Computational Toxicology andComputational Toxicology and ...S1P2 pathwayS1P2_pathway rat CLPrat_CLP...

Computational Toxicology andComputational Toxicology and Short-term Assays for Identifying Developmental ToxicantspThomas B. Knudsen, PhD

Disclaimer: views are those of the presenter and do not necessarily reflect Agency policy nor imply endorsement of software used here

Office of Research and DevelopmentNational Center for Computational Toxicology 1Office of Research and DevelopmentNational Center for Computational Toxicology

Human Health Hazards Indicators, Sacramento March 15-16, 2010

http://www.epa.gov/ncct/toxcast/

EPANTPNCGC

project to profile the biological activity of thousands of environmental chemicals using in vitro HTS assays,

identify mechanisms in high-throughput and prioritize chemicals for more extensive toxicological evaluation

build predictive computational (in silico) models of in vivo biological response (e.g., developmental toxicity)

Office of Research and DevelopmentNational Center for Computational Toxicology 2

Developmental Toxicity

WHAT: chemical exposure during formative stages of life affecting children’s healthstages of life affecting children s health

WHY: we need to predict and understand how chemical compounds disrupt:

prenatal development (birth defects) postnatal function (developmental disabilities) postnatal function (developmental disabilities) pubertal development (impaired fertility)

HOW: biological profiling, bioinformatics, systems biology and computational models


ToxCast™ in vitro profilingCell-based assaysBiochemical HTS assays

J1 mouse ES cells (ACDC)

309 chemicals471 assays


Profiling developmental toxicityhttp://www epa gov/NCCT/toxrefdb/

ToxRefDB includes:751 prenatal studies (mostly rat, rabbit)387 h i l (283 f b th i )

http://www.epa.gov/NCCT/toxrefdb/

387 chemicals (283 for both species)293 DEV endpoints (18 target systems)194 ToxCast ‘positives’

rat ( ) rabbit ( )


SOURCE: Knudsen et al. (2009) Repro Toxicol 28: 209-219

Prenatal effects in ToxRefDB:194 ToxCast™ chemicals

CRITICAL ENDPOINT NUMBER of CHEMICALS bbit t l rabbit rat overlap

Developmental (global) 111 153 70 Skeletal_Axial 55 118 18 FetalWeightReduction 49 92 6 Skeletal Appendicular 24 50 7Skeletal_Appendicular 24 50 7Skeletal_Cranial 21 41 1 Embryo-Fetal losses 33 35 5 Urogenital (renal, ureteric) 3 19 0 JawHyoid 8 14 0yCleftLipPalate 2 11 0 Neurosensory (brain and eye) 6 8 0 BodyWall (somatic) 1 6 0 Viscera (splanchnic) 9 4 0 Cardiovascular (heart, major vessels) 6 3 0

Office of Research and DevelopmentNational Center for Computational Toxicology 6SOURCE: http://www.epa.gov/NCCT/toxrefdb/

Workflow: ToxMiner v16

ToxCast™ HTS dataUNIVARIATE ASSOCIATIONS

• t-test (continuous assay data)ToxCast HTS data (AC50s)

t test (continuous assay data)• classifier (2x2 contingency table)• Fisher’s exact test (dichotomous data)

(+)ve (-)veMULTIVARIATE MODELS

• machine learning, 80/20 split • 5- or 10-fold cross-validation

(+)ve (-)ve

(+)ve TP FP

( )ve FN TN

ToxRefDB™ DEV data

• sensitivity analysis (ROC curves)

MULTICELLULAR MODELS

(-)ve FN TN

(cLELs) MULTICELLULAR MODELS• knowledge-base (VT-KB)• computer simulations (VT-SE)• biological inferences / mechanisms


1. Univariate associationsdistribution by assay platformy y p

~1% of univariate associations in ToxMiner v16 were DEV-linked

Aggregated by species Stratified by system

C50

hits

Num

ber o

f AC

Office of Research and DevelopmentNational Center for Computational Toxicology 8SOURCE: http://www.epa.gov/NCCT/toxcast/

AC50 targets: gene symbol

target assays (154 nonredundant) mapped to ‘penetrance spectrum’

TARGET FUNCTIONAL GROUP(UV) FWR MAL RESIL8CCL2

CXCL10CXCL9IL1ATGFB1

TNFRSF10BGabra6HTR7Hrh2HTR5ANPY1RADRA1AADRA2ABdkrb2CHRM2CHRM4CHRNA4Chrna7Grm1Hrh3Oprl1

ENDPOINT

chemokine‐signal

GPCR

TARGET FUNCTIONAL GROUP(UV) FWR MAL RESIL8CCL2

CXCL10CXCL9IL1ATGFB1

TNFRSF10B

ENDPOINT

chemokine‐signal

target pathways inferred from perturbation score

Oprl1OPRL1OPRM1P2RY1Tacr3DRD2

ADORA1Htr4

PTGER2AKT1AKT2

CSNK1DMAPK3

MAPKAPK2METPTPN6PTPRB

RPS6KA5SGK1SRCTEKABL1BTKFYN

GSK3B

kinase‐phosphatase

Gabra6HTR7Hrh2HTR5ANPY1RADRA1AADRA2ABdkrb2CHRM2CHRM4PPM1A

PRKACAPTPN12PTPN4PTPRCPTPRFPTPRMCHUK

CSNK2A1PTPN9LYNCD40CD38F3

MMP1PLATPLAUPLAURSELETIMP2SAA1

HLA‐DRA

tissue factor

CHRM4CHRNA4Chrna7Grm1Hrh3Oprl1OPRL1OPRM1P2RY1Tacr3DRD2

GPCR

SELPTUBA1ANos1

CYP1A1Cyp2a1Cyp2b1CYP2B6Cyp2c12CYP2C9Cyp2d1Cyp2d2CYP2E1

Cyp3a23/3a1CYP3A4HMGCS2PTGS1CYP2A6Cyp2c11Cyp2c13CYP2C18

xenobiotic‐intermediary metabolism

DRD2ADORA1Htr4

PTGER2

CYP2C18CYP2C19CYP3A5GSTA2MaoaAR

ESRRGNR1I3NR3C1PPARARARARARBRORBNR1I2PPARDTHRAEGR1HIF1AJUNSOX1

nuclear receptor

nuclear factorSOURCE: H Mortensen R Judson


SREBF1CREB3H2AFXABCG2Kcnj11Scn1aSigmar1SLC6A3TspoABCB1

SLCO1B1

channel‐transporter

SOURCE: H Mortensen, R JudsonNCCT 2009

2. Multivariate models

Office of Research and DevelopmentNational Center for Computational Toxicology 10SOURCE: N Kleinstreuer , NCCT 2010

Example: inputs to ‘cleft palate’ learnerAssay_1 Assay_2 TP FP FN TN p(max)Apoptosis rat_CLP 7 82 4 167 0.095366Cell_Cycle_G1S_Checkpoint_Regulation rat_CLP 8 97 3 152 0.116864CELL_MAP_AndrogenReceptor rat_CLP 10 137 1 112 0.065042CELL_MAP_TGFBR rat_CLP 11 165 0 84 0.030038Ceramide_Signaling rat_CLP 10 118 1 131 0.148738ERKMAPK Signaling rat CLP 11 152 0 97 0.101302_S g a g at_C 5 0 9 0 0 30Estrogen_Receptor_Signaling rabbit_CLP 2 86 0 156 0.129124FOXA_transcription_factor_networks rat_CLP 10 151 1 98 0.055945FOXM1_transcription_factor_network rabbit_CLP 2 82 0 160 0.117588Innate_Immunity_Signaling rat_CLP 8 89 3 160 0.110672KEGG_Cell_cycle rat_CLP 8 93 3 156 0.111922KEGG_mTOR_signaling_pathway rat_CLP 5 21 6 228 0.112492KEGG Neuroactive ligand receptor interaction Rattus norvegicus rat CLP 8 76 3 173 0 032864

{

KEGG_Neuroactive_ligand_receptor_interaction_Rattus_norvegicus rat_CLP 8 76 3 173 0.032864KEGG_Renal_cell_carcinoma rat_CLP 10 132 1 117 0.02988KEGG_Wnt_signaling_pathway rat_CLP 9 104 2 145 0.116546PDGFR_alpha_signaling_pathway rat_CLP 9 94 2 155 0.060048PPARaRXRa_Activation rat_CLP 11 184 0 65 0.070501Presenilin_action_in_Notch_and_Wnt_signaling rat_CLP 9 95 2 154 0.085948RAR_Activation rat_CLP 10 147 1 102 0.054288S1P2 pathway rat CLP 8 89 3 160 0 127029S1P2_pathway rat_CLP 8 89 3 160 0.127029Signaling_by_TGF_beta rat_CLP 7 68 4 181 0.065642Signaling_events_mediated_by_HDAC_Class_I rat_CLP 11 138 0 111 0.045469Signaling_events_mediated_by_HDAC_Class_II rabbit_CLP 2 86 0 156 0.129124Signaling_events_mediated_by_PRL rat_CLP 5 30 6 219 0.063597Signaling_events_regulated_by_Ret_tyrosine_kinase rat_CLP 10 119 1 130 0.149391Signaling_mediated_by_p38_alpha_and_p38_beta rat_CLP 10 138 1 111 0.066863Sphingosine 1 phosphate S1P pathway rat CLP 10 122 1 127 0 13399

{

Sphingosine_1_phosphate_S1P_pathway rat_CLP 10 122 1 127 0.13399Toll_Like_Receptor_3_TLR3_Cascade rat_CLP 8 89 3 160 0.110672Toll_like_Receptor_Signaling rat_CLP 8 94 3 155 0.148722Toll_Receptor_Cascades rat_CLP 8 89 3 160 0.110672TRAF6_Mediated_Induction_of_the_antiviral_cytokine_IFN_alphabetrat_CLP 8 89 3 160 0.110672Trk_receptor_signaling_mediated_by_the_MAPK_pathway rat_CLP 5 30 6 219 0.084657VEGF_Signaling rat_CLP 5 27 6 222 0.129374VEGFR1 ifi i l CLP 5 23 6 226 0 091649


VEGFR1_specific_signals rat_CLP 5 23 6 226 0.091649Wntbeta_catenin_Signaling rat_CLP 10 121 1 128 0.050264

SOURCE: Judson et al, MS in preparation

Hypothesis:

Multiple components in vascular development are potential targets for ToxCast™ chemicalspotential targets for ToxCast™ chemicals

corollary 1:yin vitro bioactivity profiles can be used to mine a ‘toxicity

signature’ for in vivo vascular development

corollary 2:in vitro signature can inform mechanistic models during chemical disruption of embryonic vascular development


Literature mining

Office of Research and DevelopmentNational Center for Computational Toxicology 13SOURCE: Imran Shah, NCCT 2009

Amar Singh, Lockheed Martin

Key formative processes:vasculogenesis / angiogenesis

endothelial proliferation, cell migration & chemotaxis• RTK signaling: VEGF, VEGF-r, TIE2• chemokine signaling: CCL2, CXCL10

neovascular stabilization:• endothelial cell (EC) adhesion• vascular smooth muscle cell (VSMC) recruitment

extracellular matrix (ECM) degradation extracellular matrix (ECM) degradation• plasminogen activating system (PAS)• matrix metalloproteinases (MMPs)


ST BSK_3C_MBSK_4H_MBSK_KF3CTBSK_LPS_MBSK_SAg_ BSK_SM3CBSK_BE3C_BSK_hDFCBSK_KF3CTBSK_3C_uPBSK_4H_u BSK_BE3C_BSK_SM3CBSK_3C_u BSK_4H_u BSK_BE3C_BSK_SM3CBSK_BE3C_BSK_hDFCBSK_BE3C_BSK_hDFCBSK_4H_VNVS_ENZ_Weighted_Pyridaben 5.829304 5.829304 5.829304 4.875061 5.829304 5.829304 0 0 0 5.829304 0 5.829304 0 0 0 0 0 4.875061 4.39794 0 0 4.39794 0 77.42001Pyraclostr 5.829304 5.829304 5.829304 5.829304 5.829304 4.39794 0 0 0 4.875061 4.39794 4.39794 0 0 0 0 0 4.875061 5.352183 0 0 0 0 67.66989Methylene 0 4.875061 5.352183 0 0 4.875061 0 0 0 5.352183 4.875061 0 0 0 0 5.829304 0 4.875061 5.829304 0 0 4.875061 0 67.19277Flumetrali 4.875061 4.39794 0 0 0 0 0 4.39794 5.352183 4.875061 0 0 0 0 0 5.829304 4.39794 4.39794 0 0 5.829304 0 0 64.33004Propargite 5.829304 5.829304 5.352183 5.352183 5.829304 4.39794 0 0 0 5.829304 5.352183 5.829304 4.39794 0 0 0 0 4.875061 0 0 0 0 0 63.74907Trifloxystr 5.352183 5.352183 5.352183 5.352183 5.829304 4.875061 0 0 0 4.39794 0 5.352183 0 0 0 0 0 5.352183 5.352183 0 0 0 0 63.27195Zoxamide 5.352183 4.875061 4.875061 4.875061 4.875061 5.352183 0 0 0 5.352183 0 0 4.875061 0 0 0 0 4.875061 5.352183 0 0 0 0 60.88634

ToxCast™ inclusion criteria:weighted assay score

(Z,E)‐Fenp 5.352183 5.352183 4.39794 5.352183 5.829304 5.352183 0 0 0 5.829304 0 0 0 0 0 0 0 4.875061 4.875061 0 0 0 0 56.96552Abamectin 5.829304 5.352183 0 0 5.352183 4.875061 0 0 0 5.829304 0 0 4.875061 0 0 0 0 0 5.352183 0 0 0 4.411168 56.05097Fenoxycar 4.39794 4.39794 4.39794 4.39794 4.39794 4.39794 0 0 0 4.39794 0 0 0 0 0 5.829304 0 4.39794 4.39794 0 0 0 0 54.20664Etoxazole 4.875061 4.875061 4.39794 0 4.875061 4.39794 0 0 0 0 0 4.875061 0 0 0 0 4.875061 4.875061 5.352183 0 0 0 0 53.62567Chlorotha 0 5.829304 5.829304 5.829304 5.829304 5.829304 0 0 0 0 5.829304 0 5.352183 0 0 0 0 5.829304 0 0 0 0 0 51.98661Lactofen 4.875061 4.875061 0 4.39794 4.39794 5.829304 0 0 0 4.875061 4.39794 0 0 0 0 5.829304 0 0 0 0 5.829304 0 0 51.13622Dimethom 4.875061 4.39794 0 5.352183 5.352183 4.875061 0 0 0 4.39794 0 0 4.875061 0 0 5.829304 0 0 4.875061 0 0 0 0 49.70486Difenzoqu 4.875061 4.875061 5.352183 4.875061 4.875061 0 0 0 0 5.352183 0 0 0 0 0 0 0 4.39794 4.875061 0 0 0 0 48.75061Butafenac 4.39794 0 5.352183 0 0 5.829304 0 0 0 5.829304 4.875061 0 5.829304 0 0 4.39794 0 0 5.829304 0 0 0 0 48.16964Thiram 4.39794 0 4.875061 4.39794 4.39794 4.39794 0 0 0 4.39794 0 0 4.39794 0 0 5.829304 0 0 5.352183 0 0 0 0 47.79637Cyazofami 4.875061 4.875061 0 0 4.875061 0 0 0 0 4.875061 0 5.352183 0 0 0 0 0 5.352183 0 0 5.829304 0 0 47.2154Imazalil 0 4.39794 0 0 4.39794 0 0 0 5.352183 4.39794 0 4.39794 0 0 0 0 0 4.39794 4.875061 0 0 0 0 46.84213Indoxacarb 4.875061 4.875061 0 4.875061 4.875061 0 0 0 0 0 0 5.829304 0 0 0 0 0 5.829304 4.875061 0 0 0 0 46.73828S‐Bioalleth 0 4.39794 0 0 4.39794 0 0 0 0 0 0 0 0 0 0 5.829304 0 4.39794 0 0 4.875061 4.39794 0 46.36501Tetrameth 5.352183 4.39794 0 5.352183 4.875061 4.39794 0 0 0 4.39794 4.39794 0 0 0 0 4.39794 0 0 4.39794 0 0 0 0 46.36501Emamecti 5.829304 5.352183 0 5.829304 5.829304 0 0 0 0 5.829304 5.352183 0 0 0 0 0 0 0 5.829304 0 0 0 0 45.68019Azamethip 4.39794 0 4.39794 4.39794 0 4.39794 0 0 0 4.39794 0 0 4.39794 0 0 0 0 4.39794 4.875061 0 0 0 0 44.93364Maneb 0 0 0 0 4.39794 0 4.875061 0 0 0 0 0 0 0 0 5.352183 0 0 4.875061 0 0 0 5.092589 44.52813Spirodiclo 4.875061 0 0 0 5.352183 0 0 5.829304 0 0 0 0 0 0 0 0 0 5.352183 5.829304 0 0 0 0 44.24882Butralin 4.39794 4.39794 0 0 4.39794 0 0 0 0 4.39794 0 0 0 0 0 5.829304 0 4.39794 0 0 5.829304 0 0 43.87555Fluoxastro 4.875061 4.875061 4.39794 4.875061 4.875061 4.39794 0 0 0 5.352183 0 0 0 0 0 0 0 0 4.875061 0 0 0 0 43.39843Rimsulfuro 0 0 0 0 0 0 4.875061 0 5.829304 0 0 0 0 0 0 4.875061 5.352183 0 0 0 5.829304 0 0 43.29458Thiodicarb 0 0 4.875061 4.875061 0 4.39794 0 0 0 0 0 0 4.39794 0 0 5.829304 0 4.39794 4.875061 0 0 0 0 42.921313‐Iodo‐2‐p 0 4.875061 0 4.875061 4.875061 4.875061 0 0 0 5.352183 0 4.39794 4.875061 0 0 0 0 4.39794 0 0 0 0 0 42.92131Alachlor 4.39794 4.39794 0 4.39794 4.39794 0 0 0 0 0 0 0 0 0 0 5.829304 0 4.39794 0 0 4.875061 0 0 41.96707Diniconazo 0 4.39794 4.39794 0 0 0 0 0 0 0 4.39794 5.829304 0 0 0 0 0 0 4.875061 0 0 4.39794 0 41.96707Bisphenol 4.39794 4.39794 0 5.352183 5.352183 0 0 0 0 0 0 4.875061 0 0 0 0 0 4.39794 4.39794 0 0 0 0 41.96707Quinoxyfe 0 4.875061 0 0 4.875061 4.39794 0 0 0 0 0 0 0 0 0 5.829304 0 5.829304 4.875061 0 0 0 0 41.3861Naled 0 4.39794 0 4.39794 4.39794 4.875061 0 0 0 0 4.39794 0 0 0 0 5.352183 0 0 0 0 0 4.39794 0 41.01282Tebufenpy 4.875061 4.875061 0 5.829304 5.829304 0 0 0 0 4.875061 4.39794 0 0 0 0 0 0 0 4.875061 0 0 0 0 40.43185Niclosami 0 5.829304 5.829304 0 0 5.352183 0 0 0 0 5.829304 0 5.829304 0 0 0 0 0 5.829304 0 0 0 0 40.32801Diazoxon 0 0 4.39794 0 0 4.39794 0 0 5.829304 0 0 0 0 0 0 0 0 4.39794 5.352183 0 0 0 0 39.95473Rotenone 0 4.39794 0 5.829304 5.829304 0 0 0 0 5.829304 4.39794 0 0 0 0 0 0 0 0 0 0 4.39794 0 39.47761Triclosan 0 0 0 0 4.875061 0 0 0 5.829304 0 0 4.875061 0 0 0 0 5.352183 0 0 0 5.829304 0 0 38.41952Metiram‐z 0 0 4.875061 0 0 4.39794 0 0 0 0 0 0 0 0 0 4.875061 0 0 0 4.875061 0 0 4.823909 38.36991Triflumizo 0 4.875061 0 0 4.875061 4.39794 0 0 0 0 0 4.39794 0 0 0 0 0 4.39794 5.352183 0 0 0 0 38.04625Hexythiaz 0 4.875061 0 4.39794 4.39794 0 0 0 0 4.875061 0 0 0 0 0 0 0 4.875061 4.875061 0 0 0 0 38.04625Spiroxami 0 0 0 0 0 0 0 5.352183 0 4.875061 0 0 0 0 0 5.352183 5.352183 0 0 0 5.829304 0 0 37.9424Paclobutra 0 0 0 0 4.39794 0 0 0 5.352183 4.875061 0 0 0 0 0 5.829304 0 0 0 0 5.829304 0 0 37.46528Methoxyc 0 4.875061 0 4.39794 4.875061 4.39794 0 0 0 0 0 0 0 0 0 0 0 4.39794 4.875061 0 0 0 0 37.09201Resmethri 4.875061 4.875061 0 0 4.875061 0 0 0 0 4.875061 0 0 0 0 0 0 0 4.39794 4.39794 0 0 0 0 37.09201Myclobuta 0 0 0 0 0 5.829304 0 0 5.829304 4.39794 0 0 5.352183 0 0 0 0 0 4.875061 0 0 0 0 36.98816Dazomet 4.39794 0 0 4.875061 4.875061 0 0 0 0 0 0 0 0 0 0 4.39794 0 4.39794 4.39794 0 0 0 0 36.13776Dichlorvos 4.39794 4.39794 0 4.875061 4.39794 4.39794 0 0 0 0 0 0 0 0 0 4.875061 0 4.39794 0 0 0 0 0 36.13776Prochloraz 0 4.39794 0 0 4.39794 0 0 0 0 4.39794 0 4.39794 0 0 0 0 0 4.39794 4.875061 0 0 0 0 36.13776Fenitrothi 4.39794 4.39794 4.39794 4.39794 4.39794 0 0 0 0 4.875061 0 0 0 0 0 0 0 4.39794 0 0 0 0 0 35.66064Benomyl 4.875061 0 0 0 4.39794 0 0 0 5.829304 4.875061 4.875061 0 0 0 0 4.875061 0 0 0 0 0 0 0 35.55679Propetam 0 0 0 0 0 0 4.875061 0 5.829304 0 0 0 0 0 0 4.39794 0 0 0 0 4.875061 0 0 35.55679MGK 4.39794 4.39794 0 0 4.39794 0 0 0 0 4.39794 0 0 0 0 0 0 0 4.39794 4.39794 0 0 0 0 35.18352Tetracona 4.39794 4.39794 0 4.39794 4.39794 0 0 0 0 4.39794 4.39794 0 0 0 0 0 0 0 4.39794 0 0 0 0 35.18352Cyanazine 0 0 0 0 0 0 0 0 0 0 0 0 4.39794 4.875061 0 5.829304 0 0 5.352183 4.39794 0 0 0 34.602552,2‐Bis(4‐h 5.829304 4.875061 4.39794 0 5.352183 0 0 0 0 0 0 0 4.39794 0 0 0 0 0 4.875061 0 0 0 0 34.60255Difenocon 0 5.352183 0 4.875061 4.875061 4.875061 0 0 0 4.875061 0 0 0 0 0 0 0 0 4.875061 0 0 0 0 34.60255Metribuzin 0 0 0 0 0 5.829304 0 0 5.829304 0 0 0 5.352183 0 0 0 0 0 5.829304 0 0 0 0 34.4987Chlorpyrif 0 4.39794 4.39794 0 0 0 0 0 0 0 4.39794 4.875061 4.39794 0 0 0 0 0 5.829304 0 0 0 0 34.12543Forchlorfe 4.875061 4.39794 0 4.39794 4.39794 5.829304 0 0 0 4.39794 0 0 0 0 0 5.829304 0 0 0 0 0 0 0 34.12543Fludioxon 4.875061 4.39794 0 4.875061 4.875061 0 0 0 0 5.352183 4.875061 0 0 0 0 4.875061 0 0 0 0 0 0 0 34.12543Phosalone 0 4 39794 0 4 39794 4 39794 0 0 0 0 0 0 0 0 5 352183 0 5 829304 0 0 4 39794 0 0 0 0 33 17119

g y

Targets selected by literature co-occurrence with ‘vasculogenesis’ & ‘angiogenesis’: Phosalone 0 4.39794 0 4.39794 4.39794 0 0 0 0 0 0 0 0 5.352183 0 5.829304 0 0 4.39794 0 0 0 0 33.17119

Diquat dib 0 0 0 0 0 5.829304 0 4.875061 0 0 0 0 0 0 0 5.829304 0 0 0 0 5.829304 0 0 33.06734Tebupirim 0 4.39794 4.39794 0 4.39794 5.829304 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 4.39794 0 32.21694Tribufos 0 4.39794 0 4.39794 4.39794 4.39794 0 0 0 0 0 0 0 0 0 5.829304 0 0 4.39794 0 0 0 0 32.21694Bromoxyn 0 4.39794 0 0 4.39794 0 0 0 0 4.39794 4.39794 0 5.352183 0 0 0 0 4.39794 0 0 0 0 0 31.73982Acetochlo 4.39794 4.39794 0 4.39794 4.39794 4.39794 0 0 0 0 0 0 0 0 0 0 0 0 4.875061 0 0 0 0 31.73982Pendimet 0 4.39794 0 4.39794 4.39794 0 0 0 0 0 0 0 0 0 0 0 0 0 4.39794 4.875061 0 0 0 31.73982Prallethrin 0 4.39794 0 4.39794 4.39794 4.39794 0 0 0 0 0 0 0 0 0 4.39794 0 0 4.875061 0 0 0 0 31.73982Captafol 0 4.875061 5.829304 4.875061 0 0 0 0 0 0 4.875061 0 0 5.352183 0 5.829304 0 0 0 0 0 0 0 31.63597Thiazopyr 4.39794 4.39794 0 0 4.39794 0 0 0 0 4.39794 0 0 0 0 0 4.875061 0 4.39794 0 0 0 0 0 31.2627Flumiclora 4.39794 0 5.829304 4.39794 0 0 0 0 0 0 0 0 4.39794 0 0 0 0 0 5.829304 0 0 0 0 30.68173Bentazone 0 0 0 0 0 0 0 4.39794 4.875061 0 0 0 0 0 0 0 0 0 0 0 5.829304 0 0 30.20461Oxytetracy 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 5.829304 0 4.875061 0 0 0 0 4.823909 30.05115Coumapho 0 4.875061 0 0 0 0 0 0 0 0 0 0 0 0 0 5.829304 0 4.39794 4.875061 0 0 0 0 29.25037Butachlor 0 4.875061 0 0 4.875061 4.39794 0 0 0 0 0 0 4.39794 0 0 0 0 0 5.352183 0 0 0 0 29.25037Prodiamin 0 0 0 0 4.39794 0 0 0 0 0 0 0 0 0 0 5.829304 0 4.39794 4.875061 0 0 0 0 28.77325Dithiopyr 0 4.39794 0 0 4.875061 0 0 0 0 0 4.39794 0 0 0 0 5.829304 0 0 4.39794 0 0 0 0 28.29613Tebufenoz 4.875061 0 0 0 4.39794 0 0 0 0 4.39794 0 0 0 0 0 5.829304 0 4.39794 0 0 0 0 0 28.29613Bensulide 0 4.875061 0 0 0 0 0 0 0 0 0 4.875061 0 0 0 0 0 4.39794 0 0 4.875061 0 0 28.29613Famoxado 0 4.875061 0 0 4.875061 0 0 0 0 0 0 0 0 0 0 4.875061 4.875061 4.39794 0 0 0 0 0 28.29613Folpet 0 0 0 0 0 0 0 0 0 0 0 0 0 4.875061 0 5.352183 0 4.39794 4.39794 0 0 0 0 27.819Oxyfluorfe 0 4.39794 0 0 4.39794 0 0 0 0 0 0 0 0 0 0 4.875061 4.39794 0 4.875061 0 0 0 0 27.819Cyfluthrin 4.875061 4.875061 0 0 4.875061 0 0 4.39794 0 4.39794 0 0 0 0 0 0 0 0 0 0 0 0 0 27.819Dicofol 4.875061 5.352183 0 0 0 0 0 0 0 0 0 0 0 0 0 5.829304 0 0 0 0 5.829304 0 0 27.71516Aldicarb 0 0 0 0 0 5.829304 0 0 0 0 0 0 5.829304 0 0 5.352183 0 0 5.352183 0 0 0 0 27.71516Fenpropat 0 4.39794 0 0 4.39794 0 0 0 0 0 0 0 0 0 0 0 0 4.39794 4.875061 0 0 0 0 27.34188Methyl iso 4.39794 4.39794 0 0 4.39794 0 0 0 0 0 0 0 0 0 0 4.39794 0 0 0 0 4.875061 0 0 27.34188Flufenpyr‐ 0 0 0 0 0 0 5.352183 0 0 0 0 0 0 0 0 5.829304 0 0 0 0 5.352183 0 0 27.23803Diclofop‐m 4.39794 4.39794 4.39794 0 0 0 0 0 0 4.39794 0 0 0 0 0 0 0 4.39794 0 0 0 0 0 26.38764Diclosulam 4.39794 0 0 0 4.39794 0 0 0 0 0 0 0 0 0 0 0 0 4.39794 4.39794 0 0 0 0 26.38764Flusilazole 0 4.39794 0 0 4.39794 0 0 0 0 4.39794 0 4.39794 0 0 0 0 0 0 4.39794 0 0 0 0 26.38764Profenofo 0 4.39794 0 0 4.39794 0 0 0 0 0 0 4.39794 0 0 0 0 4.39794 4.39794 0 0 0 0 0 26.38764Trifluralin 0 4.39794 0 4.39794 4.39794 0 0 0 0 0 0 0 0 0 0 4.39794 0 0 4.39794 0 0 0 0 26.38764Perfluoroo 0 0 0 0 0 0 0 0 0 4.39794 0 0 0 0 0 5.829304 0 0 0 0 0 0 5.353596 26.28803Fosthiazat 0 0 0 0 0 5.352183 0 0 5.829304 0 0 0 0 0 0 0 0 0 4.39794 0 0 0 0 25.80667Tri‐allate 0 0 4.39794 4.39794 0 0 0 0 0 0 0 0 0 0 0 5.352183 0 5.829304 0 0 0 0 0 25.80667Fluroxypy 0 0 0 0 0 4.39794 0 0 5.829304 0 0 0 0 0 0 0 0 0 4.875061 0 0 0 0 25.80667Simazine 0 0 0 0 0 0 5.352183 0 0 0 0 0 0 0 0 5.352183 0 0 4.875061 0 0 0 0 25.80667Atrazine 0 0 0 0 0 0 0 0 5.829304 0 0 0 4.39794 0 0 0 0 0 4.39794 0 0 0 0 24.85243Clofentezi 0 4.39794 0 0 0 5.829304 0 0 0 0 0 5.829304 0 0 0 0 0 4.39794 0 0 0 0 0 24.85243Pyrimetha 0 4.39794 0 0 0 0 0 5.829304 0 4.39794 0 0 0 0 0 4.39794 0 0 0 0 0 0 0 24.85243Esfenvaler 0 0 0 0 0 0 4.875061 0 0 4.875061 0 0 0 0 0 5.829304 4.39794 0 0 0 0 0 0 24.85243Methyl hy 4.875061 4.39794 4.875061 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 5.352183 0 0 0 0 24.85243Perfluoroo 0 0 0 0 0 0 0 0 0 5.352183 0 0 0 0 0 5.829304 0 0 0 0 0 0 4.496209 24.67011Fluazinam 0 0 4.875061 0 0 0 0 0 0 0 0 4.875061 4.875061 0 0 0 0 4.875061 0 0 0 0 0 24.37531Permethri 4.875061 4.875061 0 0 4.875061 0 0 0 0 0 0 0 0 0 0 0 0 0 4.875061 0 0 0 0 24.37531Parathion‐ 0 4.39794 4.39794 0 0 5.352183 0 0 0 0 0 0 0 0 0 0 0 0 4.875061 0 0 0 0 23.89819d‐cis,trans 0 4.39794 0 0 0 0 0 0 0 0 0 0 0 0 0 5.829304 4.39794 4.39794 0 0 0 0 0 23.42106Clodinafop 5.352183 4.39794 0 0 0 0 0 0 0 4.875061 0 0 0 0 0 0 0 0 4.39794 0 0 0 0 23.42106Dicrotoph 0 0 0 0 0 0 0 0 5.829304 0 0 0 0 0 0 0 0 0 0 0 5.829304 0 0 23.31722Fenarimol 0 4.39794 0 0 4.39794 0 0 0 0 4.39794 0 0 0 0 0 0 0 0 4.875061 0 0 0 0 22.94394Oxadiazon 0 4.39794 4.39794 0 4.39794 0 0 0 0 0 0 0 0 0 0 0 0 0 4.875061 0 0 0 0 22.94394Diethylhe 4.875061 4.39794 0 4.39794 4.39794 0 0 0 0 4.39794 0 0 0 0 0 0 0 0 0 0 0 0 0 22.46682Fenamido 4.39794 4.39794 0 4.39794 4.39794 0 0 0 0 4.875061 0 0 0 0 0 0 0 0 0 0 0 0 0 22.46682Hexaconaz 0 4.39794 0 0 0 4.875061 0 0 0 4.39794 0 0 0 0 0 0 0 0 4.39794 0 0 0 0 22.46682Fipronil 0 0 0 0 0 5.352183 0 0 0 0 0 0 0 0 0 5.352183 0 5.829304 0 0 0 0 0 22.36297Fenthion 0 4.39794 0 0 0 0 0 0 0 0 0 0 0 0 0 5.829304 0 0 0 0 5.829304 0 0 21.88585Carboxin 0 0 0 0 0 5.352183 0 0 0 0 0 0 4.39794 0 0 0 0 0 0 0 5.829304 0 0 21.40873

vasculogenesis & angiogenesis :

decreasedecrease VEGFR2 receptor (KDR/FLK1) decreasedecrease biochemical Tie2 activity

Fluroxypy 0 0 0 0 0 4.39794 0 0 0 0 0 0 0 0 0 5.829304 0 0 0 0 5.352183 0 0 20.93161Milbemec 0 0 4.875061 0 0 0 0 0 0 5.352183 0 0 0 0 0 0 0 0 5.352183 0 0 0 0 20.93161Propazine 5.829304 0 0 0 5.829304 0 0 0 0 0 0 0 4.39794 0 0 4.39794 0 0 0 0 0 0 0 20.45449Cyprodinil 0 4.39794 4.39794 0 0 0 0 0 0 0 0 0 0 5.352183 0 5.829304 0 0 0 0 0 0 0 19.97737Isoxaben 4.39794 0 0 0 0 5.829304 0 0 0 4.39794 0 0 0 0 0 4.875061 0 0 0 0 0 0 0 19.50025Mancozeb 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 4.39794 0 0 0 0 0 0 4.982967 19.34684Acephate 0 0 0 0 0 0 4.39794 0 0 0 0 0 0 4.39794 0 5.829304 0 0 0 0 0 0 0 19.02312Acifluorfe 0 0 0 0 0 0 4.39794 0 0 4.39794 0 0 0 0 0 5.829304 0 0 0 0 0 0 0 19.02312Azoxystro 4.39794 0 0 4.39794 0 4.39794 0 0 0 5.829304 0 0 0 0 0 0 0 0 0 0 0 0 0 19.02312Cypermet 4.39794 4.39794 0 0 0 0 0 0 0 4.39794 0 0 0 0 0 5.829304 0 0 0 0 0 0 0 19.02312Dichloran 0 0 0 0 0 0 0 0 0 4.39794 0 0 0 0 0 5.352183 0 0 4.39794 0 0 0 0 18.546Benflurali 0 0 4.39794 4.39794 0 0 0 0 0 0 0 0 0 0 0 0 0 0 4.39794 0 0 0 0 17.59176Bifenthrin 4.39794 4.39794 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 4.39794 0 0 0 0 17.59176Buprofezin 0 0 0 4.39794 4.39794 0 0 0 0 0 0 0 0 0 0 0 0 0 4.39794 0 0 0 0 17.59176Phthalic ac 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 4.39794 4.39794 0 0 0 0 17.59176Iprodione 0 0 0 0 0 0 0 0 0 4.39794 0 4.39794 0 0 0 0 0 4.39794 0 0 0 0 0 17.59176Metolachl 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 4.39794 4.39794 0 0 0 0 17.59176Parathion 0 4.39794 0 0 4.39794 0 0 0 0 0 0 0 0 0 0 0 0 0 4.39794 0 0 0 0 17.59176Boscalid 0 0 0 0 0 5.829304 0 0 5.829304 0 0 0 0 0 0 0 0 0 0 0 0 0 0 17.48791Thiobenca 5.829304 0 0 0 0 5.829304 0 0 0 0 0 0 0 0 0 5.829304 0 0 0 0 0 0 0 17.48791Clopyralid 0 0 0 0 0 5.829304 0 0 0 0 0 0 4.875061 0 0 5.829304 0 0 0 0 0 0 0 16.53367Captan 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 5.829304 0 4.875061 0 0 0 0 0 15.57943Diazinon 0 0 0 0 0 5.829304 0 0 0 0 0 0 0 0 0 0 0 0 4.875061 0 0 0 0 15.57943Ethoprop 0 0 0 0 0 0 4.875061 0 0 0 0 0 0 0 0 5.829304 0 0 0 0 0 0 0 15.57943Pirimipho 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 5.829304 0 0 4.875061 0 0 0 0 15.57943Propamoc 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 5.829304 0 0 0 0 4.875061 0 0 15.57943TCMTB 0 0 0 5.352183 0 4.875061 0 0 0 5.352183 0 0 0 0 0 0 0 0 0 0 0 0 0 15.57943Fluthiacet 0 0 0 0 0 4.39794 0 0 0 0 0 0 4.875061 0 0 5.829304 0 0 0 0 0 0 0 15.10231Tefluthrin 0 0 0 4.39794 0 0 0 0 0 0 0 0 0 0 0 0 0 0 5.352183 0 0 0 0 15.10231Ametryn 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 5.352183 0 0 4.875061 0 0 0 0 15.10231Anilazine 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 5.829304 0 0 4.39794 0 0 0 0 14.62518Dibutyl ph 0 4.39794 0 0 0 0 0 0 0 0 0 0 5.829304 0 0 4.39794 0 0 0 0 0 0 0 14.62518Piperonyl 0 0 0 0 0 0 0 0 0 4.39794 0 0 0 0 0 5.829304 4.39794 0 0 0 0 0 0 14.62518Pyriproxyf 4.39794 0 0 0 0 0 0 0 0 4.39794 0 0 0 0 0 5.829304 0 0 0 0 0 0 0 14.62518Thiophana 0 4.875061 0 0 0 0 0 0 0 4.39794 0 0 0 0 0 5.352183 0 0 0 0 0 0 0 14.62518Endosulfa 0 0 0 0 0 0 0 0 0 4.875061 0 0 0 0 0 0 0 0 4.875061 0 0 0 0 14.62518Ethalflural 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 5.352183 0 0 4.39794 0 0 0 0 14.14806Propanil 0 0 0 4.39794 0 0 0 0 0 4.39794 0 5.352183 0 0 0 0 0 0 0 0 0 0 0 14.14806Propyzam 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 5.352183 0 4.39794 0 0 0 0 0 14.14806Disulfoton 4.39794 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 4.875061 0 0 0 0 14.14806Fenoxapro 0 0 0 0 0 4.39794 0 0 0 0 0 0 0 0 0 0 0 4.875061 0 0 0 0 0 14.14806Icaridin 0 0 0 0 0 0 4.875061 0 0 0 0 0 0 0 0 4.39794 0 0 0 0 0 0 0 14.14806Fenamiph 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 4.875061 0 0 0 4.39794 0 0 0 13.67094Propicona 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 4.875061 0 0 4.39794 0 0 0 0 13.67094Azinphos‐ 0 4.39794 0 4.39794 0 0 0 0 0 4.39794 0 0 0 0 0 0 0 0 0 0 0 0 0 13.19382Chlorpyrif 0 0 0 4.39794 0 0 0 0 0 4.39794 0 0 0 0 0 4.39794 0 0 0 0 0 0 0 13.19382Ethofume 4.39794 0 0 4.39794 4.39794 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 13.19382Flufenace 0 4.39794 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 4.39794 0 0 0 0 13.19382Flutolanil 4.39794 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 4.39794 0 0 0 0 13.19382Novaluron 0 0 0 0 4.39794 4.39794 0 0 0 4.39794 0 0 0 0 0 0 0 0 0 0 0 0 0 13.19382Pirimicarb 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 4.39794 0 0 0 0 4.39794 0 0 13.19382Quintozen 4.39794 0 0 0 4.39794 0 0 0 0 4.39794 0 0 0 0 0 0 0 0 0 0 0 0 0 13.19382Triadimen 0 4.39794 0 0 4.39794 0 0 0 0 4.39794 0 0 0 0 0 0 0 0 0 0 0 0 0 13.19382Triclopyr 0 4.39794 0 0 0 4.39794 0 0 0 0 0 0 0 0 0 4.39794 0 0 0 0 0 0 0 13.19382Bromacil 0 0 0 0 0 0 5.829304 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 11.65861Butylate 0 0 0 0 0 0 0 0 5.829304 0 0 0 0 0 0 0 0 0 0 0 0 0 0 11.65861Cloprop 0 0 0 0 0 5.829304 0 0 0 0 0 0 0 0 0 5.829304 0 0 0 0 0 0 0 11.65861D i id 0 0 0 0 0 0 0 0 0 5 829304 0 0 0 0 0 5 829304 0 0 0 0 0 0 0 11 65861

y increaseincrease of CXCL10 (pro-inflammatory, anti-angiogenic) decreasedecrease of CCL2 (pro-angiogenic chemokine) increase increase or decreasedecrease of PAS via uPAR or PAI1/SERPINE1

Daminozid 0 0 0 0 0 0 0 0 0 5.829304 0 0 0 0 0 5.829304 0 0 0 0 0 0 0 11.65861Halosulfur 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 5.829304 0 0 11.65861Imazethap 0 0 0 0 0 0 0 0 0 5.829304 0 0 0 0 0 5.829304 0 0 0 0 0 0 0 11.65861Methyl ce 0 0 0 0 0 5.829304 0 0 0 5.829304 0 0 0 0 0 0 0 0 0 0 0 0 0 11.65861Propoxyca 0 0 0 0 0 0 0 0 0 5.829304 0 0 0 0 0 5.829304 0 0 0 0 0 0 0 11.65861Triflusulfu 0 0 0 0 0 0 0 0 0 5.829304 0 0 0 0 0 5.829304 0 0 0 0 0 0 0 11.65861Propoxur 0 0 0 0 0 4.875061 0 0 0 0 0 0 0 0 0 5.829304 0 0 0 0 0 0 0 10.70437Clothianid 0 0 0 0 0 5.352183 0 0 0 0 0 0 0 0 0 5.352183 0 0 0 0 0 0 0 10.70437Ethametsu 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 5.352183 0 0 0 0 10.70437Isoxafluto 0 0 0 0 0 0 5.352183 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 10.70437Methoxyfe 0 0 0 0 0 0 0 0 5.352183 0 0 0 0 0 0 0 0 0 0 0 0 0 0 10.70437Primisulfu 0 0 0 0 0 5.352183 0 0 0 5.352183 0 0 0 0 0 0 0 0 0 0 0 0 0 10.70437Amitraz 0 0 0 0 4.39794 0 0 0 0 0 0 0 0 0 0 5.829304 0 0 0 0 0 0 0 10.22724Fenbucon 0 4.39794 0 0 0 0 0 0 0 0 0 0 0 0 0 5.829304 0 0 0 0 0 0 0 10.22724Malaoxon 0 0 0 0 0 0 0 0 0 0 0 0 0 4.39794 0 5.829304 0 0 0 0 0 0 0 10.22724Pyraflufen 0 4.39794 0 0 0 0 0 0 0 0 0 0 0 0 0 5.829304 0 0 0 0 0 0 0 10.22724Carbaryl 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 4.875061 0 0 0 9.750123Diphenyla 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 4.875061 0 0 0 0 0 9.750123Oryzalin 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 4.875061 0 0 0 0 9.750123Prohexadi 0 0 0 0 0 0 4.875061 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 9.750123Tribenuro 0 0 0 0 4.875061 0 0 0 0 0 0 0 0 0 0 4.875061 0 0 0 0 0 0 0 9.7501232‐Phenylp 0 0 0 0 0 4.39794 0 0 0 0 0 0 0 0 0 4.875061 0 0 0 0 0 0 0 9.273001Clorophen 0 4.875061 0 0 0 4.39794 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 9.273001Flumetsul 0 0 0 0 0 0 0 0 0 0 0 0 4.39794 0 0 4.875061 0 0 0 0 0 0 0 9.273001Formetana 0 0 0 4.39794 4.875061 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 9.273001Isazofos 0 4.39794 0 0 0 0 0 0 0 0 0 0 0 0 0 4.875061 0 0 0 0 0 0 0 9.273001Lindane 0 4.39794 0 0 4.875061 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 9.273001Metam‐so 0 0 0 4.39794 0 0 0 0 0 0 0 0 0 0 0 4.875061 0 0 0 0 0 0 0 9.273001Mevinpho 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 4.39794 4.875061 0 0 0 0 0 0 9.273001Terbacil 0 0 0 0 4.875061 0 0 0 0 4.39794 0 0 0 0 0 0 0 0 0 0 0 0 0 9.2730016‐Deisopro 0 0 0 0 0 4.39794 0 0 0 0 0 0 0 0 0 4.39794 0 0 0 0 0 0 0 8.79588Cinmethyl 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 4.39794 0 0 0 0 0 8.79588Cyanamid 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 4.39794 0 0 0 0 8.79588Dichloben 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 4.39794 0 0 0 0 0 8.79588Diethyltol 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 4.39794 0 0 0 8.79588Linuron 0 0 0 0 0 4.39794 0 0 0 4.39794 0 0 0 0 0 0 0 0 0 0 0 0 0 8.79588Methidath 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 4.39794 0 0 0 0 0 8.79588Norflurazo 0 0 0 0 0 0 0 0 0 4.39794 0 4.39794 0 0 0 0 0 0 0 0 0 0 0 8.79588Penoxsula 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 4.39794 0 0 0 0 0 8.79588Picloram 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 4.39794 0 0 0 8.79588Quizalofop 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 4.39794 0 0 0 0 0 8.795882,4‐Dichlo 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 5.829304 0 0 0 0 0 0 0 5.829304Acetamipr 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 5.829304 0 0 0 0 0 0 0 5.829304Bifenazate 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 5.829304 0 0 0 0 0 0 0 5.829304Chloridazo 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 5.829304 0 0 0 0 0 0 0 5.829304Chlorsulfu 0 0 0 0 0 0 0 0 0 0 0 5.829304 0 0 0 0 0 0 0 0 0 0 0 5.829304Cycloate 0 0 0 0 0 5.829304 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 5.829304Cyhalofop 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 5.829304 0 0 0 0 0 0 0 5.829304Cymoxani 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 5.829304 0 0 0 0 0 0 0 5.829304Cyromazin 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 5.829304 0 0 0 0 0 0 0 5.829304Dicamba 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 5.829304 0 0 0 0 0 0 0 5.829304Ethyleneth 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 5.829304 0 0 0 0 0 0 0 5.829304Fenhexam 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 5.829304 0 0 0 0 0 0 0 5.829304Fluometur 0 0 0 0 0 5.829304 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 5.829304Imazaquin 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 5.829304 0 0 0 0 0 0 0 5.829304Iodosulfur 0 0 0 0 0 5.829304 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 5.829304Methamid 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 5.829304 0 0 0 0 0 0 0 5.829304Methomyl 0 0 0 0 0 0 0 0 0 0 0 5.829304 0 0 0 0 0 0 0 0 0 0 0 5.829304

chemicals ranked by weighted signature score, Σ ki*ASiwhere AS = [-log10(AC50(M)/100000)] y

Metsulfur 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 5.829304 0 0 0 0 0 0 0 5.829304Molinate 0 0 0 0 0 5.829304 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 5.829304Monobuty 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 5.829304 0 0 0 0 0 0 0 5.829304Prometon 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 5.829304 0 0 0 0 0 0 0 5.829304Quinclorac 0 0 0 0 0 5.829304 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 5.829304Sulfentraz 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 5.829304 0 0 0 0 0 0 0 5.829304Symclosen 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 5.829304 0 0 0 0 0 0 0 5.829304Tepraloxy 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 5.829304 0 0 0 0 0 0 0 5.829304Thiabenda 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 5.829304 0 0 0 0 0 0 0 5.829304Thiametho 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 5.829304 0 0 0 0 0 0 0 5.829304Triadimefo 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 5.829304 0 0 0 0 0 0 0 5.829304Triasulfuro 0 0 0 0 0 5.829304 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 5.829304Trichlorfon 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 5.829304 0 0 0 0 0 0 0 5.829304Bendiocar 0 0 0 0 0 0 0 0 0 5.352183 0 0 0 0 0 0 0 0 0 0 0 0 0 5.352183Chlorprop 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 5.352183 0 0 0 0 0 0 0 5.352183Clopyralid 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 5.352183 0 0 0 0 0 0 0 5.352183Dimethen 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 5.352183 0 0 0 0 0 0 0 5.352183Napropam 0 0 0 0 0 0 0 0 0 0 0 0 5.352183 0 0 0 0 0 0 0 0 0 0 5.352183Oxasulfuro 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 5.352183 0 0 0 0 0 0 0 5.352183Cacodylic 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 4.875061 0 0 0 0 0 0 0 4.875061Chloretho 0 0 0 0 0 0 0 0 0 4.875061 0 0 0 0 0 0 0 0 0 0 0 0 0 4.875061Malathion 0 0 0 0 0 0 0 0 0 4.875061 0 0 0 0 0 0 0 0 0 0 0 0 0 4.875061Maleic hyd 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 4.875061 0 0 0 0 0 0 0 4.875061Monocroto 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 4.875061 0 0 0 0 0 0 0 4.875061Triticonazo 0 0 0 0 0 0 0 0 0 0 0 0 0 4.875061 0 0 0 0 0 0 0 0 0 4.875061Clomazon 0 0 0 0 0 4.39794 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 4.39794Cyclanilide 0 0 0 0 0 0 0 0 0 4.39794 0 0 0 0 0 0 0 0 0 0 0 0 0 4.39794Dimethoa 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 4.39794 0 0 0 0 0 0 0 4.39794Fluazifop‐ 0 0 0 0 0 4.39794 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 4.39794Foramsulf 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 4.39794 0 0 0 0 0 0 0 4.39794MCPA 0 0 0 0 0 0 0 0 0 0 0 4.39794 0 0 0 0 0 0 0 0 0 0 0 4.39794Mepiquat 0 0 0 4.39794 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 4.39794Mesosulfu 0 0 0 0 0 4.39794 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 4.39794Nitrapyrin 0 0 0 4.39794 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 4.39794Prometryn 0 0 0 0 4.39794 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 4.39794Thiaclopri 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 4.39794 0 0 0 0 0 0 0 4.39794Thidiazuro 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 4.39794 0 0 0 0 0 0 0 4.397942,4‐DB 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 02,5‐Pyridin 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0Acibenzol 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0Asulam 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0Bensulfuro 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0Boric acid 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0Carfentraz 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0Chloroneb 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0Cyprocona 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0Dichlorpro 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0Dimethyl p 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0Diuron 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0EPTC 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0Ethephon 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0Etridiazole 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0Fentin 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0Fluazifop‐ 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0Flumioxaz 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0Hexazinon 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0Imazamox 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0

where AS = [-log10(AC50(M)/100000)]

Office of Research and DevelopmentNational Center for Computational Toxicology

Imazapic 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0Imazapyr 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0Imidaclop 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0Mesotrion 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0Metalaxyl 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0Oxamyl 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0Phenoxye 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0Prosulfuro 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0Pymetrozi 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0Pyrithioba 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0Sethoxydi 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0Tebuthiur 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0Tralkoxydi 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0Trifloxysu 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0Vinclozoli 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0

15SOURCE: N Kleinstreuer, NCCT 2010

‘Vascular Disruptor’ signature


VDCs Pyraclostrobin ;DEV_Rat_Skeletal_Axial;DEV_Rat_Ur;DEV_Rabbit_PregnancyRelatedSpiroxamine ;DEV_Rat_General_FetalWeightRedu;DEV_Rabbit_General_FetalWeiPaclobutrazol ;DEV_Rat_Skeletal_Axial;DEV_Rat_Ur;DEV_Rabbit_Skeletal_AxialButralin ;DEV_Rat_PregnancyRelated_Matern;DEV_Rabbit_General_FetalWeiMetribuzin ;DEV_Rat_General_FetalWeightRedu;DEV_Rabbit_Skeletal_AxialDiquat dibromide ;DEV_Rat_General_FetalWeightRedu;DEV_Rabbit_General_GeneralFTriflumizole ;DEV_Rat_General_FetalWeightRedu;DEV_Rabbit_General_FetalWeiResmethrin ;DEV_Rat_General_FetalWeightRedu;DEV_Rabbit_PregnancyRelatedTrifluralin ;DEV_Rat_PregnancyRelated_Embryo;DEV_Rabbit_Cardiovascular_HeSimazine ;DEV_Rat_General_GeneralFetalPath;DEV_Rabbit_General_FetalWeiOxadiazon ;DEV_Rat_General_FetalWeightRedu;DEV_Rabbit_General_FetalWeiHexaconazole ;DEV_Rat_General_FetalWeightRedu;DEV_Rabbit_General_FetalWeiCyprodinil ;DEV_Rat_General_FetalWeightRedu;DEV_Rabbit_Skeletal_AxialFlumetralin No Developmental Rat Study in ToxR;DEV_Rabbit_PregnancyRelatedPropargite No recorded effect ;DEV Rabbit Skeletal Axial

ToxRefDB developmental defects for putative ‘Vascular Disruptor Chemicals’

Propargite No recorded effect ;DEV_Rabbit_Skeletal_AxialTrifloxystrobin No recorded effect ;DEV_Rabbit_Skeletal_AxialFenoxycarb No recorded effect ;DEV_Rabbit_Skeletal_AxialEtoxazole No recorded effect ;DEV_Rabbit_Skeletal_AxialIndoxacarb ;DEV_Rat_General_FetalWeightRedu;DEV_Rabbit_General_FetalWeiDazomet No recorded effect ;DEV_Rabbit_General_GeneralFPyrimethanil ;DEV_Rat_General_FetalWeightRedu;DEV_Rabbit_General_FetalWeiFenthion ;DEV_Rat_PregnancyRelated_Embryo;DEV_Rabbit_General_FetalWeiFolpet No Developmental Rat Study in ToxR;DEV_Rabbit_Neurosensory_BraPyridaben ;DEV_Rat_General_FetalWeightRedu;DEV_Rabbit_PregnancyRelatedLactofen ;DEV_Rat_General_FetalWeightReduNo recorded effectThiram ;DEV_Rat_General_FetalWeightReduNo Developmental Rabbit Study(Z,E)‐Fenpyroximate ;DEV_Rat_Skeletal_Axial No recorded effectEmamectin benzoate ;DEV_Rat_General_FetalWeightReduNo recorded effectManeb ;DEV_Rat_General_FetalWeightReduNo Developmental Rabbit StudyFluoxastrobin ;DEV_Rat_Skeletal_Appendicular No recorded effectDiniconazole ;DEV_Rat_General_GeneralFetalPathNo recorded effectTebufenpyrad ;DEV_Rat_Skeletal_Axial ;DEV_Rabbit_PregnancyRelatedS‐Bioallethrin ;DEV_Rat_PregnancyRelated_Embryo;DEV_Rabbit_PregnancyRelatedMyclobutanil ;DEV_Rat_Skeletal_Axial ;DEV_Rabbit_PregnancyRelatedCyazofamid ;DEV_Rat_Skeletal_Axial No recorded effectBenomyl ;DEV_Rat_General_FetalWeightRedu;DEV_Rabbit_Urogenital_RenalTetraconazole ;DEV_Rat_General_GeneralFetalPathNo recorded effectDifenoconazole ;DEV Rat General FetalWeightRedu;DEV Rabbit General FetalWeiputative Vascular Disruptor Chemicals

~81% putative VDCs with in vivo data showed developmental effects

Difenoconazole ;DEV_Rat_General_FetalWeightRedu;DEV_Rabbit_General_FetalWeiThiodicarb ;DEV_Rat_General_FetalWeightReduNo recorded effect3‐Iodo‐2‐propynylbutylcarbamat ;DEV_Rat_General_FetalWeightRedu;DEV_Rabbit_PregnancyRelatedAcetochlor ;DEV_Rat_General_FetalWeightReduNo recorded effectHexythiazox ;DEV_Rat_Skeletal_Appendicular No recorded effectCyfluthrin ;DEV_Rat_General_FetalWeightRedu;DEV_Rabbit_PregnancyRelatedAldicarb ;DEV_Rat_General_FetalWeightReduNo Developmental Rabbit StudyMethyl isothiocyanate ;DEV_Rat_General_FetalWeightReduNo Developmental Rabbit StudyFenitrothion ;DEV_Rat_Skeletal_Axial ;DEV_Rabbit_PregnancyRelatedFlusilazole ;DEV_Rat_General_GeneralFetalPath;DEV_Rabbit_General_FetalWeiAtrazine ;DEV_Rat_Orofacial_JawHyoid;DEV_R;DEV_Rabbit_General_GeneralFPermethrin ;DEV_Rat_General_FetalWeightRedu;DEV_Rabbit_General_FetalWeiParathion‐methyl ;DEV_Rat_General_FetalWeightReduNo Developmental Rabbit StudyClodinafop‐propargyl ;DEV_Rat_General_FetalWeightRedu;DEV_Rabbit_PregnancyRelatedFenamidone ;DEV_Rat_General_FetalWeightReduNo recorded effectThiazopyr ;DEV_Rat_Skeletal_Axial No recorded effectPropazine ;DEV_Rat_General_FetalWeightReduNo recorded effectMancozeb ;DEV_Rat_General_FetalWeightRedu;DEV_Rabbit_PregnancyRelatedAcephate ;DEV_Rat_Skeletal_Appendicular;DEV;DEV_Rabbit_PregnancyRelatedDichloran ;DEV_Rat_General_FetalWeightReduNo Developmental Rabbit StudyBuprofezin ;DEV_Rat_General_FetalWeightRedu;DEV_Rabbit_PregnancyRelatedMethylene bis(thiocyanate) No recorded effect ;DEV_Rabbit_PregnancyRelatedAbamectin No Developmental Rat Study in ToxRNo Developmental Rabbit StudyZoxamide No recorded effect No recorded effect

p(eg, FWR, SKL, RES)

~7.5% showed no prenatal

Zoxamide No recorded effect No recorded effectDimethomorph ;DEV_Rat_PregnancyRelated_EmbryoNo Developmental Rabbit StudyButafenacil No recorded effect ;DEV_Rabbit_PregnancyRelatedTetramethrin No recorded effect No Developmental Rabbit StudyRimsulfuron No recorded effect ;DEV_Rabbit_PregnancyRelatedNaled ;DEV_Rat_PregnancyRelated_EmbryoNo recorded effectChlorothalonil ;DEV_Rat_PregnancyRelated_EmbryoNo recorded effectNiclosamide No Developmental Rat Study in ToxRNo Developmental Rabbit StudyDifenzoquat metilsulfate No recorded effect No Developmental Rabbit StudyRotenone ;DEV_Rat_General_FetalWeightReduNo Developmental Rabbit StudyTriclosan No recorded effect No recorded effectMetiram‐zinc ;DEV_Rat_PregnancyRelated_EmbryoNo Developmental Rabbit StudyImazalil No Developmental Rat Study in ToxRNo Developmental Rabbit StudyAzamethiphos No recorded effect ;DEV_Rabbit_PregnancyRelatedPropetamphos No recorded effect ;DEV_Rabbit_PregnancyRelatedCyanazine No recorded effect No Developmental Rabbit Study2,2‐Bis(4‐hydroxyphenyl)‐1,1,1‐t No Developmental Rat Study in ToxRNo Developmental Rabbit StudyChlorpyrifos oxon No Developmental Rat Study in ToxRNo Developmental Rabbit StudyForchlorfenuron No Developmental Rat Study in ToxRNo Developmental Rabbit StudyFludioxonil ;DEV_Rat_Urogenital_Renal;DEV_RatNo recorded effectSpirodiclofen ;DEV_Rat_Urogenital_Renal No recorded effectPhosalone ;DEV_Rat_PregnancyRelated_Embryo;DEV_Rabbit_PregnancyRelatedAlachlor ;DEV_Rat_General_FetalWeightReduNo recorded effectBisphenol A No recorded effect No Developmental Rabbit Study

effects in rat & rabbit Bisphenol A No recorded effect No Developmental Rabbit StudyTebupirimfos ;DEV_Rat_PregnancyRelated_Matern;DEV_Rabbit_PregnancyRelatedTribufos No recorded effect No recorded effectPendimethalin No recorded effect No Developmental Rabbit StudyPrallethrin ;DEV_Rat_PregnancyRelated_MaternNo recorded effectCaptafol No Developmental Rat Study in ToxRNo Developmental Rabbit StudyDiazoxon No Developmental Rat Study in ToxRNo Developmental Rabbit StudyFlumiclorac‐pentyl No recorded effect ;DEV_Rabbit_PregnancyRelatedBentazone No Developmental Rat Study in ToxRNo Developmental Rabbit StudyQuinoxyfen No recorded effect ;DEV_Rabbit_PregnancyRelatedButachlor No recorded effect ;DEV_Rabbit_General_FetalWeiDithiopyr No recorded effect No recorded effectMethoxychlor No Developmental Rat Study in ToxRNo Developmental Rabbit StudyOxyfluorfen No recorded effect ;DEV_Rabbit_PregnancyRelatedDicofol No recorded effect ;DEV_Rabbit_PregnancyRelatedDichlorvos No recorded effect ;DEV_Rabbit_PregnancyRelatedProchloraz No Developmental Rat Study in ToxRNo Developmental Rabbit StudyFlufenpyr‐ethyl No recorded effect ;DEV_Rabbit_PregnancyRelatedMGK No recorded effect No recorded effectPerfluorooctane sulfonic acid No Developmental Rat Study in ToxR;DEV_Rabbit_General_FetalWeiFosthiazate No recorded effect No recorded effectFluroxypyr‐meptyl No Developmental Rat Study in ToxRNo Developmental Rabbit StudyEsfenvalerate No recorded effect No recorded effectM th l h d hth l t N D l t l R t St d i T RN D l t l R bbit St d

Thiram ;DEV_Rat_General_FetalWeightReduNo Developmental Rabbit Study(Z,E)‐Fenpyroximate ;DEV_Rat_Skeletal_Axial No recorded effectEmamectin benzoate ;DEV_Rat_General_FetalWeightReduNo recorded effectManeb ;DEV Rat General FetalWeightReduNo Developmental Rabbit Study

Thiram ;DEV_Rat_General_FetalWeightReduNo Developmental Rabbit Study(Z,E)‐Fenpyroximate ;DEV_Rat_Skeletal_Axial No recorded effectEmamectin benzoate ;DEV_Rat_General_FetalWeightReduNo recorded effectManeb ;DEV Rat General FetalWeightReduNo Developmental Rabbit StudyMethyl hydrogen phthalate No Developmental Rat Study in ToxRNo Developmental Rabbit Study

Perfluorooctanoic acid No Developmental Rat Study in ToxRNo Developmental Rabbit StudyDicrotophos No recorded effect ;DEV_Rabbit_General_FetalWeiBromoxynil No Developmental Rat Study in ToxRNo Developmental Rabbit StudyFenarimol No Developmental Rat Study in ToxR;DEV_Rabbit_PregnancyRelatedDiethylhexyl phthalate ;DEV_Rat_General_FetalWeightReduNo Developmental Rabbit StudyCarboxin No recorded effect ;DEV_Rabbit_PregnancyRelatedFluroxypyr ;DEV_Rat_PregnancyRelated_Matern;DEV_Rabbit_PregnancyRelatedMilbemectin (mix of >70 percent No Developmental Rat Study in ToxRNo Developmental Rabbit StudyCoumaphos No Developmental Rat Study in ToxRNo Developmental Rabbit StudyOxytetracycline dihydrate No Developmental Rat Study in ToxRNo Developmental Rabbit StudyProdiamine ;DEV_Rat_Neurosensory_Eye No recorded effectIsoxaben ;DEV_Rat_General_GeneralFetalPath;DEV_Rabbit_PregnancyRelatedTebufenozide No recorded effect No recorded effectBensulide No recorded effect ;DEV_Rabbit_PregnancyRelatedFamoxadone No recorded effect ;DEV_Rabbit_PregnancyRelatedAcifluorfen No Developmental Rat Study in ToxRNo Developmental Rabbit StudyAzoxystrobin ;DEV_Rat_PregnancyRelated_MaternNo Developmental Rabbit StudyCypermethrin No recorded effect No recorded effectFenpropathrin ;DEV_Rat_PregnancyRelated_MaternNo recorded effectBenfluralin No recorded effect No recorded effectBifenthrin ;DEV_Rat_Orofacial_JawHyoid No recorded effectDiclofop‐methyl No Developmental Rat Study in ToxRNo recorded effectDi l l N d d ff DEV R bbi P R l d

Maneb ;DEV_Rat_General_FetalWeightReduNo Developmental Rabbit StudyFluoxastrobin ;DEV_Rat_Skeletal_Appendicular No recorded effectDiniconazole ;DEV_Rat_General_GeneralFetalPathNo recorded effectTebufenpyrad ;DEV_Rat_Skeletal_Axial ;DEV_Rabbit_PregnancyRelatedS‐Bioallethrin ;DEV_Rat_PregnancyRelated_Embryo;DEV_Rabbit_PregnancyRelatedMyclobutanil ;DEV_Rat_Skeletal_Axial ;DEV_Rabbit_PregnancyRelatedCyazofamid ;DEV_Rat_Skeletal_Axial No recorded effectBenomyl ;DEV_Rat_General_FetalWeightRedu;DEV_Rabbit_Urogenital_Renal

Maneb ;DEV_Rat_General_FetalWeightReduNo Developmental Rabbit StudyFluoxastrobin ;DEV_Rat_Skeletal_Appendicular No recorded effectDiniconazole ;DEV_Rat_General_GeneralFetalPathNo recorded effectTebufenpyrad ;DEV_Rat_Skeletal_Axial ;DEV_Rabbit_PregnancyRelatedS‐Bioallethrin ;DEV_Rat_PregnancyRelated_Embryo;DEV_Rabbit_PregnancyRelatedMyclobutanil ;DEV_Rat_Skeletal_Axial ;DEV_Rabbit_PregnancyRelatedCyazofamid ;DEV_Rat_Skeletal_Axial No recorded effectBenomyl ;DEV_Rat_General_FetalWeightRedu;DEV_Rabbit_Urogenital_Renal


Diclosulam No recorded effect ;DEV_Rabbit_PregnancyRelatedParathion No Developmental Rat Study in ToxRNo Developmental Rabbit StudyProfenofos ;DEV_Rat_PregnancyRelated_MaternNo recorded effectTetraconazole ;DEV_Rat_General_GeneralFetalPathNo recorded effect

Difenoconazole ;DEV_Rat_General_FetalWeightRedu;DEV_Rabbit_General_FetalWeThiodicarb ;DEV_Rat_General_FetalWeightReduNo recorded effect

Tetraconazole ;DEV_Rat_General_GeneralFetalPathNo recorded effectDifenoconazole ;DEV_Rat_General_FetalWeightRedu;DEV_Rabbit_General_FetalWeThiodicarb ;DEV_Rat_General_FetalWeightReduNo recorded effect

17

3. Virtual Embryoin silico reconstructionin silico reconstruction


Multi-cellular models APPENDICULAR SKELETONNVS_GPCR_hPY2ATG_AP_1_CISATG_ERRg_TRANSBSK_KF3CT_TIMP2_up

hits to skeletal_APP

BSK_LPS_Eselectin_upBSK_LPS_IL8_upBSK_SAg_CD40_upMESC_CellUpNVS_ENZ_hAbl_ActivatorNVS_ENZ_hBTK_ActivatorNVS_ENZ_hFynNVS_ENZ_hFyn_ActivatorNVS_ENZ_hGSK3bNVS_ENZ_hPP2Ca_ActivatorNVS_ENZ_hPTPLARNVS_ENZ_hPTPMUNVS_ENZ_hPTPPESTNVS_ENZ_rMAOACNVS_GPCR_gBK2NVS_GPCR_hAdra2ANVS_NR_hPPARaNVS_NR_hRARPS_Gene_ABL1PS_Gene_ADRA2APS_Gene_Bdkrb2_Cavia_porcellusPS_Gene_BTKPS_Gene_ESRRGPS_Gene_FYNPS_Gene_GSK3BPS_Gene_Maoa_Rattus_norvegicusPS_Gene_P2RY1PS_Gene_PPM1APS_Gene_PTPN12PS_Gene_PTPRFPS_Gene_PTPRMPS_Ingenuity_0_cAMP_mediated_SignalingPS_Ingenuity_0_Caveolar_mediated_EndocytosisPS_Ingenuity_0_Fcgamma_Receptor_mediated_Phagocytosis_in_Macrophages_and_MonocytesPS_Ingenuity_0_G_Protein_Coupled_Receptor_SignalingPS_Ingenuity_0_Hypoxia_Signaling_in_the_Cardiovascular_SystemPS_Ingenuity_0_PDGF_SignalingPS_Ingenuity_0_T_Cell_Receptor_SignalingPS_Ingenuity_0_Wntbeta_catenin_SignalingPS_Ingenuity_a_Adrenergic_SignalingPS_Ingenuity_Synaptic_Long_Term_DepressionPS_KEGG_0_Axon_guidancePS_KEGG_0_B_cell_receptor_signaling_pathwayPS_KEGG_0_Fc_epsilon_RI_signaling_pathwayPS_KEGG_0_Pancreatic_cancerPS_KEGG_0_VEGF_signaling_pathwayPS_KEGG_Axon_guidancePS_KEGG_Long_term_depressionPS_PathwayCommons_0_CELL_MAP_Alpha6Beta4IntegrinPS_PathwayCommons_0_CELL_MAP_KitReceptorPS_PathwayCommons_0_NCI_NATURE_Angiopoietin_receptor_Tie2_mediated_signalingPS_PathwayCommons_0_NCI_NATURE_Aurora_A_signalingPS_PathwayCommons_0_NCI_NATURE_Class_I_PI3K_signaling_events_mediated_by_AktPS_PathwayCommons_0_NCI_NATURE_Fc_epsilon_receptor_I_signaling_in_mast_cellsPS_PathwayCommons_0_NCI_NATURE_PDGFR_beta_signaling_pathway

Office of Research and DevelopmentNational Center for Computational Toxicology 19Modeled in www.CompuCell3d.org environment

N Poplawski (chick limb) M Rountree (mouse limb)

PS_PathwayCommons_0_NCI_NATURE_S1P1_pathway

Cell Signaling Networks

FGF8

Gene network for limb outgrowth

FGF4

SOURCE: Benazet et al. (2009) Science 323:1050Mackem & Lewandoski (2009) Science Signaling 2:pe33

Multicellular model of FGF


Multicellular model of FGF signaling built in CC3D

Vascular development

Merks, Perryn, Shirinifard, and Glazier ( ) C CBates, Taylor, and Newgreen (2002) The (2008) Contact-Inhibited Chemotaxis in De Novo and Sprouting Blood-Vessel Growth. PLoS Comput Biol 4(9): e1000163

Bates, Taylor, and Newgreen (2002) The Pattern of Neurovascular Development in the Forelimb of the Quail Embryo. Dev Bio 249:300-320


Validation:zebrafish vascular developmentzebrafish vascular development

72 h control (20x) 72 h treated (20x)72 h control (20x) 72 h treated (20x)

intersomitic vessel development monitored via Fli1 VEGFR transgene expression

SOURCE: M Bondesson & C McCollum, TIVS – University of Houston


Summary

ToxCast™ is a resource to compile in vitro signatures into computational models that are diagnostic of in vivo toxicity

toxicity in an intact organism results from numerous y gcomplex and inter-related events at a multi-cellular scale

systems level models that recapitulate in vivo biology can systems-level models that recapitulate in vivo biology can be used to assess the plausibility of diagnostic signatures

multicellular ‘virtual tissue’ models can help bridge the gap between in vitro profiling and in vivo response


Credits

Virtual Embryo (NCCT)Tom Knudsen A Si h (LHM)

Virtual Embryo (NHEERL)Sid Hunter St h i P dill

Virtual Liver (NCCT)Amar Singh (LHM)Michael Rountree (SSC)Richard Spencer (EMVL)Rob DeWoskin (NCEA)

Stephanie PadillaKelly Chandler

Imran Shah John WambaughWoody SetzerJohn JackRob DeWoskin (NCEA)

Nikal KeinstreuerNisha Sipes

Indiana University (CC3D) T C t™

John Jack

Texas-Indiana Virtual STAR Center (NCER)Maria Bondesson (U Houston)

Indiana University (CC3D)Jim GlazierNiko PoplawskiMaciej Swat

ToxCast™ (NCCT)

Bob KavlockDavid Dix

Jan-Ake Gustafsson (U Houston)Don Fox (U Houston)Richard Finnell (Texas A&M)Jim Glazier (Indiana U)Maciej Swat

Abbas ShirinifardRoland Merks

Richard JudsonKeith HouckMatt Martin

Jim Glazier (Indiana U)


http://www.epa.gov/ncct/v-Embryo/ David ReifHolly Mortensen

Date post:	28-Jul-2020
Category:	Documents
Upload:	others
View:	3 times
Download:	0 times

Computational Toxicology andComputational Toxicology and ...S1P2 pathwayS1P2_pathway rat CLPrat_CLP...

Documents