher DNA repair capacity as compared to its polymorphic genotype CC (Gln). These data indicate that ERCC2/XPD Lys751Gln polymorphism affects DNA repair capacity after exposure to environmental carcinogens such as B[a]P in this well-controlled in vitro system and could act as a biomarker to increase the predictive value to develop cancer.
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http://dx.doi.org/10.1016/j.tiv.2016.04.015DOI Listing
August 2016

Genetic Polymorphisms in XRCC1, CD3EAP, PPP1R13L, XPB, XPC, and XPF and the Risk of Chronic Benzene Poisoning in a Chinese Occupational Population.

PLoS One 2015 17;10(12):e0144458. Epub 2015 Dec 17.

Department of Toxicology, School of Public Health, China Medical University, Shenyang, Liaoning, P.R. China.

Objectives: Individual variations in the capacity of DNA repair machinery to relieve benzene-induced DNA damage may be the key to developing chronic benzene poisoning (CBP), an increasingly prevalent occupational disease in China. ERCC1 (Excision repair cross complementation group 1) is located on chromosome 19q13.2-3 and participates in the crucial steps of Nucleotide Excision Repair (NER); moreover, we determined that one of its polymorphisms, ERCC1 rs11615, is a biomarker for CBP susceptibility in our previous report. Our aim is to further explore the deeper association between some genetic variations related to ERCC1 polymorphisms and CBP risk.

Methods: Nine single nucleotide polymorphisms (SNPs) of XRCC1 (X-ray repair cross-complementing 1), CD3EAP (CD3e molecule, epsilon associated protein), PPP1R13L (protein phosphatase 1, regulatory subunit 13 like), XPB (Xeroderma pigmentosum group B), XPC (Xeroderma pigmentosum group C) and XPF (Xeroderma pigmentosum group F) were genotyped by the Snapshot and TaqMan-MGB® probe techniques, in a study involving 102 CBP patients and 204 controls. The potential interactions between these SNPs and lifestyle factors, such as smoking and drinking, were assessed using a stratified analysis.

Results: An XRCC1 allele, rs25487, was related to a higher risk of CBP (P<0.001) even after stratifying for potential confounders. Carriers of the TT genotype of XRCC1 rs1799782 who were alcohol drinkers (OR = 8.000; 95% CI: 1.316-48.645; P = 0.022), male (OR = 9.333; 95% CI: 1.593-54.672; P = 0.019), and had an exposure of ≤12 years (OR = 2.612; 95% CI: 1.048-6.510; P = 0.035) had an increased risk of CBP. However, the T allele in PPP1R13L rs1005165 (P<0.05) and the GA allele in CD3EAP rs967591 (OR = 0.162; 95% CI: 0039~0.666; P = 0.037) decreased the risk of CBP in men. The haplotype analysis of XRCC1 indicated that XRCC1 rs25487A, rs25489G and rs1799782T (OR = 15.469; 95% CI: 5.536-43.225; P<0.001) were associated with a high risk of CBP.

Conclusions: The findings showed that the rs25487 and rs1799782 polymorphisms of XRCC1 may contribute to an individual's susceptibility to CBP and may be used as valid biomarkers. Overall, the genes on chromosome 19q13.2-3 may have a special significance in the development of CBP in occupationally exposed Chinese populations.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0144458PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4683048PMC
June 2016

Protective Role of tert-Butylhydroquinone Against Sodium Fluoride-Induced Oxidative Stress and Apoptosis in PC12 Cells.

Cell Mol Neurobiol 2015 Oct 25;35(7):1017-25. Epub 2015 Apr 25.

Department of Toxicology, School of Public Health, China Medical University, Shenyang, 110013, Liaoning, China.

The neurotoxicity of fluoride is associated with oxidative stress due to imbalance between production and removal of reactive oxygen species (ROS). In contrast, induction of detoxifying and antioxidant genes through activation of NF-E2-related factor 2 (Nrf2) has been implicated in preventing oxidative stress and apoptosis in neurodegenerative diseases. The present study aimed to investigate the possible neuroprotective role of tert-butylhydroquinone (tBHQ), a general Nrf2 activator, on sodium fluoride (NaF)-induced oxidation damage and apoptosis in neuron-like rat pheochromocytoma (PC12) cells. Pretreatment with tBHQ protected PC12 cells against NaF-induced cytotoxicity as measured by MTT assay and apoptosis detection, simultaneously, inhibited NaF-induced overproduction of intracellular ROS and reduction of total glutathione content. Furthermore, NaF or tBHQ induced the stabilization of Nrf2, and enhanced expression of heme oxygenase-1 (HO-1) and γ-glutamylcysteine synthetase (γ-GCS) as a consequence of Nrf2 inducing. These findings indicated that tBHQ pretreatment conferred protective effect on PC12 cells against NaF-induced apoptotic cell death and oxidation-redox imbalance through stabilization of Nrf2 and elevation of downstream HO-1 and γ-GCS expressions.
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http://dx.doi.org/10.1007/s10571-015-0196-4DOI Listing
October 2015

Lanthanum chloride impairs spatial memory through ERK/MSK1 signaling pathway of hippocampus in rats.

Neurochem Res 2014 Dec 15;39(12):2479-91. Epub 2014 Oct 15.

Department of Toxicology, School of Public Health, China Medical University, 92 North 2nd Road, Heping District, Shenyang, 110001, Liaoning, People's Republic of China.

Rare earth elements (REEs) are used in many fields for their diverse physical and chemical properties. Surveys have shown that REEs can impair learning and memory in children and cause neurobehavioral defects in animals. However, the mechanism underlying these impairments has not yet been completely elucidated. Lanthanum (La) is often selected to study the effects of REEs. The aim of this study was to investigate the spatial memory impairments induced by lanthanum chloride (LaCl3) and the probable underlying mechanism. Wistar rats were exposed to LaCl3 in drinking water at 0 % (control, 0 mM), 0.25 % (18 mM), 0.50 % (36 mM), and 1.00 % (72 mM) from birth to 2 months after weaning. LaCl3 considerably impaired the spatial learning and memory of rats in the Morris water maze test, damaged the synaptic ultrastructure and downregulated the expression of p-MEK1/2, p-ERK1/2, p-MSK1, p-CREB, c-FOS and BDNF in the hippocampus. These results indicate that LaCl3 exposure impairs the spatial learning and memory of rats, which may be attributed to disruption of the synaptic ultrastructure and inhibition of the ERK/MSK1 signaling pathway in the hippocampus.
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http://dx.doi.org/10.1007/s11064-014-1452-6DOI Listing
December 2014
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