Repeated administration of ethambutol in therapeutic dose causes testes alteration and spermatogenesis disruption in Wistar rats
Ethambutol (EMB) is conventionally used to treat tuberculosis and atypical Mycobacterium infections in combination with other antimycobacterial drugs. Eventually, EMB testicular toxicity has not been explored extensively yet. The aim of the study is to evaluate testicular toxicity of EMB. We explore...
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| Veröffentlicht in: | Human & experimental toxicology 2017-05, Vol.36 (5), p.520-533 |
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| creator | Shayakhmetova, GM Bondarenko, LB Voronina, AK Matvienko, AV Kitam, V Kovalenko, VM |
| description | Ethambutol (EMB) is conventionally used to treat tuberculosis and atypical Mycobacterium infections in combination with other antimycobacterial drugs. Eventually, EMB testicular toxicity has not been explored extensively yet. The aim of the study is to evaluate testicular toxicity of EMB. We explored the impact of EMB on male rats’ fertility, testosterone level and germ cells state, testicular pro- and anti-oxidant status and DNA damage, as well as identified EMB effects on cytochrome P-450 2E1 (CYP2E1) both with computer simulation and in vivo. We demonstrated that EMB administration to male rats decreased in epididymal sperm count (19%) and fertility index (53%). These events were accompanied by reduction in serum testosterone content (1.6 times) and appearance of spermatogenic epithelium damages. It was also found in testes the intensification of lipid peroxidation, decrease in reduced glutathione content and changes in DNA fragmentation. Additionally, computer simulation showed direct interaction of EMB with CYP2E1 active site and heme. On the top of this, we demonstrated that level of testicular CYP2E1 messenger RNA in EMB-treated rats was increased 8.7 folds and p-nitrophenol hydroxylase activity in testes rose three folds. As this shows, EMB-caused CYP2E1 induction, oxidative stress, and apoptosis in the testes contribute to inhibition of steroidogenesis enzymes and spermatogenesis disruption. |
| doi_str_mv | 10.1177/0960327116655390 |
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Eventually, EMB testicular toxicity has not been explored extensively yet. The aim of the study is to evaluate testicular toxicity of EMB. We explored the impact of EMB on male rats’ fertility, testosterone level and germ cells state, testicular pro- and anti-oxidant status and DNA damage, as well as identified EMB effects on cytochrome P-450 2E1 (CYP2E1) both with computer simulation and in vivo. We demonstrated that EMB administration to male rats decreased in epididymal sperm count (19%) and fertility index (53%). These events were accompanied by reduction in serum testosterone content (1.6 times) and appearance of spermatogenic epithelium damages. It was also found in testes the intensification of lipid peroxidation, decrease in reduced glutathione content and changes in DNA fragmentation. Additionally, computer simulation showed direct interaction of EMB with CYP2E1 active site and heme. On the top of this, we demonstrated that level of testicular CYP2E1 messenger RNA in EMB-treated rats was increased 8.7 folds and p-nitrophenol hydroxylase activity in testes rose three folds. As this shows, EMB-caused CYP2E1 induction, oxidative stress, and apoptosis in the testes contribute to inhibition of steroidogenesis enzymes and spermatogenesis disruption.</description><identifier>ISSN: 0960-3271</identifier><identifier>EISSN: 1477-0903</identifier><identifier>DOI: 10.1177/0960327116655390</identifier><identifier>PMID: 27334974</identifier><language>eng</language><publisher>London, England: SAGE Publications</publisher><subject>Amplification ; Animals ; Antitubercular Agents - toxicity ; Apoptosis ; Biocompatibility ; Computer simulation ; Cytochrome ; Cytochrome P-450 CYP2E1 - genetics ; Cytochrome P-450 CYP2E1 - metabolism ; Damage detection ; Deoxyribonucleic acid ; Disruption ; DNA ; DNA damage ; DNA Fragmentation ; Drugs ; Enzymes ; Epithelium ; Ethambutol ; Ethambutol - toxicity ; Fertility ; Fertility - drug effects ; Fragmentation ; Germ cells ; Glutathione ; Heme ; Hydroxylase ; Inhibition ; Lipid peroxidation ; Male ; mRNA ; Nitrophenol ; Oxidative stress ; Peroxidation ; Rats ; Rats, Wistar ; Ribonucleic acid ; RNA ; RNA, Messenger - metabolism ; Rodents ; Sperm ; Sperm Count ; Spermatogenesis ; Spermatogenesis - drug effects ; Steroidogenesis ; Studies ; Testes ; Testis - drug effects ; Testis - metabolism ; Testis - pathology ; Testosterone ; Testosterone - blood ; Toxicity ; Tuberculosis</subject><ispartof>Human & experimental toxicology, 2017-05, Vol.36 (5), p.520-533</ispartof><rights>The Author(s) 2016</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c365t-ef56d8563468131724b4a53331b05c93d05246098e46f7f0627c5aafb230e5ce3</citedby><cites>FETCH-LOGICAL-c365t-ef56d8563468131724b4a53331b05c93d05246098e46f7f0627c5aafb230e5ce3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://journals.sagepub.com/doi/pdf/10.1177/0960327116655390$$EPDF$$P50$$Gsage$$H</linktopdf><linktohtml>$$Uhttps://journals.sagepub.com/doi/10.1177/0960327116655390$$EHTML$$P50$$Gsage$$H</linktohtml><link.rule.ids>314,776,780,21945,27830,27901,27902,44921,45309</link.rule.ids><linktorsrc>$$Uhttps://journals.sagepub.com/doi/full/10.1177/0960327116655390?utm_source=summon&utm_medium=discovery-provider$$EView_record_in_SAGE_Publications$$FView_record_in_$$GSAGE_Publications</linktorsrc><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/27334974$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Shayakhmetova, GM</creatorcontrib><creatorcontrib>Bondarenko, LB</creatorcontrib><creatorcontrib>Voronina, AK</creatorcontrib><creatorcontrib>Matvienko, AV</creatorcontrib><creatorcontrib>Kitam, V</creatorcontrib><creatorcontrib>Kovalenko, VM</creatorcontrib><title>Repeated administration of ethambutol in therapeutic dose causes testes alteration and spermatogenesis disruption in Wistar rats</title><title>Human & experimental toxicology</title><addtitle>Hum Exp Toxicol</addtitle><description>Ethambutol (EMB) is conventionally used to treat tuberculosis and atypical Mycobacterium infections in combination with other antimycobacterial drugs. Eventually, EMB testicular toxicity has not been explored extensively yet. The aim of the study is to evaluate testicular toxicity of EMB. We explored the impact of EMB on male rats’ fertility, testosterone level and germ cells state, testicular pro- and anti-oxidant status and DNA damage, as well as identified EMB effects on cytochrome P-450 2E1 (CYP2E1) both with computer simulation and in vivo. We demonstrated that EMB administration to male rats decreased in epididymal sperm count (19%) and fertility index (53%). These events were accompanied by reduction in serum testosterone content (1.6 times) and appearance of spermatogenic epithelium damages. It was also found in testes the intensification of lipid peroxidation, decrease in reduced glutathione content and changes in DNA fragmentation. Additionally, computer simulation showed direct interaction of EMB with CYP2E1 active site and heme. On the top of this, we demonstrated that level of testicular CYP2E1 messenger RNA in EMB-treated rats was increased 8.7 folds and p-nitrophenol hydroxylase activity in testes rose three folds. As this shows, EMB-caused CYP2E1 induction, oxidative stress, and apoptosis in the testes contribute to inhibition of steroidogenesis enzymes and spermatogenesis disruption.</description><subject>Amplification</subject><subject>Animals</subject><subject>Antitubercular Agents - toxicity</subject><subject>Apoptosis</subject><subject>Biocompatibility</subject><subject>Computer simulation</subject><subject>Cytochrome</subject><subject>Cytochrome P-450 CYP2E1 - genetics</subject><subject>Cytochrome P-450 CYP2E1 - metabolism</subject><subject>Damage detection</subject><subject>Deoxyribonucleic acid</subject><subject>Disruption</subject><subject>DNA</subject><subject>DNA damage</subject><subject>DNA Fragmentation</subject><subject>Drugs</subject><subject>Enzymes</subject><subject>Epithelium</subject><subject>Ethambutol</subject><subject>Ethambutol - toxicity</subject><subject>Fertility</subject><subject>Fertility - drug effects</subject><subject>Fragmentation</subject><subject>Germ cells</subject><subject>Glutathione</subject><subject>Heme</subject><subject>Hydroxylase</subject><subject>Inhibition</subject><subject>Lipid peroxidation</subject><subject>Male</subject><subject>mRNA</subject><subject>Nitrophenol</subject><subject>Oxidative stress</subject><subject>Peroxidation</subject><subject>Rats</subject><subject>Rats, Wistar</subject><subject>Ribonucleic acid</subject><subject>RNA</subject><subject>RNA, Messenger - metabolism</subject><subject>Rodents</subject><subject>Sperm</subject><subject>Sperm Count</subject><subject>Spermatogenesis</subject><subject>Spermatogenesis - drug effects</subject><subject>Steroidogenesis</subject><subject>Studies</subject><subject>Testes</subject><subject>Testis - drug effects</subject><subject>Testis - metabolism</subject><subject>Testis - pathology</subject><subject>Testosterone</subject><subject>Testosterone - blood</subject><subject>Toxicity</subject><subject>Tuberculosis</subject><issn>0960-3271</issn><issn>1477-0903</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp1kc1r1UAUxQdR7Gt170oG3LiJvfOdLKVULRSEYnEZJslNOyXJxLmThTv_dOf1PUUKwoW7OL9z7oXD2BsBH4Rw7hwaC0o6Iaw1RjXwjO2Edq6CBtRzttvL1V4_YadEDwBgGyNeshPplNKN0zv26wZX9BkH7oc5LIFy8jnEhceRY773c7flOPGw8HyPya-45dDzIRLy3m-ExDNSGe6njEerXwZOK6bZ53iHC1IgPgRK2_ool6zv5Y5PvPD0ir0Y_UT4-rjP2O2ny28XX6rrr5-vLj5eV72yJlc4GjvUxipta6GEk7rT3iilRAemb9QARmoLTY3ajm4EK11vvB87qQBNj-qMvT_krin-2MrP7Ryox2nyC8aNWlFL60Cp2hX03RP0IW5pKd-1ohFSWiu0KRQcqD5FooRju6Yw-_SzFdDu22mftlMsb4_BWzfj8Nfwp44CVAeA_B3-c_V_gb8B9keYQw</recordid><startdate>201705</startdate><enddate>201705</enddate><creator>Shayakhmetova, GM</creator><creator>Bondarenko, LB</creator><creator>Voronina, AK</creator><creator>Matvienko, AV</creator><creator>Kitam, V</creator><creator>Kovalenko, VM</creator><general>SAGE Publications</general><general>Sage Publications Ltd</general><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>7ST</scope><scope>7TK</scope><scope>7U7</scope><scope>C1K</scope><scope>K9.</scope><scope>NAPCQ</scope><scope>SOI</scope><scope>7X8</scope></search><sort><creationdate>201705</creationdate><title>Repeated administration of ethambutol in therapeutic dose causes testes alteration and spermatogenesis disruption in Wistar rats</title><author>Shayakhmetova, GM ; Bondarenko, LB ; Voronina, AK ; Matvienko, AV ; Kitam, V ; Kovalenko, VM</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c365t-ef56d8563468131724b4a53331b05c93d05246098e46f7f0627c5aafb230e5ce3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>Amplification</topic><topic>Animals</topic><topic>Antitubercular Agents - toxicity</topic><topic>Apoptosis</topic><topic>Biocompatibility</topic><topic>Computer simulation</topic><topic>Cytochrome</topic><topic>Cytochrome P-450 CYP2E1 - genetics</topic><topic>Cytochrome P-450 CYP2E1 - metabolism</topic><topic>Damage detection</topic><topic>Deoxyribonucleic acid</topic><topic>Disruption</topic><topic>DNA</topic><topic>DNA damage</topic><topic>DNA Fragmentation</topic><topic>Drugs</topic><topic>Enzymes</topic><topic>Epithelium</topic><topic>Ethambutol</topic><topic>Ethambutol - toxicity</topic><topic>Fertility</topic><topic>Fertility - drug effects</topic><topic>Fragmentation</topic><topic>Germ cells</topic><topic>Glutathione</topic><topic>Heme</topic><topic>Hydroxylase</topic><topic>Inhibition</topic><topic>Lipid peroxidation</topic><topic>Male</topic><topic>mRNA</topic><topic>Nitrophenol</topic><topic>Oxidative stress</topic><topic>Peroxidation</topic><topic>Rats</topic><topic>Rats, Wistar</topic><topic>Ribonucleic acid</topic><topic>RNA</topic><topic>RNA, Messenger - metabolism</topic><topic>Rodents</topic><topic>Sperm</topic><topic>Sperm Count</topic><topic>Spermatogenesis</topic><topic>Spermatogenesis - drug effects</topic><topic>Steroidogenesis</topic><topic>Studies</topic><topic>Testes</topic><topic>Testis - drug effects</topic><topic>Testis - metabolism</topic><topic>Testis - pathology</topic><topic>Testosterone</topic><topic>Testosterone - blood</topic><topic>Toxicity</topic><topic>Tuberculosis</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Shayakhmetova, GM</creatorcontrib><creatorcontrib>Bondarenko, LB</creatorcontrib><creatorcontrib>Voronina, AK</creatorcontrib><creatorcontrib>Matvienko, AV</creatorcontrib><creatorcontrib>Kitam, V</creatorcontrib><creatorcontrib>Kovalenko, VM</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Environment Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Toxicology Abstracts</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Premium</collection><collection>Environment Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Human & experimental toxicology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext_linktorsrc</fulltext></delivery><addata><au>Shayakhmetova, GM</au><au>Bondarenko, LB</au><au>Voronina, AK</au><au>Matvienko, AV</au><au>Kitam, V</au><au>Kovalenko, VM</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Repeated administration of ethambutol in therapeutic dose causes testes alteration and spermatogenesis disruption in Wistar rats</atitle><jtitle>Human & experimental toxicology</jtitle><addtitle>Hum Exp Toxicol</addtitle><date>2017-05</date><risdate>2017</risdate><volume>36</volume><issue>5</issue><spage>520</spage><epage>533</epage><pages>520-533</pages><issn>0960-3271</issn><eissn>1477-0903</eissn><abstract>Ethambutol (EMB) is conventionally used to treat tuberculosis and atypical Mycobacterium infections in combination with other antimycobacterial drugs. Eventually, EMB testicular toxicity has not been explored extensively yet. The aim of the study is to evaluate testicular toxicity of EMB. We explored the impact of EMB on male rats’ fertility, testosterone level and germ cells state, testicular pro- and anti-oxidant status and DNA damage, as well as identified EMB effects on cytochrome P-450 2E1 (CYP2E1) both with computer simulation and in vivo. We demonstrated that EMB administration to male rats decreased in epididymal sperm count (19%) and fertility index (53%). These events were accompanied by reduction in serum testosterone content (1.6 times) and appearance of spermatogenic epithelium damages. It was also found in testes the intensification of lipid peroxidation, decrease in reduced glutathione content and changes in DNA fragmentation. Additionally, computer simulation showed direct interaction of EMB with CYP2E1 active site and heme. On the top of this, we demonstrated that level of testicular CYP2E1 messenger RNA in EMB-treated rats was increased 8.7 folds and p-nitrophenol hydroxylase activity in testes rose three folds. As this shows, EMB-caused CYP2E1 induction, oxidative stress, and apoptosis in the testes contribute to inhibition of steroidogenesis enzymes and spermatogenesis disruption.</abstract><cop>London, England</cop><pub>SAGE Publications</pub><pmid>27334974</pmid><doi>10.1177/0960327116655390</doi><tpages>14</tpages></addata></record> |
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| subjects | Amplification Animals Antitubercular Agents - toxicity Apoptosis Biocompatibility Computer simulation Cytochrome Cytochrome P-450 CYP2E1 - genetics Cytochrome P-450 CYP2E1 - metabolism Damage detection Deoxyribonucleic acid Disruption DNA DNA damage DNA Fragmentation Drugs Enzymes Epithelium Ethambutol Ethambutol - toxicity Fertility Fertility - drug effects Fragmentation Germ cells Glutathione Heme Hydroxylase Inhibition Lipid peroxidation Male mRNA Nitrophenol Oxidative stress Peroxidation Rats Rats, Wistar Ribonucleic acid RNA RNA, Messenger - metabolism Rodents Sperm Sperm Count Spermatogenesis Spermatogenesis - drug effects Steroidogenesis Studies Testes Testis - drug effects Testis - metabolism Testis - pathology Testosterone Testosterone - blood Toxicity Tuberculosis |
| title | Repeated administration of ethambutol in therapeutic dose causes testes alteration and spermatogenesis disruption in Wistar rats |
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