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Identification of Differentially Expressed Genes Response to TCDD in Rat Brain After Long-Term Low-Dose Exposure

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Identification of Differentially Expressed Genes Response to TCDD in Rat Brain After Long-Term Low-Dose Exposure JOURNAL OF ENVIRONMENTAL SCIENCES 62 (2017) 92– 99 Available online at www.sciencedirect.com ScienceDirect www.elsevier.com/locate/jes Identification of differentially expressed genes response to TCDD in rat brain after long-term low-dose exposure Yangsheng Chen1,2, ⁎⁎,LiXu1,2, ⁎⁎, Heidi Q.H. Xie1,2, ⁎, Tuan Xu1,2, Hualing Fu1,2, Songyan Zhang1,2, Rui Sha1,2, Yingjie Xia1,2, Bin Zhao1,2, ⁎ 1. State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China 2. University of Chinese Academy of Sciences, Beijing 100049, China ARTICLE INFO ABSTRACT Article history: Several cohort studies have reported that dioxin and dioxin-like polychlorinated biphenyls Received 31 March 2017 might impair the nervous system and lead to neurological or neurodegenerative diseases in Revised 9 July 2017 the elder people, but there is limited research on the involved mechanism. By using Accepted 11 July 2017 microarray analysis, we figured out the differentially expressed genes between brain Available online 19 July 2017 samples from SD rats after low-dose (0.1 μg/(kg▪bw)) dioxin exposure for six months and controls. To investigate the function changes in the course of dioxin exposure, Gene Keywords: Ontology (GO) annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway TCDD analysis were performed on the differentially expressed genes. And the changes of several Long-term exposure picked genes have been verified by real-time PCR. A total of 145 up-regulated and 64 Neurotoxicity down-regulated genes were identified. The metabolic processes, interleukin-1 secretion Microarray and production were significantly associated with the differentially expressed genes. And Neuroinflammation the genes regulated by dioxin also clustered to cholinergic synapse and long-term potentiation. Candidate biomarker genes such as egr1, gad2, gabrb3, abca1, ccr5 and pycard may be toxicological targets for dioxin. Furthermore, synaptic plasticity and neuro-immune system may be two principal affected areas by dioxin. © 2017 The Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences. Published by Elsevier B.V. Introduction several researches also tried to demonstrate the mechanism involved in the neurotoxicity of dioxin on the neurodevelopment Dioxin represents a group of persistent organic pollutants which by both animal behavior tests and molecular experiments exerts threats on human health. Recently, many studies focused (Mitsuhashi et al., 2010; Nayyar et al., 2002; Nguyen et al., 2013; on the neuronal effects of dioxin. The cohort studies focusing on Williamson et al., 2005). the neurotoxicity of dioxin could be classified into two categories But to the other category, in which the cohorts concerned based on the age of people in the cohorts. One major category about the effects of dioxin on the nervous system of elder people, aiming at children after perinatal dioxin exposure, demonstrated there is limited relevant research on the mechanisms. A study to that dioxin might disrupt regular neuronal development and lead evaluate the consequences of severe occupational intoxication to cognitive deficiency. The results of cohort studies have been with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) that occurred verified by animal experiments (Kakeyama et al., 2014), and during production of the herbicide trichlorophenoxyacetic acid ⁎ Corresponding authors. E-mails: [email protected] (Heidi Q.H. Xie), [email protected] (Bin Zhao). ⁎⁎ The authors contributed equally to this work. http://dx.doi.org/10.1016/j.jes.2017.07.010 1001-0742/© 2017 The Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences. Published by Elsevier B.V. JOURNAL OF ENVIRONMENTAL SCIENCES 62 (2017) 92– 99 93 in the period 1965–1968, indicated that even forty years past, the gavage every other week. Dose used in the current study was blood level of TCDD was still 100 times in the intoxication people based on previous TCDD chronic exposure reports (Bell et al., higher than in the general population, and a high percent of 2007; Chen et al., 2009). After 24 weeks of exposure, brain tissue subjects suffered from neurological and vascular disorders wasdissectedandstoredin−80°C for further studies. All animal (Pelclova et al., 2009). Another study carried out in 2014 also experiments were conducted in accordance with animal proto- suggested that dioxin exposure several decades earlier might colsapprovedbytheAnimalCareandUseCommitteeof increase morbidity from Alzheimer disease and peripheral Institute of Psychology (CAS). polyneuropathies (Yi et al., 2014). Generally, dietary exposure is the main way for dioxin to enter human body, especially for the 1.2. Ribonucleic acid (RNA) isolation, quality control and majority population. It has been reported that the elder Michigan microarray analysis residents who consume amount of fish from the Great Lakes, get impairments in memory and learning due to the dioxin-like Rat brain tissue was thoroughly grinded in liquid nitrogen. Polychlorinated bipheny (PCB) intake from the fish (Schantz et Total RNA of rat brain tissue was isolated using the Thermo al., 2001). Even in the developed countries like the U.S, older Scientific GeneJET RNA Purification Kit (Thermo) and geno- individuals suffer from high body burden, and their cognitive mic Deoxyribonucleic acid (DNA) was removal by RapidOut score was significantly affected by serum concentration of DNA Removal Kit following the manufacturer's instructions. dioxin-like PCB (Bouchard et al., 1999). These results suggest One microliter total RNA aliquots were used for quality that exposure levels were higher in the past, resulting in older control by agarose gel electrophoresis and quantified by individuals perhaps having high dioxin body burden compared Nanodrop 2000. All RNA samples used in this study showed to younger people. In addition, the lower compensation capacity no sign of degradation and the ratio of A260/A280 reached might lead the aging nervous system more vulnerable to to 2.0. neurotoxicant insults (Weiss, 2000). However, there are limited Preparation of cDNA, complementary ribonucleic acid data on possible mechanism involved in the neurotoxic effects of (cRNA), hybridization and scanning of microarrays was per- dioxin in the aging nervous system. Recently, researchers are formed following manufacturer's protocol. cDNA and biotinyl- keeping on finding target genes of dioxin on nervous system. For ated cRNAs were synthesized from 5 μgRNAsampleswiththe example, the suppression of dioxin on the AChE activity is a new Genechip expression 3′ amplification reagents (one-cycle cDNA explanation for the neuronal defects induced by dioxin (Xie et al., synthesis, and IVT labeling) kits of Affymetrix, and biotinylated 2013). Finding out more target genes is necessary for the further probes were hybridized to an Affymetrix Rat Genome 230 2.0 investigation of the neurotoxicity of dioxin. array. Microarrays were washed and scanned in an Affymetrix In the present study, to screen differentially expression gene GeneChip Scanner 3000, and the comparison of gene expression in response to dioxin toxicity in the brain, complementary profiles between the control and treated samples was per- deoxyribonucleic acid (cRNA) microarray analysis was applied formed by using a standard significance analysis of microarray to investigate a global view of molecular changes associated with software (Affymetrix Microarray Suite 5.0). the mechanisms underlying toxicity following dioxin exposure. The neurotoxicity of dioxin leading to multiple types of neuro- 1.3. Gene Ontology (GO) and pathway enrichment analysis logical disorder in aging brain, might be resulted by interaction of various types of cells and through complex processes. So we Genes showing differential expression were functionally classi- investigate the whole brain to obtain gene altered by dioxin and fied based on the GO database using the Database for Annota- predict possible biological processes and signal pathways affect- tion, Visualization and Integrated Discovery rate (DAVID) tool ed by dioxin. (Huang et al., 2009). The significantly altered GO functions with a false discovery rate (FDR) < 0.05 were identified. To identify the pathways significantly associated with the 1. Methods and materials genes of interest, the potentially altered pathways with a p-value <0.05 were predicted using Kyoto Encyclopedia of 1.1. Animals and TCDD exposure Genes and Genomes (KEGG) Orthology-Based Annotation System (KOBAS) based on the cumulative hypergeometric Twenty-four male Sprague–Dawley (SD) rats were purchased distribution algorithm (Wu et al., 2006). from Vital River Laboratories (VRL; Beijing, China) and housed in the Institute of Psychology (CAS) under specific pathogen-free 1.4. Quantitative RT-PCR conditions, at a controlled temperature of (24 ± 2)°C and humidity of 50% ± 10%, with a cycle of 12 hr light and 12 hr Real-time quantitative real-time polymerase chain reaction dark. Animals were provided with pellet foods and water ad (RT-PCR) was used to confirm the differential expression of libitum, and randomly assigned into two groups, TCDD-treated several dioxin-responsive genes detected in the microarray groups and one vehicle control (Rat received Dimethyl sulfoxide analysis. First strand complementary cDNA synthesis was (DMSO) diluted in olive oil served as the control). TCDD (Toronto performed on 2 μg RNA (RevertAid First Strand
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