Computational Systems Biology Modeling of DNA-damage Stress Pathways for Assessing Mutation Rates at Low Doses

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1 Computational Systems Biology Modeling of DNA-damage Stress Pathways for Assessing Mutation Rates at Low Doses Rebecca Clewell Society of Toxicology March 25, 2015

2 Exposure & Consumer Use Assessment High-content information in vitro assays in human cells & models Dose-response assessments Computational models of the circuitry of the relevant toxicity pathways DNA damage Oxidative Stress ER PPARa AhR PBPK models supporting in vitro to in vivo extrapolations Risk assessment based on exposures below the levels of significant pathway perturbations 2

3 Dose response (log-linear axes) Corresponding Lutz threshold model fit 3

4 Threshold shaped dose-response is a result of protective mechanisms in the cell Region of Safety Cellular Adversity Adaptation Background DNA repair Cell cycle? Apoptosis? Unrepaired DNA damage Heritable mutation MN 4

5 Regardless of chemical, transcriptional responses occur at the same concentrations as micronuclei Transcriptional responses cannot protect the cells from low dose genotoxicity Total p53 % Responder Total p Concentration ( M) x 5

6 Finding out that post-translational processes determine the shape of the D-R curve UV DSBs ATR ATM Adaptation Cellular Adversity Chk1 Chk2 Background Repair foci formation & resolution Micronuclei (mutation) p53 p53 H2AX ATM BRCA1 Non-transcriptional Modulation of Stress p53 Transcriptional Response to Excess Stressor Clewell et al., Toxicol. Sci. 142(1) 6

7 DNA repair centers 24h p-h2ax p53 BP1 Overlay Con 1 um ETP NCS 400 ng/ml 7

8 Fast post-translational response coupled with slow transcriptional response could give a threshold shaped response curve (p53) 4 DNA-Repair Enzymes Genotoxicant (S) DNA-Damage (Y) DNA-Repair Centers Y S micronuclei = f (Y) 8

9 Quantitation of repair centers 9

10 Response * NOEL = 0.5 ng/ml * 5 NOEL = 5 ng/ml Dose (ng/ml) 10

11 Simple empirical model gamma irradiation RIFs formed in higher yield at lower doses Assuming direct proportionality between DSB and radiation dose: 1.0 DSB/RIF at 0.4 Gy 2.3 DSB/RIF at 2.0 Gy Neumaier et al., 2012, PNAS 109(2):

12 Simple empirical model Radiation (D) α DSB (C 0 ) Where C 0 = Average number of DSB per cell at a given time C 1 = Average number of foci per cell at a given time α = number of naked DSB/Gy of radiation before formation of the foci ( efficiency of dose to cause DSB) K 1 = rate of RIF formation K 2 = rate of RIF resolution Dose Alpha k1 K K1 Repair Center (C 1 ) K2 Repair Center Resolution Neumaier et al., 2012, PNAS 109(2):

13 Computational model for DRC kinetics 13

14 Key Model Features 1. p53bp1 is a reasonable surrogate for other repair center proteins 2. Fixed pool of binding protein 1(BP1) available for formation of repair centers 3. Phosphorylation of p53 is fast and abundant not rate limiting 4. Repair center resolution rate reduces as dose increases 5. All proteins involved in creation of RC get destroyed when RC is resolved 14

15 Testing model description with experiments Assumption: Phosphorylation of p53 is fast and abundant Test: Evaluate rate of formation and resolution of individual foci in living cells over time 15

16 Testing model description with experiments Assumption: Resolution rate decreases as the amount of damage increases Test: Evaluate rate of formation and resolution of individual foci in living cells over time 16

17 17

18 The DNA damage pathway team: Hamner Collaborators Salil Pendse Bin Sun Sean Rowley Patrick McMullen Pergentino Balbuena Joe Trask Susan Ross Linda Pluta Qiang Zhang Melvin Andersen Rebecca Clewell Unilever Collaborators Yeyejide Adeleye Paul Carmichael Paul Fowler Michael Davies Matt Dent Sophie Malcomber Andy Scott Andy White Beate Nichol Litron Laboratories Steve Bryce 18

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