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Multiscale Systems Modeling of Male Reproductive Tract Defects: from Genes to Populations EPA Maxwell C.K

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Multiscale Systems Modeling of Male Reproductive Tract Defects: from Genes to Populations EPA Maxwell C.K Multiscale Systems Modeling of Male Reproductive Tract Defects: From Genes to Populations EPA Maxwell C.K. Leung1,2, Richard M. Spencer3, and Thomas B. Knudsen1 1 National Center for Computational Toxicology, U.S. Environmental Protection Agency, Research Triangle Park, NC, United States 27711; 2 Oak Ridge Institute for Science and Education, Oak Ridge, TN, United States 37831; 3 Lockheed Martin, Research Triangle Park, NC, www.epa.gov United States 27709 Maxwell C.K. Leung l [email protected] l 919-541-2721 o Sensitive to genetic (e.g., SHH, FGFs, EHPB, TGFB pathways) and Background chemical (e.g., estrogenic or anti-androgenic) perturbation Results of the modeling Model predictions Experimental evidence and epidemiological findings suggest a common Ventral midline fusion is a critical event, leading to urethral closure in o o Urethral tube closure was the emergent property of the model that 100% SHH sufficiency origin for several disorders of the male reproductive tract (hypogonadism, male fetuses was linked to gender-specific rates of ventral mesenchymal (64 simulations) 1 cryptorchidism, hypospadias, and germline cancers; ). The male o Multicellular agent-based models provide the cell-level decision proliferation and urethral plate endodermal apoptosis, both under developmental toxicity of 54 chemicals are reported in ToxRefDB, which is making in addition to patterning systems and extracellular gradients control of androgen signaling. associated with 156 out of a total of 293 (53%) molecular targets in the that drive individual cell behaviors and integrate them into a ToxCastDB based on the screening results of 541 biochemical and cellular coordinated multicellular response (3). Gestational Day 13.5 high-throughput assays (2). Such complexity calls for a computational Spatially dynamic signals (e.g., SHH, FGF10, and androgen) were approach to study embryogenesis as a system and the consequences of o implemented in the model to address differential adhesion, cell Hypospadias altered developmental patterning. CYP2J2 threshold Fenthion motility, proliferation, and apoptosis. Dipentyl phthalate Pentachlorophenol Carbendazim Monobenzyl phthalate Urethral Plate Epithelium (UPE) CYP2A6 THBD CYCPY3PA22C6V SOX1 1 Isoeugenol CCL2 SERPINE1 Dimethoate PTPN1 3 PPP1CA PLAUR IL1 ADORA2A A HLA-DRA PLAU Gestational Day 17.5 Sulfluramid Thiamethoxam Target node: Acetaminophen Apoptosis Growth PPARG TGFB1 CD38 Source node: F3 TP53 Dibutyl phthalatPeLAT TIMP2 Cyprodinil CSF1 SAA1 CD69 Methamidophos Atrazine Molecular ICAM1TIMP1 Novaluron TNF SELP CXCL10 CYP2C9 Chemical POU2F1 PDE5A PDE4A only for excluded UPE Tributyltin chloride ADORA1 MAOA CYP1A2 SLC18A2 target(s) CXCL9 VCAM1 STAT3CEBPB FOSJUN CD40 NFIA 2-Ethylhexanoic acid HIF1A Hexazinone 2,4- Probability of urethral closure defects was predicted on minimal SELE Dinitrotoluene Thiobencarb SMAD1 CYP2C1C9SNK2A1 o ACHE RORA CCL26 TACR1 CXCL8 NFE2L2 CYP2C12 Diethyl phthalate Dihexyl phthalate RORCRORB Color: Biological function PPARD NR4A2 Formamide THRA Methomyl MMP1 Dicyclohexyl phthalate GLI1/2/3 AR disruption of cell signaling pathways in combination PPARA Linuron Metconazole CYP2A1 RXRB Thickness: Gene Score MTF1 NR1H3 Aspirin CSF1R VDR MAOB EGRN1PY1R SMO FGFR2IIIb AHR 6-Propyl-2-thiouracil ACP1 FOXA2 Vinclozolin CYP2C1 PTGER2 1 NR1I3 Procymidone COMT MAPK3 PTCH1 The model predicted hypospadias could occur at 70% SHH, 70% FGF10 trans-Retinoic acidCYP1A1 RXRA THRB NR1I2 TSPO o CYP2A2 RARG MMP9 p,p'-DDE Steroid homeostasis and xenobiotic 2,4-Dichlorophenol CYP19A1 PTPRF RARB Spiroxamine RARA 4-Nonylphenol, branched Bisphenol PGR sufficiency, and a ≥5% reduction in AR sufficiency. metabolism NFKB1 A EGFR Diethylstilbestrol SAR115740 4- Flutamide SHH FGF10 Androgen Methyl methanesulfonate PTPN2 Octylphenol Triadimefon SB243213A PTEN ESR2 AR NR1H2 CYP3A4 PTPN1 MMP3 Developmental regulation ESR1 IL6 NR1H4 17beta-Estradiol COL3A1 CREB3 CSNK1D TBXA2R SREBF1 Disruption of SHH, FGF10, or androgen signaling leads to urethral Vascularization and angiogenesis Molinate SLC6A3 PTCH1 o NR3C1 CYP2B6 17alpha-Ethinylestradiol Mesenchyme Clothianidin LDLR HTR2C HRH1 HTR6 SMO FGFR1 MET closure defects (e.g., hypospadias). Inflammation SSR240612 HTR5A Conclusion HTR1A DRD4 TFAP2A TFAP2B GLI1/2/3 GLRA TFAP2D AR (only for preputial 1 NPY2R DRD2 SLC6A2 Neural activity SCN1A SSR150106 KCNH2 CHRM4 mesenchyme) CHRNA2 CHRM2 CHRM3 Nitrofurazon e HDAC3 CHRNA7 ADRA2B CYP2D6 Chlorpromazine hydrochloride A multicellular agent-based model successfully simulated the HTR7SLC6A4 o PHA-00543613 ADRA2C ADRA1 DRD1 ADRA1A B ADRB1 Di(2-ethylhexyl) phthalate HTR2A NEK2 only for core mesenchyme interactions between some morphoregulatory, endocrine, and HRH3 CHRM5 ADRA2A HTR3A CHRM1 GABRA1 Apoptosis Growth chemical influences during GT development. GOAL: The objective of this study is to build a multicellular agent-based Androgen Androgen Androgen Androgen o Further studies will simulate (a) additional dynamic signals identified model of genital tubercle (GT) development that simulates urethrogenesis in the chemical-target network (2), including estrogen and retinoic from the sexually-indifferent urethral plate stage to urethral tube closure. acid; and (b) population-level responses to reveal critical thresholds in Distal o Urethral tube closure was a stochastic event driven by UPE (contact, Urethral Plate fusion apoptosis) and preputial mesenchyme (proliferation, teratogenesis for complex interactions between genetic (e.g., FGF10 Epithelium (UPE) Core condensation, migration). polymorphism), environmental (e.g., androgen receptor disruption), Modeling genital tubercle (GT) Mesenchyme and lifestyle (e.g., cholesterol deficiency for SHH) factors (1, 4, 5). Androgenization Phenotype (MCS 4000) development (n = 10 sims) Septation Fusion Conden. Closure Index 100% 6/10 8/10 10/10 0.80 References Extracellular o GT development is Initially indifferent in male and female embryos 67% 2/10 5/10 10/10 0.57 Dorsal Matrix 33% 0/10 4/10 0/10 0.13 (SHH, FGF10) Lateral (1) Skakkebæk et al., 2016, Physiol. Rev. 96:55-97; (2) Leung et al., 2015, 0% 0/10 2/10 0/10 0.07 Environ. Health Perspect. (advanced publication); (3) Leung et al. o Androgen signaling drives subsequent growth and development of the male GT (submitted); (4) Carmichael et al., 2013, J. Urol. 190:1884-1892; (5) Jeong J. Clin. Invest. Proximal and McMahon, 2002, 110:591-596. Region of Preputial Ventral Ectoderm UPE Fusion Lumen Mesenchyme U.S. Environmental Protection Agency Office of Research and Development Disclaimer: This poster does not reflect EPA policy.
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