{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T05:07:15Z","timestamp":1790226435447,"version":"4.1.0"},"reference-count":98,"publisher":"American Chemical Society (ACS)","issue":"7","license":[{"start":{"date-parts":[[2017,12,29]],"date-time":"2017-12-29T00:00:00Z","timestamp":1514505600000},"content-version":"vor","delay-in-days":749,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2016,7,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background:<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objective:<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods:<\/jats:title>\n                    <jats:p>We used U.S. EPA\u2019s 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\u2019s in vitro high-throughput screening (HTS) database (ToxCastDB) to profile their bioactivity across approximately 800 molecular and cellular features.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results:<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion:<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Citation:<\/jats:title>\n                    <jats:p>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\u20131061;\u2002http:\/\/dx.doi.org\/10.1289\/ehp.1510385<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1289\/ehp.1510385","type":"journal-article","created":{"date-parts":[[2015,12,11]],"date-time":"2015-12-11T15:55:54Z","timestamp":1449849354000},"page":"1050-1061","source":"Crossref","is-referenced-by-count":49,"title":["Systems Toxicology of Male Reproductive Development: Profiling 774 Chemicals for Molecular Targets and Adverse Outcomes"],"prefix":"10.1021","volume":"124","author":[{"given":"Maxwell C.K.","family":"Leung","sequence":"first","affiliation":[{"name":"Oak Ridge Institute for Science and Education, Oak Ridge, Tennessee"},{"name":"National Center for Computational Toxicology, U.S. Environmental Protection Agency (EPA), Research Triangle Park, North Carolina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jimmy","family":"Phuong","sequence":"additional","affiliation":[{"name":"National Center for Computational Toxicology, U.S. Environmental Protection Agency (EPA), Research Triangle Park, North Carolina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nancy C.","family":"Baker","sequence":"additional","affiliation":[{"name":"Lockheed Martin, Research Triangle Park, North Carolina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nisha S.","family":"Sipes","sequence":"additional","affiliation":[{"name":"Oak Ridge Institute for Science and Education, Oak Ridge, Tennessee"},{"name":"National Center for Computational Toxicology, U.S. Environmental Protection Agency (EPA), Research Triangle Park, North Carolina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gary R.","family":"Klinefelter","sequence":"additional","affiliation":[{"name":"National Health and Environmental Effects Research Laboratory, U.S. EPA, Research Triangle Park, North Carolina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew T.","family":"Martin","sequence":"additional","affiliation":[{"name":"National Center for Computational Toxicology, U.S. Environmental Protection Agency (EPA), Research Triangle Park, North Carolina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keith W.","family":"McLaurin","sequence":"additional","affiliation":[{"name":"Oak Ridge Institute for Science and Education, Oak Ridge, Tennessee"},{"name":"National Center for Computational Toxicology, U.S. Environmental Protection Agency (EPA), Research Triangle Park, North Carolina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R. Woodrow","family":"Setzer","sequence":"additional","affiliation":[{"name":"National Center for Computational Toxicology, U.S. Environmental Protection Agency (EPA), Research Triangle Park, North Carolina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sally Perreault","family":"Darney","sequence":"additional","affiliation":[{"name":"National Health and Environmental Effects Research Laboratory, U.S. EPA, Research Triangle Park, North Carolina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard S.","family":"Judson","sequence":"additional","affiliation":[{"name":"National Center for Computational Toxicology, U.S. Environmental Protection Agency (EPA), Research Triangle Park, North Carolina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas B.","family":"Knudsen","sequence":"additional","affiliation":[{"name":"National Center for Computational Toxicology, U.S. Environmental Protection Agency (EPA), Research Triangle Park, North 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