Systems Toxicology of Male Reproductive Development: Profiling 774 Chemicals for Molecular Targets and Adverse Outcomes
Trends in male reproductive health have been reported for increased rates of testicular germ cell tumors, low semen quality, cryptorchidism, and hypospadias, which have been associated with prenatal environmental chemical exposure based on human and animal studies. In the present study we aimed to i...
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| creator | Leung, Maxwell C K Phuong, Jimmy Baker, Nancy C Sipes, Nisha S Klinefelter, Gary R Martin, Matthew T McLaurin, Keith W Setzer, R Woodrow Darney, Sally Perreault Judson, Richard S Knudsen, Thomas B |
| description | Trends in male reproductive health have been reported for increased rates of testicular germ cell tumors, low semen quality, cryptorchidism, and hypospadias, which have been associated with prenatal environmental chemical exposure based on human and animal studies.
In the present study we aimed to identify significant correlations between environmental chemicals, molecular targets, and adverse outcomes across a broad chemical landscape with emphasis on developmental toxicity of the male reproductive system.
We used U.S. EPA's animal study database (ToxRefDB) and a comprehensive literature analysis to identify 774 chemicals that have been evaluated for adverse effects on male reproductive parameters, and then used U.S. EPA's in vitro high-throughput screening (HTS) database (ToxCastDB) to profile their bioactivity across approximately 800 molecular and cellular features.
A phenotypic hierarchy of testicular atrophy, sperm effects, tumors, and malformations, a composite resembling the human testicular dysgenesis syndrome (TDS) hypothesis, was observed in 281 chemicals. A subset of 54 chemicals with male developmental consequences had in vitro bioactivity on molecular targets that could be condensed into 156 gene annotations in a bipartite network.
Computational modeling of available in vivo and in vitro data for chemicals that produce adverse effects on male reproductive end points revealed a phenotypic hierarchy across animal studies consistent with the human TDS hypothesis. We confirmed the known role of estrogen and androgen signaling pathways in rodent TDS, and importantly, broadened the list of molecular targets to include retinoic acid signaling, vascular remodeling proteins, G-protein coupled receptors (GPCRs), and cytochrome P450s.
Leung MC, Phuong J, Baker NC, Sipes NS, Klinefelter GR, Martin MT, McLaurin KW, Setzer RW, Darney SP, Judson RS, Knudsen TB. 2016. Systems toxicology of male reproductive development: profiling 774 chemicals for molecular targets and adverse outcomes. Environ Health Perspect 124:1050-1061; http://dx.doi.org/10.1289/ehp.1510385. |
| doi_str_mv | 10.1289/ehp.1510385 |
| format | Article |
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In the present study we aimed to identify significant correlations between environmental chemicals, molecular targets, and adverse outcomes across a broad chemical landscape with emphasis on developmental toxicity of the male reproductive system.
We used U.S. EPA's animal study database (ToxRefDB) and a comprehensive literature analysis to identify 774 chemicals that have been evaluated for adverse effects on male reproductive parameters, and then used U.S. EPA's in vitro high-throughput screening (HTS) database (ToxCastDB) to profile their bioactivity across approximately 800 molecular and cellular features.
A phenotypic hierarchy of testicular atrophy, sperm effects, tumors, and malformations, a composite resembling the human testicular dysgenesis syndrome (TDS) hypothesis, was observed in 281 chemicals. A subset of 54 chemicals with male developmental consequences had in vitro bioactivity on molecular targets that could be condensed into 156 gene annotations in a bipartite network.
Computational modeling of available in vivo and in vitro data for chemicals that produce adverse effects on male reproductive end points revealed a phenotypic hierarchy across animal studies consistent with the human TDS hypothesis. We confirmed the known role of estrogen and androgen signaling pathways in rodent TDS, and importantly, broadened the list of molecular targets to include retinoic acid signaling, vascular remodeling proteins, G-protein coupled receptors (GPCRs), and cytochrome P450s.
Leung MC, Phuong J, Baker NC, Sipes NS, Klinefelter GR, Martin MT, McLaurin KW, Setzer RW, Darney SP, Judson RS, Knudsen TB. 2016. Systems toxicology of male reproductive development: profiling 774 chemicals for molecular targets and adverse outcomes. Environ Health Perspect 124:1050-1061; http://dx.doi.org/10.1289/ehp.1510385.</description><identifier>ISSN: 0091-6765</identifier><identifier>EISSN: 1552-9924</identifier><identifier>DOI: 10.1289/ehp.1510385</identifier><identifier>PMID: 26662846</identifier><language>eng</language><publisher>United States: National Institute of Environmental Health Sciences</publisher><subject>Abnormalities ; Androgens ; Cell adhesion & migration ; Chemicals ; Computational biology ; Cryptorchidism ; Databases, Factual ; Defects ; Disease susceptibility ; Environmental aspects ; Environmental Exposure - statistics & numerical data ; Environmental health ; Environmental Pollutants - toxicity ; Estrogens ; Growth factors ; Homeostasis ; Humans ; Hypospadias ; Hypotheses ; Infertility ; Laboratory animals ; Male ; Male reproductive system ; Medical research ; Medicine, Experimental ; Methods ; Mutation ; Neoplasms, Germ Cell and Embryonal ; Prenatal development ; Quality ; Reproduction ; Reproductive health ; Reproductive organs, Male ; Reproductive system ; Rodents ; Semen Analysis ; Side effects ; Sperm ; Studies ; Systems Analysis ; Testes ; Testicular Neoplasms ; Testis - drug effects ; Testis - growth & development ; Testosterone ; Toxicity ; Toxicology ; Tumors</subject><ispartof>Environmental health perspectives, 2016-07, Vol.124 (7), p.1050-1061</ispartof><rights>COPYRIGHT 2016 National Institute of Environmental Health Sciences</rights><rights>Copyright National Institute of Environmental Health Sciences Jul 2016</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c646t-577aa427a83112961cc8dfb82bf70a9e61ff00898c369a0fbf5e0cd5b344917d3</citedby><cites>FETCH-LOGICAL-c646t-577aa427a83112961cc8dfb82bf70a9e61ff00898c369a0fbf5e0cd5b344917d3</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/PMC4937872/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4937872/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,315,728,781,785,865,886,27928,27929,53795,53797</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26662846$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Leung, Maxwell C K</creatorcontrib><creatorcontrib>Phuong, Jimmy</creatorcontrib><creatorcontrib>Baker, Nancy C</creatorcontrib><creatorcontrib>Sipes, Nisha S</creatorcontrib><creatorcontrib>Klinefelter, Gary R</creatorcontrib><creatorcontrib>Martin, Matthew T</creatorcontrib><creatorcontrib>McLaurin, Keith W</creatorcontrib><creatorcontrib>Setzer, R Woodrow</creatorcontrib><creatorcontrib>Darney, Sally Perreault</creatorcontrib><creatorcontrib>Judson, Richard S</creatorcontrib><creatorcontrib>Knudsen, Thomas B</creatorcontrib><title>Systems Toxicology of Male Reproductive Development: Profiling 774 Chemicals for Molecular Targets and Adverse Outcomes</title><title>Environmental health perspectives</title><addtitle>Environ Health Perspect</addtitle><description>Trends in male reproductive health have been reported for increased rates of testicular germ cell tumors, low semen quality, cryptorchidism, and hypospadias, which have been associated with prenatal environmental chemical exposure based on human and animal studies.
In the present study we aimed to identify significant correlations between environmental chemicals, molecular targets, and adverse outcomes across a broad chemical landscape with emphasis on developmental toxicity of the male reproductive system.
We used U.S. EPA's animal study database (ToxRefDB) and a comprehensive literature analysis to identify 774 chemicals that have been evaluated for adverse effects on male reproductive parameters, and then used U.S. EPA's in vitro high-throughput screening (HTS) database (ToxCastDB) to profile their bioactivity across approximately 800 molecular and cellular features.
A phenotypic hierarchy of testicular atrophy, sperm effects, tumors, and malformations, a composite resembling the human testicular dysgenesis syndrome (TDS) hypothesis, was observed in 281 chemicals. A subset of 54 chemicals with male developmental consequences had in vitro bioactivity on molecular targets that could be condensed into 156 gene annotations in a bipartite network.
Computational modeling of available in vivo and in vitro data for chemicals that produce adverse effects on male reproductive end points revealed a phenotypic hierarchy across animal studies consistent with the human TDS hypothesis. We confirmed the known role of estrogen and androgen signaling pathways in rodent TDS, and importantly, broadened the list of molecular targets to include retinoic acid signaling, vascular remodeling proteins, G-protein coupled receptors (GPCRs), and cytochrome P450s.
Leung MC, Phuong J, Baker NC, Sipes NS, Klinefelter GR, Martin MT, McLaurin KW, Setzer RW, Darney SP, Judson RS, Knudsen TB. 2016. Systems toxicology of male reproductive development: profiling 774 chemicals for molecular targets and adverse outcomes. Environ Health Perspect 124:1050-1061; http://dx.doi.org/10.1289/ehp.1510385.</description><subject>Abnormalities</subject><subject>Androgens</subject><subject>Cell adhesion & migration</subject><subject>Chemicals</subject><subject>Computational biology</subject><subject>Cryptorchidism</subject><subject>Databases, Factual</subject><subject>Defects</subject><subject>Disease susceptibility</subject><subject>Environmental aspects</subject><subject>Environmental Exposure - statistics & numerical data</subject><subject>Environmental health</subject><subject>Environmental Pollutants - toxicity</subject><subject>Estrogens</subject><subject>Growth factors</subject><subject>Homeostasis</subject><subject>Humans</subject><subject>Hypospadias</subject><subject>Hypotheses</subject><subject>Infertility</subject><subject>Laboratory animals</subject><subject>Male</subject><subject>Male reproductive system</subject><subject>Medical research</subject><subject>Medicine, Experimental</subject><subject>Methods</subject><subject>Mutation</subject><subject>Neoplasms, Germ Cell and Embryonal</subject><subject>Prenatal development</subject><subject>Quality</subject><subject>Reproduction</subject><subject>Reproductive health</subject><subject>Reproductive organs, Male</subject><subject>Reproductive system</subject><subject>Rodents</subject><subject>Semen Analysis</subject><subject>Side effects</subject><subject>Sperm</subject><subject>Studies</subject><subject>Systems Analysis</subject><subject>Testes</subject><subject>Testicular Neoplasms</subject><subject>Testis - drug effects</subject><subject>Testis - growth & 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Toxicology of Male Reproductive Development: Profiling 774 Chemicals for Molecular Targets and Adverse Outcomes</title><author>Leung, Maxwell C K ; Phuong, Jimmy ; Baker, Nancy C ; Sipes, Nisha S ; Klinefelter, Gary R ; Martin, Matthew T ; McLaurin, Keith W ; Setzer, R Woodrow ; Darney, Sally Perreault ; Judson, Richard S ; Knudsen, Thomas B</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c646t-577aa427a83112961cc8dfb82bf70a9e61ff00898c369a0fbf5e0cd5b344917d3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2016</creationdate><topic>Abnormalities</topic><topic>Androgens</topic><topic>Cell adhesion & migration</topic><topic>Chemicals</topic><topic>Computational biology</topic><topic>Cryptorchidism</topic><topic>Databases, Factual</topic><topic>Defects</topic><topic>Disease susceptibility</topic><topic>Environmental aspects</topic><topic>Environmental Exposure - statistics & numerical 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Perspect</addtitle><date>2016-07-01</date><risdate>2016</risdate><volume>124</volume><issue>7</issue><spage>1050</spage><epage>1061</epage><pages>1050-1061</pages><issn>0091-6765</issn><eissn>1552-9924</eissn><abstract>Trends in male reproductive health have been reported for increased rates of testicular germ cell tumors, low semen quality, cryptorchidism, and hypospadias, which have been associated with prenatal environmental chemical exposure based on human and animal studies.
In the present study we aimed to identify significant correlations between environmental chemicals, molecular targets, and adverse outcomes across a broad chemical landscape with emphasis on developmental toxicity of the male reproductive system.
We used U.S. EPA's animal study database (ToxRefDB) and a comprehensive literature analysis to identify 774 chemicals that have been evaluated for adverse effects on male reproductive parameters, and then used U.S. EPA's in vitro high-throughput screening (HTS) database (ToxCastDB) to profile their bioactivity across approximately 800 molecular and cellular features.
A phenotypic hierarchy of testicular atrophy, sperm effects, tumors, and malformations, a composite resembling the human testicular dysgenesis syndrome (TDS) hypothesis, was observed in 281 chemicals. A subset of 54 chemicals with male developmental consequences had in vitro bioactivity on molecular targets that could be condensed into 156 gene annotations in a bipartite network.
Computational modeling of available in vivo and in vitro data for chemicals that produce adverse effects on male reproductive end points revealed a phenotypic hierarchy across animal studies consistent with the human TDS hypothesis. We confirmed the known role of estrogen and androgen signaling pathways in rodent TDS, and importantly, broadened the list of molecular targets to include retinoic acid signaling, vascular remodeling proteins, G-protein coupled receptors (GPCRs), and cytochrome P450s.
Leung MC, Phuong J, Baker NC, Sipes NS, Klinefelter GR, Martin MT, McLaurin KW, Setzer RW, Darney SP, Judson RS, Knudsen TB. 2016. Systems toxicology of male reproductive development: profiling 774 chemicals for molecular targets and adverse outcomes. Environ Health Perspect 124:1050-1061; http://dx.doi.org/10.1289/ehp.1510385.</abstract><cop>United States</cop><pub>National Institute of Environmental Health Sciences</pub><pmid>26662846</pmid><doi>10.1289/ehp.1510385</doi><oa>free_for_read</oa></addata></record> |
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| ispartof | Environmental health perspectives, 2016-07, Vol.124 (7), p.1050-1061 |
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| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_4937872 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central Open Access; JSTOR Archive Collection A-Z Listing; PubMed Central |
| subjects | Abnormalities Androgens Cell adhesion & migration Chemicals Computational biology Cryptorchidism Databases, Factual Defects Disease susceptibility Environmental aspects Environmental Exposure - statistics & numerical data Environmental health Environmental Pollutants - toxicity Estrogens Growth factors Homeostasis Humans Hypospadias Hypotheses Infertility Laboratory animals Male Male reproductive system Medical research Medicine, Experimental Methods Mutation Neoplasms, Germ Cell and Embryonal Prenatal development Quality Reproduction Reproductive health Reproductive organs, Male Reproductive system Rodents Semen Analysis Side effects Sperm Studies Systems Analysis Testes Testicular Neoplasms Testis - drug effects Testis - growth & development Testosterone Toxicity Toxicology Tumors |
| title | Systems Toxicology of Male Reproductive Development: Profiling 774 Chemicals for Molecular Targets and Adverse Outcomes |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-16T23%3A52%3A36IST&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=Systems%20Toxicology%20of%20Male%20Reproductive%20Development:%20Profiling%20774%20Chemicals%20for%20Molecular%20Targets%20and%20Adverse%20Outcomes&rft.jtitle=Environmental%20health%20perspectives&rft.au=Leung,%20Maxwell%20C%20K&rft.date=2016-07-01&rft.volume=124&rft.issue=7&rft.spage=1050&rft.epage=1061&rft.pages=1050-1061&rft.issn=0091-6765&rft.eissn=1552-9924&rft_id=info:doi/10.1289/ehp.1510385&rft_dat=%3Cgale_pubme%3EA457693833%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=1801036391&rft_id=info:pmid/26662846&rft_galeid=A457693833&rfr_iscdi=true |