Typical neurobehavioral methods and transcriptome analysis reveal the neurotoxicity and mechanisms of di(2-ethylhexyl) phthalate on pubertal male ICR mice with type 2 diabetes mellitus

In the present study, the neurotoxicity and mechanisms of di-(2-ethylhexyl) phthalate (DEHP) exposure on pubertal normal (P-normal) and pubertal type 2 diabetes mellitus (P-T2DM) mice were investigated by typical neurobehavioral methods and transcriptome analysis. Pubertal male ICR mice were orally...

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Veröffentlicht in:Archives of toxicology 2020-04, Vol.94 (4), p.1279-1302
Hauptverfasser: Feng, Weiwei, Liu, Yongchao, Ding, Yangyang, Mao, Guanghua, Zhao, Ting, Chen, Kun, Qiu, Xuchun, Xu, Tong, Zhao, XiaoFeng, Wu, Xiangyang, Yang, Liuqing
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container_issue 4
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container_title Archives of toxicology
container_volume 94
creator Feng, Weiwei
Liu, Yongchao
Ding, Yangyang
Mao, Guanghua
Zhao, Ting
Chen, Kun
Qiu, Xuchun
Xu, Tong
Zhao, XiaoFeng
Wu, Xiangyang
Yang, Liuqing
description In the present study, the neurotoxicity and mechanisms of di-(2-ethylhexyl) phthalate (DEHP) exposure on pubertal normal (P-normal) and pubertal type 2 diabetes mellitus (P-T2DM) mice were investigated by typical neurobehavioral methods and transcriptome analysis. Pubertal male ICR mice were orally exposed to DEHP (0.18, 1.8, 18 and 180 mg/kg/d) for 3 weeks. In Open field test, DEHP significantly increased the time in central area staying and decreased the total distance and clockwise (CW) rotation of P-normal and P-T2DM mice. Morris water maze showed that DEHP significantly increased the latency in locating platform and decreased the original platform quadrant and residence time in target quadrant of P-normal and P-T2DM mice. Transcriptome analysis results revealed the effects of DEHP exposure on neural signaling pathway including biogenic amines neurotransmitters, nerve receptors, neurobiological processes, etc. Enzyme-linked immunosorbent assay (ELISA) and western blotting results showed that DEHP significantly decreased the contents of 5-HT, cAMP, GABA and Ca 2+ , the levels of CREB, phosphorylation of PKA, ERK1/2 and CREB, increased the levels of CaM and phosphorylation of CaMKII in P-normal and P-T2DM mice. Factorial analysis results showed that P-T2DM mice were more sensitive than those of P-normal mice. The potential neurotoxicity mechanism of DEHP may be synergistically mediated by the cAMP–PKA–ERK1/2–CREB signaling and the Ca 2+ signaling pathway. Article highlights DEHP can cause neurotoxicity in P-normal and P-T2DM mice. P-T2DM mice were more sensitive to DEHP than P-normal mice. Transcriptome analysis revealed genes associated with nervous system. DEHP may be synergistically mediated by the cAMP–PKA–ERK1/2–CREB signaling and the Ca 2+ signaling pathway.
doi_str_mv 10.1007/s00204-020-02683-9
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Pubertal male ICR mice were orally exposed to DEHP (0.18, 1.8, 18 and 180 mg/kg/d) for 3 weeks. In Open field test, DEHP significantly increased the time in central area staying and decreased the total distance and clockwise (CW) rotation of P-normal and P-T2DM mice. Morris water maze showed that DEHP significantly increased the latency in locating platform and decreased the original platform quadrant and residence time in target quadrant of P-normal and P-T2DM mice. Transcriptome analysis results revealed the effects of DEHP exposure on neural signaling pathway including biogenic amines neurotransmitters, nerve receptors, neurobiological processes, etc. Enzyme-linked immunosorbent assay (ELISA) and western blotting results showed that DEHP significantly decreased the contents of 5-HT, cAMP, GABA and Ca 2+ , the levels of CREB, phosphorylation of PKA, ERK1/2 and CREB, increased the levels of CaM and phosphorylation of CaMKII in P-normal and P-T2DM mice. Factorial analysis results showed that P-T2DM mice were more sensitive than those of P-normal mice. The potential neurotoxicity mechanism of DEHP may be synergistically mediated by the cAMP–PKA–ERK1/2–CREB signaling and the Ca 2+ signaling pathway. Article highlights DEHP can cause neurotoxicity in P-normal and P-T2DM mice. P-T2DM mice were more sensitive to DEHP than P-normal mice. Transcriptome analysis revealed genes associated with nervous system. DEHP may be synergistically mediated by the cAMP–PKA–ERK1/2–CREB signaling and the Ca 2+ signaling pathway.</description><identifier>ISSN: 0340-5761</identifier><identifier>EISSN: 1432-0738</identifier><identifier>DOI: 10.1007/s00204-020-02683-9</identifier><identifier>PMID: 32303808</identifier><language>eng</language><publisher>Berlin/Heidelberg: Springer Berlin Heidelberg</publisher><subject>Amines ; Animals ; Biogenic amines ; Biomedical and Life Sciences ; Biomedicine ; Ca2+/calmodulin-dependent protein kinase II ; Calcium ions ; Calcium signalling ; Cyclic AMP response element-binding protein ; Diabetes ; Diabetes mellitus ; Diabetes mellitus (non-insulin dependent) ; Diabetes Mellitus, Type 2 ; Diethylhexyl Phthalate - toxicity ; Endocrine Disruptors - toxicity ; Environmental Health ; Enzyme-linked immunosorbent assay ; Exposure ; Factorial analysis ; Field tests ; Gene expression ; Gene Expression Profiling ; Kinases ; Latency ; Life Sciences &amp; Biomedicine ; Male ; Mice ; Mice, Inbred ICR ; Nervous system ; Nervous System - drug effects ; Nervous System - metabolism ; Neurotoxicity ; Neurotoxicity Syndromes ; Neurotransmitters ; Occupational Medicine/Industrial Medicine ; Open-field behavior ; Organ Toxicity and Mechanisms ; Pharmacology/Toxicology ; Phosphorylation ; Phthalates ; Phthalic Acids ; Protein kinase A ; Science &amp; Technology ; Signal transduction ; Signaling ; Toxicology ; Western blotting ; γ-Aminobutyric acid</subject><ispartof>Archives of toxicology, 2020-04, Vol.94 (4), p.1279-1302</ispartof><rights>Springer-Verlag GmbH Germany, part of Springer Nature 2020</rights><rights>Springer-Verlag GmbH Germany, part of Springer Nature 2020.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>true</woscitedreferencessubscribed><woscitedreferencescount>22</woscitedreferencescount><woscitedreferencesoriginalsourcerecordid>wos000532990200015</woscitedreferencesoriginalsourcerecordid><citedby>FETCH-LOGICAL-c375t-9cffa609ec7bd602d0091d911fc1bb453f014c5e533477e50e505b160de5a53a3</citedby><cites>FETCH-LOGICAL-c375t-9cffa609ec7bd602d0091d911fc1bb453f014c5e533477e50e505b160de5a53a3</cites><orcidid>0000-0002-3856-5539 ; 0000-0002-1974-1824</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1007/s00204-020-02683-9$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1007/s00204-020-02683-9$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>315,782,786,27931,27932,28255,41495,42564,51326</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/32303808$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Feng, Weiwei</creatorcontrib><creatorcontrib>Liu, Yongchao</creatorcontrib><creatorcontrib>Ding, Yangyang</creatorcontrib><creatorcontrib>Mao, Guanghua</creatorcontrib><creatorcontrib>Zhao, Ting</creatorcontrib><creatorcontrib>Chen, Kun</creatorcontrib><creatorcontrib>Qiu, Xuchun</creatorcontrib><creatorcontrib>Xu, Tong</creatorcontrib><creatorcontrib>Zhao, XiaoFeng</creatorcontrib><creatorcontrib>Wu, Xiangyang</creatorcontrib><creatorcontrib>Yang, Liuqing</creatorcontrib><title>Typical neurobehavioral methods and transcriptome analysis reveal the neurotoxicity and mechanisms of di(2-ethylhexyl) phthalate on pubertal male ICR mice with type 2 diabetes mellitus</title><title>Archives of toxicology</title><addtitle>Arch Toxicol</addtitle><addtitle>ARCH TOXICOL</addtitle><addtitle>Arch Toxicol</addtitle><description>In the present study, the neurotoxicity and mechanisms of di-(2-ethylhexyl) phthalate (DEHP) exposure on pubertal normal (P-normal) and pubertal type 2 diabetes mellitus (P-T2DM) mice were investigated by typical neurobehavioral methods and transcriptome analysis. Pubertal male ICR mice were orally exposed to DEHP (0.18, 1.8, 18 and 180 mg/kg/d) for 3 weeks. In Open field test, DEHP significantly increased the time in central area staying and decreased the total distance and clockwise (CW) rotation of P-normal and P-T2DM mice. Morris water maze showed that DEHP significantly increased the latency in locating platform and decreased the original platform quadrant and residence time in target quadrant of P-normal and P-T2DM mice. Transcriptome analysis results revealed the effects of DEHP exposure on neural signaling pathway including biogenic amines neurotransmitters, nerve receptors, neurobiological processes, etc. Enzyme-linked immunosorbent assay (ELISA) and western blotting results showed that DEHP significantly decreased the contents of 5-HT, cAMP, GABA and Ca 2+ , the levels of CREB, phosphorylation of PKA, ERK1/2 and CREB, increased the levels of CaM and phosphorylation of CaMKII in P-normal and P-T2DM mice. Factorial analysis results showed that P-T2DM mice were more sensitive than those of P-normal mice. The potential neurotoxicity mechanism of DEHP may be synergistically mediated by the cAMP–PKA–ERK1/2–CREB signaling and the Ca 2+ signaling pathway. Article highlights DEHP can cause neurotoxicity in P-normal and P-T2DM mice. P-T2DM mice were more sensitive to DEHP than P-normal mice. Transcriptome analysis revealed genes associated with nervous system. DEHP may be synergistically mediated by the cAMP–PKA–ERK1/2–CREB signaling and the Ca 2+ signaling pathway.</description><subject>Amines</subject><subject>Animals</subject><subject>Biogenic amines</subject><subject>Biomedical and Life Sciences</subject><subject>Biomedicine</subject><subject>Ca2+/calmodulin-dependent protein kinase II</subject><subject>Calcium ions</subject><subject>Calcium signalling</subject><subject>Cyclic AMP response element-binding protein</subject><subject>Diabetes</subject><subject>Diabetes mellitus</subject><subject>Diabetes mellitus (non-insulin dependent)</subject><subject>Diabetes Mellitus, Type 2</subject><subject>Diethylhexyl Phthalate - toxicity</subject><subject>Endocrine Disruptors - toxicity</subject><subject>Environmental Health</subject><subject>Enzyme-linked immunosorbent assay</subject><subject>Exposure</subject><subject>Factorial analysis</subject><subject>Field tests</subject><subject>Gene expression</subject><subject>Gene Expression Profiling</subject><subject>Kinases</subject><subject>Latency</subject><subject>Life Sciences &amp; Biomedicine</subject><subject>Male</subject><subject>Mice</subject><subject>Mice, Inbred ICR</subject><subject>Nervous system</subject><subject>Nervous System - drug effects</subject><subject>Nervous System - metabolism</subject><subject>Neurotoxicity</subject><subject>Neurotoxicity Syndromes</subject><subject>Neurotransmitters</subject><subject>Occupational Medicine/Industrial Medicine</subject><subject>Open-field behavior</subject><subject>Organ Toxicity and Mechanisms</subject><subject>Pharmacology/Toxicology</subject><subject>Phosphorylation</subject><subject>Phthalates</subject><subject>Phthalic Acids</subject><subject>Protein kinase A</subject><subject>Science &amp; Technology</subject><subject>Signal transduction</subject><subject>Signaling</subject><subject>Toxicology</subject><subject>Western blotting</subject><subject>γ-Aminobutyric acid</subject><issn>0340-5761</issn><issn>1432-0738</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>AOWDO</sourceid><sourceid>EIF</sourceid><sourceid>8G5</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNqNkV1r1zAUxoso7u_0C3ghAW8UqZ4kTV8uR_FlMBBkXpc0PbUZbVOTdFu_mR_P81_nvBMhOSHh9zwnyZMkLzm85wDFhwAgIEup0MxLmVaPkgPPpEihkOXj5AAyg1QVOT9JnoVwBcBFWcmnyYkUEmQJ5SH5dbkt1uiRzbh61-Kgr63ztJ8wDq4LTM8di17PwXi7RDchnehxCzYwj9dIZBxwV0d3a42N251mQjPo2YYpMNezzr4RKTlu44C32_iWLUMc9KgjMjezZW3Rx2NTPSI7r7-xyRpkNzYOLG4LMkEGusWIgXzH0cY1PE-e9HoM-OJ-PU2-f_p4WX9JL75-Pq_PLlIjCxXTyvS9zqFCU7RdDqIDqHhXcd4b3raZkj3wzChUUmZFgQpoqJbn0KHSSmp5mrzefRfvfq4YYnPlVk9fEBqRgSgpCVURJXbKeBeCx75ZvJ203xoOzTGsZg-rodLchdUcRa_urdd2wu5B8icdAt7twA22rg_G4mzwAQPqLEVVkSUlq4gu_5-ubdTRurl26xxJKndpIHz-gf7vI_9x_9_tC8QJ</recordid><startdate>20200401</startdate><enddate>20200401</enddate><creator>Feng, Weiwei</creator><creator>Liu, Yongchao</creator><creator>Ding, Yangyang</creator><creator>Mao, Guanghua</creator><creator>Zhao, Ting</creator><creator>Chen, Kun</creator><creator>Qiu, Xuchun</creator><creator>Xu, Tong</creator><creator>Zhao, XiaoFeng</creator><creator>Wu, Xiangyang</creator><creator>Yang, Liuqing</creator><general>Springer Berlin Heidelberg</general><general>Springer Nature</general><general>Springer Nature B.V</general><scope>AOWDO</scope><scope>BLEPL</scope><scope>DTL</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7T2</scope><scope>7TK</scope><scope>7U7</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>88I</scope><scope>8AO</scope><scope>8C1</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>8G5</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>GUQSH</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>M0S</scope><scope>M1P</scope><scope>M2O</scope><scope>M2P</scope><scope>MBDVC</scope><scope>PATMY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PYCSY</scope><scope>Q9U</scope><orcidid>https://orcid.org/0000-0002-3856-5539</orcidid><orcidid>https://orcid.org/0000-0002-1974-1824</orcidid></search><sort><creationdate>20200401</creationdate><title>Typical neurobehavioral methods and transcriptome analysis reveal the neurotoxicity and mechanisms of di(2-ethylhexyl) phthalate on pubertal male ICR mice with type 2 diabetes mellitus</title><author>Feng, Weiwei ; Liu, Yongchao ; Ding, Yangyang ; Mao, Guanghua ; Zhao, Ting ; Chen, Kun ; Qiu, Xuchun ; Xu, Tong ; Zhao, XiaoFeng ; Wu, Xiangyang ; Yang, Liuqing</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c375t-9cffa609ec7bd602d0091d911fc1bb453f014c5e533477e50e505b160de5a53a3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>Amines</topic><topic>Animals</topic><topic>Biogenic amines</topic><topic>Biomedical and Life Sciences</topic><topic>Biomedicine</topic><topic>Ca2+/calmodulin-dependent protein kinase II</topic><topic>Calcium ions</topic><topic>Calcium signalling</topic><topic>Cyclic AMP response element-binding protein</topic><topic>Diabetes</topic><topic>Diabetes mellitus</topic><topic>Diabetes mellitus (non-insulin dependent)</topic><topic>Diabetes Mellitus, Type 2</topic><topic>Diethylhexyl Phthalate - toxicity</topic><topic>Endocrine Disruptors - toxicity</topic><topic>Environmental Health</topic><topic>Enzyme-linked immunosorbent assay</topic><topic>Exposure</topic><topic>Factorial analysis</topic><topic>Field tests</topic><topic>Gene expression</topic><topic>Gene Expression Profiling</topic><topic>Kinases</topic><topic>Latency</topic><topic>Life Sciences &amp; Biomedicine</topic><topic>Male</topic><topic>Mice</topic><topic>Mice, Inbred ICR</topic><topic>Nervous system</topic><topic>Nervous System - drug effects</topic><topic>Nervous System - metabolism</topic><topic>Neurotoxicity</topic><topic>Neurotoxicity Syndromes</topic><topic>Neurotransmitters</topic><topic>Occupational Medicine/Industrial Medicine</topic><topic>Open-field behavior</topic><topic>Organ Toxicity and Mechanisms</topic><topic>Pharmacology/Toxicology</topic><topic>Phosphorylation</topic><topic>Phthalates</topic><topic>Phthalic Acids</topic><topic>Protein kinase A</topic><topic>Science &amp; Technology</topic><topic>Signal transduction</topic><topic>Signaling</topic><topic>Toxicology</topic><topic>Western blotting</topic><topic>γ-Aminobutyric acid</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Feng, Weiwei</creatorcontrib><creatorcontrib>Liu, Yongchao</creatorcontrib><creatorcontrib>Ding, Yangyang</creatorcontrib><creatorcontrib>Mao, Guanghua</creatorcontrib><creatorcontrib>Zhao, Ting</creatorcontrib><creatorcontrib>Chen, Kun</creatorcontrib><creatorcontrib>Qiu, Xuchun</creatorcontrib><creatorcontrib>Xu, Tong</creatorcontrib><creatorcontrib>Zhao, XiaoFeng</creatorcontrib><creatorcontrib>Wu, Xiangyang</creatorcontrib><creatorcontrib>Yang, Liuqing</creatorcontrib><collection>Web of Science - Science Citation Index Expanded - 2020</collection><collection>Web of Science Core Collection</collection><collection>Science Citation Index Expanded</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Health and Safety Science Abstracts (Full archive)</collection><collection>Neurosciences Abstracts</collection><collection>Toxicology Abstracts</collection><collection>Health &amp; 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Pubertal male ICR mice were orally exposed to DEHP (0.18, 1.8, 18 and 180 mg/kg/d) for 3 weeks. In Open field test, DEHP significantly increased the time in central area staying and decreased the total distance and clockwise (CW) rotation of P-normal and P-T2DM mice. Morris water maze showed that DEHP significantly increased the latency in locating platform and decreased the original platform quadrant and residence time in target quadrant of P-normal and P-T2DM mice. Transcriptome analysis results revealed the effects of DEHP exposure on neural signaling pathway including biogenic amines neurotransmitters, nerve receptors, neurobiological processes, etc. Enzyme-linked immunosorbent assay (ELISA) and western blotting results showed that DEHP significantly decreased the contents of 5-HT, cAMP, GABA and Ca 2+ , the levels of CREB, phosphorylation of PKA, ERK1/2 and CREB, increased the levels of CaM and phosphorylation of CaMKII in P-normal and P-T2DM mice. Factorial analysis results showed that P-T2DM mice were more sensitive than those of P-normal mice. The potential neurotoxicity mechanism of DEHP may be synergistically mediated by the cAMP–PKA–ERK1/2–CREB signaling and the Ca 2+ signaling pathway. Article highlights DEHP can cause neurotoxicity in P-normal and P-T2DM mice. P-T2DM mice were more sensitive to DEHP than P-normal mice. Transcriptome analysis revealed genes associated with nervous system. DEHP may be synergistically mediated by the cAMP–PKA–ERK1/2–CREB signaling and the Ca 2+ signaling pathway.</abstract><cop>Berlin/Heidelberg</cop><pub>Springer Berlin Heidelberg</pub><pmid>32303808</pmid><doi>10.1007/s00204-020-02683-9</doi><tpages>24</tpages><orcidid>https://orcid.org/0000-0002-3856-5539</orcidid><orcidid>https://orcid.org/0000-0002-1974-1824</orcidid></addata></record>
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subjects Amines
Animals
Biogenic amines
Biomedical and Life Sciences
Biomedicine
Ca2+/calmodulin-dependent protein kinase II
Calcium ions
Calcium signalling
Cyclic AMP response element-binding protein
Diabetes
Diabetes mellitus
Diabetes mellitus (non-insulin dependent)
Diabetes Mellitus, Type 2
Diethylhexyl Phthalate - toxicity
Endocrine Disruptors - toxicity
Environmental Health
Enzyme-linked immunosorbent assay
Exposure
Factorial analysis
Field tests
Gene expression
Gene Expression Profiling
Kinases
Latency
Life Sciences & Biomedicine
Male
Mice
Mice, Inbred ICR
Nervous system
Nervous System - drug effects
Nervous System - metabolism
Neurotoxicity
Neurotoxicity Syndromes
Neurotransmitters
Occupational Medicine/Industrial Medicine
Open-field behavior
Organ Toxicity and Mechanisms
Pharmacology/Toxicology
Phosphorylation
Phthalates
Phthalic Acids
Protein kinase A
Science & Technology
Signal transduction
Signaling
Toxicology
Western blotting
γ-Aminobutyric acid
title Typical neurobehavioral methods and transcriptome analysis reveal the neurotoxicity and mechanisms of di(2-ethylhexyl) phthalate on pubertal male ICR mice with type 2 diabetes mellitus
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