a systems biology approach to environmental biology...in environmental biology? case study –...
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A Systems Biology Approach to Environmental Biology
Philipp Antczak
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Why Systems Biology?
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Phosphorylated p120-catenin expression has predictive value for oral cancer progression J. Clin. Pathol. April 1, 2012 65: 315-319
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How do we deal with that much information?
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Genetic Algorithms and Bayesian Variable SelectionTrevino, V, & F Falciani, ‘GALGO: an R package for multivariate variable selection using genetic algorithms.’, Bioinformatics vol. 22, no. 9, 2006, pp. 1154-1156.
Sha N, Vannucci M, Tadesse MG, Brown PJ, Dragoni I, Davies N, Roberts TC, Contestabile A, Salmon M, Buckley C, Falciani F. Bayesian variable selection in multinomial probit models to identify molecular signatures of disease stage.Biometrics. 2004 Sep;60(3):812-9.
A supervised classification/regression problem
Variable Selection
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Linking endpoints to molecular response
Pred
icte
d LC
50
Observed LC50
Wnt Signalling Pathway
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Regulatory networks
CBF1
GAL4
SWI5
GAL80
ASH1
Static Dynamic
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Gene-level analyses can be hard to interpret!
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Simplifying the Problem by previous knowledge
KEGG PATHWAY
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Simplifying the problem by expression similarity
Gene Expression
Clustering Methodologies
Expr
essio
n
Expr
essio
n
Cluster 1 Cluster 2
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Measured Phenotypic ResponseDevelop Links to pathways
Differential Gene Expression AnalysisStep 1 Step 2
Combination into Workflows
Gene Clusters
Step 3
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How can we apply these techniques in environmental biology?
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Case Study – Ovarian Maturation
Martyniuk CJ, Prucha MS, Doperalski NJ, Antczak P, Kroll KJ, et al. (2013) Gene Expression Networks Underlying Ovarian Development in Wild Largemouth Bass (Micropterus salmoides). PLoS ONE 8(3): e59093. doi:10.1371/journal.pone.0059093
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PC2
PC1
PN CA
VtgOM
OV
- Vitellogenin (Vtg), estradiol (E2) and Gonadosomatic index (GSI) measurmentswere taken at the sampling time.
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FDR <= 1% FDR<= 5% FDR<= 10%
One class timecourse One class timecourse One class timecourse
Multiclass MulticlassMulticlass
46
1874
936
2223
2090
95
2142
2905
152
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How does pollution perturb this network?
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TerbufosFonofosBenzo(a)pyreneEstradiolCholesterol, LDLPiroxicamAflatoxin B1CytarabineParathionProgesteroneTestosterone
MidazolamFelbamate
CD437Aflatoxin B13-(4'-hydroxy-3'-adamantylbiphenyl-4-yl)acrylic acidProgesteroneRotenoneHydralazineDiallyl trisulfideCalcitriolPiroxicamTerbufosEstradiolTestosterone
Aflatoxin B1CD437
P-value < 0.01
P-value < 0.05
P-value < 0.2
Estradiol
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Discovering Adverse Outcome Pathways from molecular data
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Example of complexity
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Single chemical
exposures
Meta-analysis of PD and
legacy datasets
Mixture exposures
Molecular targets of single chemical
exposures
Molecular targets of mixture exposures
Molecular pathways activated only in
mixtures
Chronic physiology endpoints
Statistical analysis
Statistical analysis
In silico subtraction
Single Compound Targets Full Genome
Physiological Endpoints
s1
s2
s3
M1 Phx
Non-additive mixture KEGG Pathways
High Level approach to pAOPs
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Experimental SystemStickleback (Gasterosteus aculeatus):•widespread•native UK species•annual reproductive cycle•Cefas experience
Benzo(a)pyrene: 10µg/lPAHLC50: 1200, HEC: 96 µg/l
Cadmium: 65µg/lHeavy metalLC50: 6500, HEC: 4000 µg/l
Dibutyl phthalate: 35µg/lPlasticizerLC50: 350, HEC : 170 µg/l
Ethinyl estradiol: 0.06 µg/lEndocrine disrupterLC50: 1600, HEC 0.04 µg/l
Fluoxetine: 10µg/lSSRI antidepressantLC50: 700, HEC 1 µg/l
Cd2+
Gemfibrozil: 50 µg/lFibrateLC50: 22000, HEC : 5 µg/l
Ibuprofen: 50 µg/lPainkillerLC50: 7100, HEC : 28 µg/l
Levonorgestrel: 0.05 µg/lProgestinLC50: 6500, HEC : 0.015 µg/l
PCB-118: 1 µg/lPCBLC50: 15 µg/l, HEC : 123 µg/kg (sed)
Triclosan: 20 µg/lAntibacterial/fungalLC50: 260, HEC : 5 µg/l
DMSO: 88 mg/l (0.008%)Solvent
LC50: Lowest found for stickleback or most sensitive fish species. HEC: Highest environmental concentration found
•microarray and biomarkers developed•large enough to dissect tissues•small enough to maintain in the laboratory•well annotated draft genome sequence
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Individual Chemicalsand
Chemical Mixtures
Transcriptomics: Hepatic 8x15k Agilent stickleback microarrayMetabolomics:Hepatic polar and non-polar FT-ICR Mass Spectrometry
Stickleback Chemical Exposures
Stickleback morphologyCortisol assay on tank waterReproductive behaviour & outputVitellogenin & Spiggin assaysImmunocompetence by pathogen challenge
Acute Chronic
Experimental Scheme
female male
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Exposure WC SC BaP Cd DBP EE2 Fluo Gem Ibu Levo PCB Tri V01 V02 V03 V04 V05 V06 V07 V08 V09 V10 V11 V12 V13 V14 V15 V16 V17 V18 V19 V20 V21 V22 V23 V24 V25 V26
Solvent 0 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1
Benzo[a]pyrene 0 0 1 0 0 0 0 0 0 0 0 0 0 1 1 0 0 0 1 1 0 0 1 1 0 0 0 1 1 1 0 0 1 0 0 0 1 1
Cadmium 0 0 0 1 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 1 1 1 0 0 0 1 0 0 1 1 1 0 0 1 0 1 0 1
Dibutyl phthalate 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 1 0 0 0 0 1 0 0 0 1 1 1 0 1 1 0 1 1 1 1 1 1 1
Ethinyl-oestradiol 0 0 0 0 0 1 0 0 0 0 0 0 1 0 1 1 0 0 1 1 1 0 1 1 1 0 1 1 0 0 1 0 1 1 0 1 1 1
Fluoxetine 0 0 0 0 0 0 1 0 0 0 0 0 0 1 0 0 1 1 1 0 1 0 0 0 0 1 1 1 1 0 0 0 0 0 1 1 0 1
Gemfibrozil 0 0 0 0 0 0 0 1 0 0 0 0 1 0 1 1 0 1 1 0 0 1 1 0 1 0 0 0 0 1 0 1 0 0 1 0 0 1
Ibuprofen 0 0 0 0 0 0 0 0 1 0 0 0 0 1 1 0 1 1 0 0 1 0 0 1 0 1 1 0 0 0 1 1 1 1 1 0 0 1
Levonorgestrel 0 0 0 0 0 0 0 0 0 1 0 0 1 0 0 1 1 0 1 1 0 1 1 1 1 0 0 1 1 1 1 1 0 0 1 1 1 1
PCB-118 0 0 0 0 0 0 0 0 0 0 1 0 1 1 0 0 1 1 0 0 0 1 1 0 1 0 0 0 0 0 0 1 1 1 0 0 0 1
Triclosan 0 0 0 0 0 0 0 0 0 0 0 1 0 1 1 1 1 1 0 1 0 1 0 1 0 1 1 1 0 0 1 0 0 0 0 0 1 1
Exposures: •Each of 10 compounds singly, plus solvent•25 mixtures of 5 components plus solvent, one of all 10•10 sticklebacks per tank (mixed male and female)•Solvent and water controls•Duplicate tanks for each exposure = 80 tanks with 800 fish•Acute = 4 day exposure (complete) •800 sticklebacks sexed, livers dissected and frozen at -80C•Chronic = 4 months (2014)•Chemical analysis: Passive samplers (selected tanks; 2013-14)
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Multi-Step Modelling Procedure
AcuteHigh ConcentrationsTranscriptomics
Single Mixtures
Predictive Modelling Predictive Modelling
Model 1 – Prediction of Compound presence
Comparison of Models
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Benz
o(a)
pyre
ne
Cadm
ium
Dibu
tylp
htha
late
Ethi
nyle
stra
diol
Fluo
xetin
e
Gem
fibro
zil
Ibup
rofe
n
Levo
norg
estr
el
PCB-
118
Tric
losa
n
Chemical OnlyOther Chemical
Mixtures
Single Models
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PCB-118
TriclosanGemfibrozil
Benzo(a)pyrenePCB-118
Gemfibrozil
Cadmium
Triclosan
Dibutyl phthalate
Ibuprofen
Benzo(a)pyrene
Levonorgestrel
Ethinyl estradiol
Fluoxetine
Comparing Model Space
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Multi-Step Modelling Procedure
Single Mixtures
Predictive Modelling
Model 2 – Model Refinement
Building Models Predictive in both Single and Mixtures
AcuteHigh ConcentrationsTranscriptomics
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Predicting exposure to single and mixture exposures
Levonorgestrel – 3 genes Fluoxetine – 4 genes
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Benzo(a)pyrene
Cadmium
Dibutyl phthalate
Ethinyl estradiol
Fluoxetine
Gemfibrozil
Ibuprofen
Levonorgestrel
PCB-118
Triclosan
0.0
0.2
0.4
0.6
0.8
Models predictive of both Single and Mixtures
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Multi-Step Modelling ProcedureModel 3 – Linking Chronic phenotypes to early molecular response
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Pathway to Phenotype Association
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Multi-Step Modelling Procedure
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Non additive effect Pathways
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Specific Molecular Response
Ribosomal ProcessingTransportEnergy
TranslationProtein Modification
EnergyCell cycle
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Underlying model
• Genetic Algorithm based optimization technique (GALGO library R)– RandomForest regression
𝑃𝑃𝑃𝑃𝑖𝑖,𝑘𝑘= 𝑔𝑔𝑔𝑔𝑔𝑔𝑔𝑔𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶 + 𝑔𝑔𝑔𝑔𝑔𝑔𝑔𝑔𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶+ 𝑔𝑔𝑔𝑔𝑔𝑔𝑔𝑔𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶 + 𝑑𝑑 + 𝜖𝜖
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s1
s2
s3
M1
Phx
Single Compound Targets
Physiological Endpoints
Putative mixture AOPs
Identify Pathways only expressed in mixtures
Identify differentially expressed genes from
Single exposures
Link genes from single exposures (1 per
compound) to pathways
Link physiological endpoints to pathways
Derive mixture AOP based on best model fit
Non-additive Pathway
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Chemical carcinogenesis
A2LD1
POLR3B
DNAJC27
Gemfibrozil
PCB-118
Levonorgestrel Condition index0.01 FDRρ = -0.40
Fitness R2 = 0.81 – CV R2 = 0.67 – CV SD = 0.10
Mean length
Mean weight
Mean VTG0.06 FDRρ = -0.25
Integrating and identifying pAOPs
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Pentose and glucuronateinterconversions
GCNT7
CD2
selt2
Triclosan
Ibuprofen
Fluoxetine
Fitness R2 = 0.81– CV R2 = 0.58 – CV SD = 0.14
Condition index0.08 FDRρ = -0.36
Mean length
Mean weight
Mean VTG0.10 FDRρ = -0.30
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Chemical Carcinogenesis
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Pentose and glucuronateInterconversions
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Shortest Paths within KEGG+MiMI
P < 0P < 0.001
P < 0.01
P < 0.11
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Summary
• Molecular data can be used as a predictive tool to identify and classify samples
• We are able to develop models linking single chemical exposure, non-additive mixture effect and phenotypic endpoints to develop putative mixture adverse outcome pathways
• We need to develop more quantitative/predictive Adverse Outcome Pathways to support risk assessment.
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The next challenge
• Predictive/quantitative Adverse Outcome Pathways• Cross species extrapolation of adverse outcome
pathways• Interactions between chemicals and a changing
environment• Robust molecular models for mTIE (molecular toxicity
identification and evaluation) across large numbers of compounds
• Mixture AOPs linking single exposures to expected phenotypic effect and population outcome
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AcknowledgementsUniversity of Liverpool
Prof. Francesco FalcianiKim ClarkeJaanika KronbergJohn HerbertJohn AnkersPeter Davidsen
CefasIoanna KatsiadakiMarion SebireJessica TaskerJenni ProkkolaBrett LyonsTim Bean
University of BirminghamProf. Mark ViantTom WhiteProf. Kevin Chipman