TY - JOUR
T1 - Systems toxicology of male reproductive development
T2 - Profiling 774 chemicals for molecular targets and adverse outcomes
AU - Leung, Maxwell C.K.
AU - Phuong, Jimmy
AU - Baker, Nancy C.
AU - Sipes, Nisha S.
AU - Klinefelter, Gary R.
AU - Martin, Matthew T.
AU - McLaurin, Keith W.
AU - Woodrow Setzer, R.
AU - Darney, Sally Perreault
AU - Judson, Richard S.
AU - Knudsen, Thomas B.
N1 - Publisher Copyright:
© 2016, Public Health Services, US Dept of Health and Human Services. All rights reserved.
PY - 2016/7
Y1 - 2016/7
N2 - Background: 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. oBjective: 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. Methods: 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 reproduc-tive 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. results: 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. conclusion: 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.
AB - Background: 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. oBjective: 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. Methods: 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 reproduc-tive 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. results: 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. conclusion: 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.
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U2 - 10.1289/ehp.1510385
DO - 10.1289/ehp.1510385
M3 - Article
C2 - 26662846
AN - SCOPUS:84977160684
SN - 0091-6765
VL - 124
SP - 1050
EP - 1061
JO - Environmental health perspectives
JF - Environmental health perspectives
IS - 7
ER -