Environmental Electrophile-Mediated Toxicity in Mice Lacking Nrf2, CSE, or Both
Transcription factor Nrf2 (nuclear factor-erythroid 2-related factor 2) plays a key role in detoxification of electrophiles via formation of glutathione (GSH) adducts and subsequent excretion into extracellular spaces. We found that reactive sulfur species (RSS), such as cysteine persulfides produce...
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| Veröffentlicht in: | Environmental health perspectives 2019-06, Vol.127 (6), p.67002 |
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| creator | Akiyama, Masahiro Unoki, Takamitsu Shinkai, Yasuhiro Ishii, Isao Ida, Tomoaki Akaike, Takaaki Yamamoto, Masayuki Kumagai, Yoshito |
| description | Transcription factor Nrf2 (nuclear factor-erythroid 2-related factor 2) plays a key role in detoxification of electrophiles via formation of glutathione (GSH) adducts and subsequent excretion into extracellular spaces. We found that reactive sulfur species (RSS), such as cysteine persulfides produced by cystathionine [Formula: see text] (CSE), capture environmental electrophiles through formation of sulfur adducts. However, contributions of Nrf2 and CSE to the blockage of environmental electrophile-mediated toxicity remain to be evaluated.
The aim of this study was to clarify roles that CSE and Nrf2 play in the protection against various environmental electrophiles. We also wished to clarify the molecular basis of the developmental window of toxicity through investigating expression levels of Nrf2, RSS-producing enzymes, and sulfur nucleophiles during developmental stages of mice.
Wild-type (WT), CSE knockout (KO), Nrf2 KO, Nrf2/CSE double KO (DKO) mice, and their primary hepatocytes were analyzed in this study. Cadmium (Cd), methylmercury (MeHg), 1,4-naphthoquinone, crotonaldehyde, and acrylamide were used. We conducted Western blotting, real-time polymerase chain reaction (PCR), 3-(4,5-dimethylthiazol-2-yl)-2,5-triphenyl tetrazolium bromide (MTT) assays, liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS) analysis, alanine transaminase (ALT) activity, histopathological analysis, and rotarod test.
Primary hepatocytes from DKO mice were significantly more sensitive to the environmental electrophiles than each single KO counterpart. Both Nrf2 and CSE single KO mice were highly susceptible to Cd and MeHg, and such sensitivity was further exacerbated in the DKO mice. Lower-level expressions of CSE and sulfur nucleophiles than those in adult mice were observed in a window of developmental stage.
Our mouse model provided new insights into the response to environmental electrophiles; while Nrf2 is recognized as a key transcription factor for detoxification of environmental electrophiles, CSE is crucial factor to repress their toxicity in a parallel mode. In addition, the sensitivity of fetuses to MeHg appears to be, at least in part, associated with the restricted production of RSS due to low-level expression of CSE. https://doi.org/10.1289/EHP4949. |
| doi_str_mv | 10.1289/ehp4949 |
| format | Article |
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The aim of this study was to clarify roles that CSE and Nrf2 play in the protection against various environmental electrophiles. We also wished to clarify the molecular basis of the developmental window of toxicity through investigating expression levels of Nrf2, RSS-producing enzymes, and sulfur nucleophiles during developmental stages of mice.
Wild-type (WT), CSE knockout (KO), Nrf2 KO, Nrf2/CSE double KO (DKO) mice, and their primary hepatocytes were analyzed in this study. Cadmium (Cd), methylmercury (MeHg), 1,4-naphthoquinone, crotonaldehyde, and acrylamide were used. We conducted Western blotting, real-time polymerase chain reaction (PCR), 3-(4,5-dimethylthiazol-2-yl)-2,5-triphenyl tetrazolium bromide (MTT) assays, liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS) analysis, alanine transaminase (ALT) activity, histopathological analysis, and rotarod test.
Primary hepatocytes from DKO mice were significantly more sensitive to the environmental electrophiles than each single KO counterpart. Both Nrf2 and CSE single KO mice were highly susceptible to Cd and MeHg, and such sensitivity was further exacerbated in the DKO mice. Lower-level expressions of CSE and sulfur nucleophiles than those in adult mice were observed in a window of developmental stage.
Our mouse model provided new insights into the response to environmental electrophiles; while Nrf2 is recognized as a key transcription factor for detoxification of environmental electrophiles, CSE is crucial factor to repress their toxicity in a parallel mode. In addition, the sensitivity of fetuses to MeHg appears to be, at least in part, associated with the restricted production of RSS due to low-level expression of CSE. https://doi.org/10.1289/EHP4949.</description><identifier>ISSN: 0091-6765</identifier><identifier>EISSN: 1552-9924</identifier><identifier>DOI: 10.1289/ehp4949</identifier><identifier>PMID: 31166132</identifier><language>eng</language><publisher>United States: National Institute of Environmental Health Sciences</publisher><subject>Acrylamide ; Acrylamide - toxicity ; Adducts ; Alanine ; Alanine transaminase ; Aldehydes - toxicity ; Animals ; Cadmium ; Cadmium - toxicity ; Chemicals ; Cystathionine gamma-Lyase - genetics ; Cystathionine gamma-Lyase - metabolism ; Detoxification ; Developmental stages ; Dimethylmercury ; Enzymes ; Excretion ; Female ; Females ; Fetuses ; Gene Expression Regulation, Enzymologic - drug effects ; Genotype & phenotype ; Glutathione ; Hepatocytes ; Hepatocytes - drug effects ; Hepatocytes - metabolism ; Homeostasis ; Ionization ; Liquid chromatography ; Male ; Mass spectrometry ; Mass spectroscopy ; Mercury (metal) ; Metabolism ; Metabolites ; Methylmercury ; Methylmercury Compounds - toxicity ; Mice ; Mice, Knockout ; Naphthoquinones - toxicity ; NF-E2-Related Factor 2 - genetics ; NF-E2-Related Factor 2 - metabolism ; Nucleophiles ; Polymerase chain reaction ; Proteins ; Rodents ; Sensitivity ; Signal transduction ; Sulfides - chemistry ; Sulfur ; Toxicity ; Transaminase ; Western blotting</subject><ispartof>Environmental health perspectives, 2019-06, Vol.127 (6), p.67002</ispartof><rights>COPYRIGHT 2019 National Institute of Environmental Health Sciences</rights><rights>Reproduced from Environmental Health Perspectives. This article is published under https://ehp.niehs.nih.gov/about-ehp/copyright-permissions (the “License”). Notwithstanding the ProQuest Terms and conditions, you may use this content in accordance with the terms of the License.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c711t-c902c7c4652586732d921ac2796509d9260c8ceeb18c4c7c7f7d32352f42cf0b3</citedby><cites>FETCH-LOGICAL-c711t-c902c7c4652586732d921ac2796509d9260c8ceeb18c4c7c7f7d32352f42cf0b3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6794492/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6794492/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,27924,27925,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/31166132$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Akiyama, Masahiro</creatorcontrib><creatorcontrib>Unoki, Takamitsu</creatorcontrib><creatorcontrib>Shinkai, Yasuhiro</creatorcontrib><creatorcontrib>Ishii, Isao</creatorcontrib><creatorcontrib>Ida, Tomoaki</creatorcontrib><creatorcontrib>Akaike, Takaaki</creatorcontrib><creatorcontrib>Yamamoto, Masayuki</creatorcontrib><creatorcontrib>Kumagai, Yoshito</creatorcontrib><title>Environmental Electrophile-Mediated Toxicity in Mice Lacking Nrf2, CSE, or Both</title><title>Environmental health perspectives</title><addtitle>Environ Health Perspect</addtitle><description>Transcription factor Nrf2 (nuclear factor-erythroid 2-related factor 2) plays a key role in detoxification of electrophiles via formation of glutathione (GSH) adducts and subsequent excretion into extracellular spaces. We found that reactive sulfur species (RSS), such as cysteine persulfides produced by cystathionine [Formula: see text] (CSE), capture environmental electrophiles through formation of sulfur adducts. However, contributions of Nrf2 and CSE to the blockage of environmental electrophile-mediated toxicity remain to be evaluated.
The aim of this study was to clarify roles that CSE and Nrf2 play in the protection against various environmental electrophiles. We also wished to clarify the molecular basis of the developmental window of toxicity through investigating expression levels of Nrf2, RSS-producing enzymes, and sulfur nucleophiles during developmental stages of mice.
Wild-type (WT), CSE knockout (KO), Nrf2 KO, Nrf2/CSE double KO (DKO) mice, and their primary hepatocytes were analyzed in this study. Cadmium (Cd), methylmercury (MeHg), 1,4-naphthoquinone, crotonaldehyde, and acrylamide were used. We conducted Western blotting, real-time polymerase chain reaction (PCR), 3-(4,5-dimethylthiazol-2-yl)-2,5-triphenyl tetrazolium bromide (MTT) assays, liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS) analysis, alanine transaminase (ALT) activity, histopathological analysis, and rotarod test.
Primary hepatocytes from DKO mice were significantly more sensitive to the environmental electrophiles than each single KO counterpart. Both Nrf2 and CSE single KO mice were highly susceptible to Cd and MeHg, and such sensitivity was further exacerbated in the DKO mice. Lower-level expressions of CSE and sulfur nucleophiles than those in adult mice were observed in a window of developmental stage.
Our mouse model provided new insights into the response to environmental electrophiles; while Nrf2 is recognized as a key transcription factor for detoxification of environmental electrophiles, CSE is crucial factor to repress their toxicity in a parallel mode. In addition, the sensitivity of fetuses to MeHg appears to be, at least in part, associated with the restricted production of RSS due to low-level expression of CSE. https://doi.org/10.1289/EHP4949.</description><subject>Acrylamide</subject><subject>Acrylamide - toxicity</subject><subject>Adducts</subject><subject>Alanine</subject><subject>Alanine transaminase</subject><subject>Aldehydes - toxicity</subject><subject>Animals</subject><subject>Cadmium</subject><subject>Cadmium - toxicity</subject><subject>Chemicals</subject><subject>Cystathionine gamma-Lyase - genetics</subject><subject>Cystathionine gamma-Lyase - metabolism</subject><subject>Detoxification</subject><subject>Developmental stages</subject><subject>Dimethylmercury</subject><subject>Enzymes</subject><subject>Excretion</subject><subject>Female</subject><subject>Females</subject><subject>Fetuses</subject><subject>Gene Expression Regulation, Enzymologic - drug effects</subject><subject>Genotype & phenotype</subject><subject>Glutathione</subject><subject>Hepatocytes</subject><subject>Hepatocytes - drug effects</subject><subject>Hepatocytes - metabolism</subject><subject>Homeostasis</subject><subject>Ionization</subject><subject>Liquid chromatography</subject><subject>Male</subject><subject>Mass spectrometry</subject><subject>Mass spectroscopy</subject><subject>Mercury (metal)</subject><subject>Metabolism</subject><subject>Metabolites</subject><subject>Methylmercury</subject><subject>Methylmercury Compounds - toxicity</subject><subject>Mice</subject><subject>Mice, Knockout</subject><subject>Naphthoquinones - toxicity</subject><subject>NF-E2-Related Factor 2 - genetics</subject><subject>NF-E2-Related Factor 2 - metabolism</subject><subject>Nucleophiles</subject><subject>Polymerase chain reaction</subject><subject>Proteins</subject><subject>Rodents</subject><subject>Sensitivity</subject><subject>Signal transduction</subject><subject>Sulfides - chemistry</subject><subject>Sulfur</subject><subject>Toxicity</subject><subject>Transaminase</subject><subject>Western 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Electrophile-Mediated Toxicity in Mice Lacking Nrf2, CSE, or Both</title><author>Akiyama, Masahiro ; Unoki, Takamitsu ; Shinkai, Yasuhiro ; Ishii, Isao ; Ida, Tomoaki ; Akaike, Takaaki ; Yamamoto, Masayuki ; Kumagai, Yoshito</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c711t-c902c7c4652586732d921ac2796509d9260c8ceeb18c4c7c7f7d32352f42cf0b3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><topic>Acrylamide</topic><topic>Acrylamide - toxicity</topic><topic>Adducts</topic><topic>Alanine</topic><topic>Alanine transaminase</topic><topic>Aldehydes - toxicity</topic><topic>Animals</topic><topic>Cadmium</topic><topic>Cadmium - toxicity</topic><topic>Chemicals</topic><topic>Cystathionine gamma-Lyase - genetics</topic><topic>Cystathionine gamma-Lyase - metabolism</topic><topic>Detoxification</topic><topic>Developmental 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reaction</topic><topic>Proteins</topic><topic>Rodents</topic><topic>Sensitivity</topic><topic>Signal transduction</topic><topic>Sulfides - chemistry</topic><topic>Sulfur</topic><topic>Toxicity</topic><topic>Transaminase</topic><topic>Western blotting</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Akiyama, Masahiro</creatorcontrib><creatorcontrib>Unoki, Takamitsu</creatorcontrib><creatorcontrib>Shinkai, Yasuhiro</creatorcontrib><creatorcontrib>Ishii, Isao</creatorcontrib><creatorcontrib>Ida, Tomoaki</creatorcontrib><creatorcontrib>Akaike, Takaaki</creatorcontrib><creatorcontrib>Yamamoto, Masayuki</creatorcontrib><creatorcontrib>Kumagai, Yoshito</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Gale In Context: Opposing 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Editorial</collection><collection>Environment Abstracts</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Environmental health perspectives</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Akiyama, Masahiro</au><au>Unoki, Takamitsu</au><au>Shinkai, Yasuhiro</au><au>Ishii, Isao</au><au>Ida, Tomoaki</au><au>Akaike, Takaaki</au><au>Yamamoto, Masayuki</au><au>Kumagai, Yoshito</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Environmental Electrophile-Mediated Toxicity in Mice Lacking Nrf2, CSE, or Both</atitle><jtitle>Environmental health perspectives</jtitle><addtitle>Environ Health Perspect</addtitle><date>2019-06-01</date><risdate>2019</risdate><volume>127</volume><issue>6</issue><spage>67002</spage><pages>67002-</pages><issn>0091-6765</issn><eissn>1552-9924</eissn><abstract>Transcription factor Nrf2 (nuclear factor-erythroid 2-related factor 2) plays a key role in detoxification of electrophiles via formation of glutathione (GSH) adducts and subsequent excretion into extracellular spaces. We found that reactive sulfur species (RSS), such as cysteine persulfides produced by cystathionine [Formula: see text] (CSE), capture environmental electrophiles through formation of sulfur adducts. However, contributions of Nrf2 and CSE to the blockage of environmental electrophile-mediated toxicity remain to be evaluated.
The aim of this study was to clarify roles that CSE and Nrf2 play in the protection against various environmental electrophiles. We also wished to clarify the molecular basis of the developmental window of toxicity through investigating expression levels of Nrf2, RSS-producing enzymes, and sulfur nucleophiles during developmental stages of mice.
Wild-type (WT), CSE knockout (KO), Nrf2 KO, Nrf2/CSE double KO (DKO) mice, and their primary hepatocytes were analyzed in this study. Cadmium (Cd), methylmercury (MeHg), 1,4-naphthoquinone, crotonaldehyde, and acrylamide were used. We conducted Western blotting, real-time polymerase chain reaction (PCR), 3-(4,5-dimethylthiazol-2-yl)-2,5-triphenyl tetrazolium bromide (MTT) assays, liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS) analysis, alanine transaminase (ALT) activity, histopathological analysis, and rotarod test.
Primary hepatocytes from DKO mice were significantly more sensitive to the environmental electrophiles than each single KO counterpart. Both Nrf2 and CSE single KO mice were highly susceptible to Cd and MeHg, and such sensitivity was further exacerbated in the DKO mice. Lower-level expressions of CSE and sulfur nucleophiles than those in adult mice were observed in a window of developmental stage.
Our mouse model provided new insights into the response to environmental electrophiles; while Nrf2 is recognized as a key transcription factor for detoxification of environmental electrophiles, CSE is crucial factor to repress their toxicity in a parallel mode. In addition, the sensitivity of fetuses to MeHg appears to be, at least in part, associated with the restricted production of RSS due to low-level expression of CSE. https://doi.org/10.1289/EHP4949.</abstract><cop>United States</cop><pub>National Institute of Environmental Health Sciences</pub><pmid>31166132</pmid><doi>10.1289/ehp4949</doi><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0091-6765 |
| ispartof | Environmental health perspectives, 2019-06, Vol.127 (6), p.67002 |
| issn | 0091-6765 1552-9924 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_6794492 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; PubMed Central Open Access; Jstor Complete Legacy; EZB-FREE-00999 freely available EZB journals; PubMed Central |
| subjects | Acrylamide Acrylamide - toxicity Adducts Alanine Alanine transaminase Aldehydes - toxicity Animals Cadmium Cadmium - toxicity Chemicals Cystathionine gamma-Lyase - genetics Cystathionine gamma-Lyase - metabolism Detoxification Developmental stages Dimethylmercury Enzymes Excretion Female Females Fetuses Gene Expression Regulation, Enzymologic - drug effects Genotype & phenotype Glutathione Hepatocytes Hepatocytes - drug effects Hepatocytes - metabolism Homeostasis Ionization Liquid chromatography Male Mass spectrometry Mass spectroscopy Mercury (metal) Metabolism Metabolites Methylmercury Methylmercury Compounds - toxicity Mice Mice, Knockout Naphthoquinones - toxicity NF-E2-Related Factor 2 - genetics NF-E2-Related Factor 2 - metabolism Nucleophiles Polymerase chain reaction Proteins Rodents Sensitivity Signal transduction Sulfides - chemistry Sulfur Toxicity Transaminase Western blotting |
| title | Environmental Electrophile-Mediated Toxicity in Mice Lacking Nrf2, CSE, or Both |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-20T11%3A22%3A37IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Environmental%20Electrophile-Mediated%20Toxicity%20in%20Mice%20Lacking%20Nrf2,%20CSE,%20or%20Both&rft.jtitle=Environmental%20health%20perspectives&rft.au=Akiyama,%20Masahiro&rft.date=2019-06-01&rft.volume=127&rft.issue=6&rft.spage=67002&rft.pages=67002-&rft.issn=0091-6765&rft.eissn=1552-9924&rft_id=info:doi/10.1289/ehp4949&rft_dat=%3Cgale_pubme%3EA647358522%3C/gale_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2285238080&rft_id=info:pmid/31166132&rft_galeid=A647358522&rfr_iscdi=true |