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Systems Toxicology of Male Reproductive Development: Profiling 774 Chemicals for Molecular Targets and Adverse Outcomes
Leung, M., J. Phuong, N. Baker, N. Sipes, G. Klinefelter, M. Martin, K. McLaurin, Woodrow Setzer, S. Darney, R. Judson, AND T. Knudsen. Systems Toxicology of Male Reproductive Development: Profiling 774 Chemicals for Molecular Targets and Adverse Outcomes. ENVIRONMENTAL HEALTH PERSPECTIVES. National Institute of Environmental Health Sciences (NIEHS), Research Triangle Park, NC, 124(7):1050-1061, (2016).
Imbalances in androgen and estrogen signaling have been a general focus in male reproductive toxicology research. While a number of recent studies have demonstrated that both hormonal and non-hormonal signaling is involved in male reproductive developmental defects, the present study extends these findings, showing androgen and estrogen receptors to be only a subset of the potential landscape of molecular targets. Nuclear receptors and vascular remodeling proteins are identified as two important parameters for further multi-scale modeling of MRDT, which will capture the spatio-temporal patterns of male reproductive tract development. In combination with further HTS experiments that cover more molecular targets in embryonic development, this a posteriori approach will provide novel mechanistic insights for MDRT in general and TDS in particular, and enable prediction of whether the occurrence of one adverse outcome may predict the risk of another.
Adverse trends in male reproductive health have been reported for increased rates of testicular germ cell tumor, low semen quality, cryptorchidism, and hypospadias. An association with prenatal environmental exposure has been inferred from human and animal studies underlying male reproductive developmental defects. The present study established the links between environmental chemicals, molecular targets, and adverse outcomes using U.S. EPA animal study (ToxRefDB) and high-throughput screening (ToxCast) databases. This systems-based approach revealed a phenotypic hierarchy across 63 chemicals and a pleiotropic in vitro bioactivity profile. Although estrogenic and anti-androgenic activities have been extensively studied in male reproductive developmental toxicity, the present study showed these receptor targets to be only a subset of the potential landscape of molecular targets. A variety of chemical (e.g. phthalates, conazoles, carbamates, and phenol compounds) and bioactivity (e.g. nuclear receptors, vascular remodeling proteins, and cytochrome-P450 reductases) clusters further suggested multiple pathways leading to the adverse outcomes. This points to the need for multi-scale systems models to predict whether the occurrence of one adverse outcome may predict the risk of another.