Comparative toxicoproteogenomics of mouse and rat liver identifies TCDD-resistance genes

  • Stephenie D. Prokopec
  • Aileen Lu
  • Sandy Che-Eun S. Lee
  • Cindy Q. Yao
  • Ren X. Sun
  • John D. Watson
  • Rabah Soliymani
  • Richard de Borja
  • Ada Wong
  • Michelle Sam
  • Philip Zuzarte
  • John D. McPherson
  • Allan B. OkeyEmail author
  • Raimo PohjanvirtaEmail author
  • Paul C. BoutrosEmail author
Organ Toxicity and Mechanisms


The aryl hydrocarbon receptor (AHR) mediates many toxic effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). However, the AHR alone does not explain the widely different outcomes among organisms. To identify the other factors involved, we evaluated three transgenic mouse lines, each expressing a different rat AHR isoform (rWT, DEL, and INS) providing widely different resistance to TCDD toxicity, as well as C57BL/6 and DBA/2 mice which exhibit a ~ tenfold divergence in TCDD sensitivity (exposures of 5-1000 μg/kg TCDD). We supplement these with whole-genome sequencing, together with transcriptomic and proteomic analyses of the corresponding rat models, Long–Evans (L–E) and Han/Wistar (H/W) rats (having a ~ 1000-fold difference in their TCDD sensitivities; 100 μg/kg TCDD), to identify genes associated with TCDD-response phenotypes. Overall, we identified up to 50% of genes with altered mRNA abundance following TCDD exposure are associated with a single AHR isoform (33.8%, 11.7%, 5.2% and 0.3% of 3076 genes altered unique to rWT, DEL, C57BL/6 and INS respectively following 1000 μg/kg TCDD). Hepatic Pxdc1 was significantly repressed in all three TCDD-sensitive animal models (C57BL/6 and rWT mice, and L–E rat) after TCDD exposure. Three genes, including Cxxc5, Sugp1 and Hgfac, demonstrated different AHRE-1 (full) motif occurrences within their promoter regions between rat strains, as well as different patterns of mRNA abundance. Several hepatic proteins showed parallel up- or downward alterations with their RNAs, with three genes (SNRK, IGTP and IMPA2) showing consistent, strain-dependent changes. These data show the value of integrating genomic, transcriptomic and proteomic evidence across multi-species models in toxicologic studies.


Model organisms Whole-genome sequencing Transcriptomics Proteomics TCDD AhR 



The authors thank Hanbert Chen, Alexander Wu, Ashley Smith, Janne Korkalainen, Arja Moilanen, and Virpi Tiihonen for excellent technical assistance and support. Additional thanks to Marc Baumann and staff at the Meilahti Clinical & Basic Proteomics Core Facility. This work was supported by the Canadian Institutes of Health Research [grant number MOP-57903 to ABO and PCB], the Academy of Finland [grant number 123345 to RP], and with the support of the Ontario Institute for Cancer Research to PCB through funding provided by the Government of Ontario. PCB was supported by a Terry Fox Research Institute New Investigator Award and a Canadian Institutes of Health Research New Investigator Award.

Author contributions

JDW and SDP carried out the sample preparation for transcriptomic analyses. AW, MS and PZ were involved in library preparation and genome sequencing. RS performed proteomics work. AL, SDP, SL and RDB performed statistical and bioinformatics analyses. AL and SDP wrote the first draft of the manuscript. AL, CQY, SDP, RXS and RP generated tools and reagents. ABO, RP and PCB initiated the project. JDM, ABO, RP and PCB supervised the research. All authors approved the manuscript.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All study plans were approved by the Finnish National Animal Experiment Board (Eläinkoelautakunta, ELLA; permit code: ESLH-2008-07223/Ym-23). All animal handling and reporting comply with ARRIVE guidelines (Kilkenny et al. 2010).

Supplementary material

204_2019_2560_MOESM1_ESM.xlsx (19 kb)
Supplementary material 1 (XLSX 19 kb)
204_2019_2560_MOESM2_ESM.pdf (1.9 mb)
Supplementary material 2 (PDF 1937 kb)
204_2019_2560_MOESM3_ESM.xlsx (15.3 mb)
Supplementary material 3 (XLSX 15684 kb)


  1. Aras S, Pak O, Sommer N, Finley R Jr, Huttemann M, Weissmann N, Grossman LI (2013) Oxygen-dependent expression of cytochrome c oxidase subunit 4-2 gene expression is mediated by transcription factors RBPJ, CXXC5 and CHCHD2. Nucleic Acids Res 41:2255–2266CrossRefGoogle Scholar
  2. Assie G, Libe R, Espiard S, Rizk-Rabin M, Guimier A, Luscap W, Barreau O, Lefevre L, Sibony M, Guignat L et al (2013) ARMC5 mutations in macronodular adrenal hyperplasia with Cushing’s syndrome. N Engl J Med 369:2105–2114CrossRefGoogle Scholar
  3. Atanur SS, Diaz AG, Maratou K, Sarkis A, Rotival M, Game L, Tschannen MR, Kaisaki PJ, Otto GW, Ma MC et al (2013) Genome sequencing reveals loci under artificial selection that underlie disease phenotypes in the laboratory rat. Cell 154:691–703CrossRefGoogle Scholar
  4. Boutros PC, Yan R, Moffat ID, Pohjanvirta R, Okey AB (2008) Transcriptomic responses to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in liver: comparison of rat and mouse. BMC Genom 9:419CrossRefGoogle Scholar
  5. Boutros PC, Bielefeld KA, Pohjanvirta R, Harper PA (2009) Dioxin-dependent and dioxin-independent gene batteries: comparison of liver and kidney in AHR-null mice. Toxicol Sci 112:245–256CrossRefGoogle Scholar
  6. Boutros PC, Yao CQ, Watson JD, Wu AH, Moffat ID, Prokopec SD, Smith AB, Okey AB, Pohjanvirta R (2011) Hepatic transcriptomic responses to TCDD in dioxin-sensitive and dioxin-resistant rats during the onset of toxicity. Toxicol Appl Pharmacol 251:119–129CrossRefGoogle Scholar
  7. Boverhof DR, Burgoon LD, Tashiro C, Sharratt B, Chittim B, Harkema JR, Mendrick DL, Zacharewski TR (2006) Comparative toxicogenomic analysis of the hepatotoxic effects of TCDD in Sprague Dawley rats and C57BL/6 mice. Toxicol Sci 94:398–416CrossRefGoogle Scholar
  8. Chang C, Smith DR, Prasad VS, Sidman CL, Nebert DW, Puga A (1993) Ten nucleotide differences, five of which cause amino acid changes, are associated with the Ah receptor locus polymorphism of C57BL/6 and DBA/2 mice. Pharmacogenetics 3:312–321CrossRefGoogle Scholar
  9. Chapman DE, Schiller CM (1985) Dose-related effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in C57BL/6 J and DBA/2 J mice. Toxicol Appl Pharmacol 78:147–157CrossRefGoogle Scholar
  10. Chen H, Boutros PC (2011) VennDiagram: a package for the generation of highly-customizable Venn and Euler diagrams in R. BMC Bioinform 12:35CrossRefGoogle Scholar
  11. Dai M, Wang P, Boyd AD, Kostov G, Athey B, Jones EG, Bunney WE, Myers RM, Speed TP, Akil H et al (2005) Evolving gene/transcript definitions significantly alter the interpretation of GeneChip data. Nucleic Acids Res 33:e175CrossRefGoogle Scholar
  12. Deb S, Bandiera SM (2010) Characterization of a new cytochrome P450 enzyme, CYP2S1, in rats: its regulation by aryl hydrocarbon receptor agonists. Toxicology 267:91–98CrossRefGoogle Scholar
  13. Denison MS, Fisher JM, Whitlock JP Jr (1988) The DNA recognition site for the dioxin-Ah receptor complex. Nucleotide sequence and functional analysis. J Biol Chem 263:17221–17224Google Scholar
  14. Dixon WJ (1950) Analysis of extreme values. Ann Math Statist 21:488–506CrossRefGoogle Scholar
  15. Dong B, Nishimura N, Vogel CF, Tohyama C, Matsumura F (2010) TCDD-induced cyclooxygenase-2 expression is mediated by the nongenomic pathway in mouse MMDD1 macula densa cells and kidneys. Biochem Pharmacol 79:487–497CrossRefGoogle Scholar
  16. Fernandez-Salguero PM, Hilbert DM, Rudikoff S, Ward JM, Gonzalez FJ (1996) Aryl-hydrocarbon receptor-deficient mice are resistant to 2,3,7,8-tetrachlorodibenzo-p-dioxin-induced toxicity. Toxicol Appl Pharmacol 140:173–179CrossRefGoogle Scholar
  17. Gautier L, Cope L, Bolstad BM, Irizarry RA (2004) affy–analysis of Affymetrix GeneChip data at the probe level. Bioinformatics 20:307–315CrossRefGoogle Scholar
  18. Gentleman RC, Carey VJ, Bates DM, Bolstad B, Dettling M, Dudoit S, Ellis B, Gautier L, Ge Y, Gentry J et al (2004) Bioconductor: open software development for computational biology and bioinformatics. Genome Biol 5:R80CrossRefGoogle Scholar
  19. Hahn ME, Karchner SI, Shapiro MA, Perera SA (1997) Molecular evolution of two vertebrate aryl hydrocarbon (dioxin) receptors (AHR1 and AHR2) and the PAS family. Proc Natl Acad Sci USA 94:13743–13748CrossRefGoogle Scholar
  20. Harrill JA, Layko D, Nyska A, Hukkanen RR, Manno RA, Grassetti A, Lawson M, Martin G, Budinsky RA, Rowlands JC et al (2016) Aryl hydrocarbon receptor knockout rats are insensitive to the pathological effects of repeated oral exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin. J Appl Toxicol 36:802–814CrossRefGoogle Scholar
  21. Huuskonen H, Unkila M, Pohjanvirta R, Tuomisto J (1994) Developmental toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in the most TCDD-resistant and -susceptible rat strains. Toxicol Appl Pharmacol 124:174–180CrossRefGoogle Scholar
  22. Irizarry RA, Bolstad BM, Collin F, Cope LM, Hobbs B, Speed TP (2003) Summaries of Affymetrix GeneChip probe level data. Nucleic Acids Res 31:e15CrossRefGoogle Scholar
  23. Karolchik D, Baertsch R, Diekhans M, Furey TS, Hinrichs A, Lu YT, Roskin KM, Schwartz M, Sugnet CW, Thomas DJ et al (2003) The UCSC genome browser database. Nucleic Acids Res 31:51–54CrossRefGoogle Scholar
  24. Kilkenny C, Browne WJ, Cuthill IC, Emerson M, Altman DG (2010) Improving bioscience research reporting: the ARRIVE guidelines for reporting animal research. PLoS Biol 8:e1000412CrossRefGoogle Scholar
  25. Kransler KM, McGarrigle BP, Olson JR (2007) Comparative developmental toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin in the hamster, rat and guinea pig. Toxicology 229:214–225CrossRefGoogle Scholar
  26. Lee J, Prokopec SD, Watson JD, Sun RX, Pohjanvirta R, Boutros PC (2015) Male and female mice show significant differences in hepatic transcriptomic response to 2,3,7,8-tetrachlorodibenzo-p-dioxin. BMC Genom 16:625CrossRefGoogle Scholar
  27. Linden J, Lensu S, Pohjanvirta R (2014) Effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on hormones of energy balance in a TCDD-sensitive and a TCDD-resistant rat strain. Int J Mol Sci 15:13938–13966CrossRefGoogle Scholar
  28. Lusska A, Shen E, Whitlock JP Jr (1993) Protein-DNA interactions at a dioxin-responsive enhancer. Analysis of six bona fide DNA-binding sites for the liganded Ah receptor. J Biol Chem 268:6575–6580Google Scholar
  29. Matsumura F (2009) The significance of the nongenomic pathway in mediating inflammatory signaling of the dioxin-activated Ah receptor to cause toxic effects. Biochem Pharmacol 77:608–626CrossRefGoogle Scholar
  30. Mimura J, Yamashita K, Nakamura K, Morita M, Takagi TN, Nakao K, Ema M, Sogawa K, Yasuda M, Katsuki M et al (1997) Loss of teratogenic response to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in mice lacking the Ah (dioxin) receptor. Genes Cells 2:645–654CrossRefGoogle Scholar
  31. Moffat ID, Roblin S, Harper PA, Okey AB, Pohjanvirta R (2007) Aryl hydrocarbon receptor splice variants in the dioxin-resistant rat: tissue expression and transactivational activity. Mol Pharmacol 72:956–966CrossRefGoogle Scholar
  32. Moffat ID, Boutros PC, Chen H, Okey AB, Pohjanvirta R (2010) Aryl hydrocarbon receptor (AHR)-regulated transcriptomic changes in rats sensitive or resistant to major dioxin toxicities. BMC Genom 11:263CrossRefGoogle Scholar
  33. Morgan MA, Morgan JI (2012) Pcp4l1 contains an auto-inhibitory element that prevents its IQ motif from binding to calmodulin. J Neurochem 121:843–851CrossRefGoogle Scholar
  34. Nebert DW, Puga A, Vasiliou V (1993) Role of the Ah receptor and the dioxin-inducible [Ah] gene battery in toxicity, cancer, and signal transduction. Ann NY Acad Sci 685:624–640CrossRefGoogle Scholar
  35. Okey AB, Vella LM, Harper PA (1989) Detection and characterization of a low affinity form of cytosolic Ah receptor in livers of mice nonresponsive to induction of cytochrome P1-450 by 3-methylcholanthrene. Mol Pharmacol 35:823–830Google Scholar
  36. P’ng C, Green J, Chong LC, Waggott D, Prokopec SD, Shamsi M, Nguyen F, Mak DYF, Lam F, Albuquerque MA et al (2017) BPG: seamless, automated and interactive visualization of scientific data. bioRxiv Google Scholar
  37. Pohjanvirta R (1990) TCDD resistance is inherited as an autosomal dominant trait in the rat. Toxicol Lett 50:49–56CrossRefGoogle Scholar
  38. Pohjanvirta R (2009) Transgenic mouse lines expressing rat AH receptor variants–a new animal model for research on AH receptor function and dioxin toxicity mechanisms. Toxicol Appl Pharmacol 236:166–182CrossRefGoogle Scholar
  39. Pohjanvirta R (ed) (2011) The AH receptor in biology and toxicology. Wiley, HobokenGoogle Scholar
  40. Pohjanvirta R, Tuomisto J (1990) Mechanism of action of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Toxicol Appl Pharmacol 105:508–509CrossRefGoogle Scholar
  41. Pohjanvirta R, Kulju T, Morselt AF, Tuominen R, Juvonen R, Rozman K, Mannisto P, Collan Y, Sainio EL, Tuomisto J (1989) Target tissue morphology and serum biochemistry following 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure in a TCDD-susceptible and a TCDD-resistant rat strain. Fundam Appl Toxicol 12:698–712CrossRefGoogle Scholar
  42. Pohjanvirta R, Unkila M, Tuomisto J (1993) Comparative acute lethality of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), 1,2,3,7,8-pentachlorodibenzo-p-dioxin and 1,2,3,4,7,8-hexachlorodibenzo-p-dioxin in the most TCDD-susceptible and the most TCDD-resistant rat strain. Pharmacol Toxicol 73:52–56CrossRefGoogle Scholar
  43. Pohjanvirta R, Wong JM, Li W, Harper PA, Tuomisto J, Okey AB (1998) Point mutation in intron sequence causes altered carboxyl-terminal structure in the aryl hydrocarbon receptor of the most 2,3,7,8-tetrachlorodibenzo-p-dioxin-resistant rat strain. Mol Pharmacol 54:86–93CrossRefGoogle Scholar
  44. Pohjanvirta R, Viluksela M, Tuomisto JT, Unkila M, Karasinska J, Franc MA, Holowenko M, Giannone JV, Harper PA, Tuomisto J et al (1999) Physicochemical differences in the AH receptors of the most TCDD-susceptible and the most TCDD-resistant rat strains. Toxicol Appl Pharmacol 155:82–95CrossRefGoogle Scholar
  45. Pohjanvirta R, Korkalainen M, Moffat ID, Boutros PC, Okey AB (2011) Role of the AHR and its structure in TCDD toxicity. In: Pohjanvirta R (ed) The AH receptor in biology and toxicology. Wiley, Hoboken, pp 181–196CrossRefGoogle Scholar
  46. Pohjanvirta R, Miettinen H, Sankari S, Hegde N, Linden J (2012) Unexpected gender difference in sensitivity to the acute toxicity of dioxin in mice. Toxicol Appl Pharmacol 262:167–176CrossRefGoogle Scholar
  47. Prokopec SD, Watson JD, Lee J, Pohjanvirta R, Boutros PC (2015) Sex-related differences in murine hepatic transcriptional and proteomic responses to TCDD. Toxicol Appl Pharmacol 284:188–196CrossRefGoogle Scholar
  48. Prokopec SD, Houlahan KE, Sun RX, Watson JD, Yao CQ, Lee J, P’ng C, Pang R, Wu AH, Chong LC et al (2017) Compendium of TCDD-mediated transcriptomic response datasets in mammalian model systems. BMC Genom 18:78CrossRefGoogle Scholar
  49. Rowlands JC, Gustafsson JA (1997) Aryl hydrocarbon receptor-mediated signal transduction. Crit Rev Toxicol 27:109–134CrossRefGoogle Scholar
  50. Rushmore TH, Morton MR, Pickett CB (1991) The antioxidant responsive element. Activation by oxidative stress and identification of the DNA consensus sequence required for functional activity. J Biol Chem 266:11632–11639Google Scholar
  51. Schmidt JV, Su GH, Reddy JK, Simon MC, Bradfield CA (1996) Characterization of a murine Ahr null allele: involvement of the Ah receptor in hepatic growth and development. Proc Natl Acad Sci USA 93:6731–6736CrossRefGoogle Scholar
  52. Scifo E, Szwajda A, Soliymani R, Pezzini F, Bianchi M, Dapkunas A, Debski J, Uusi-Rauva K, Dadlez M, Gingras AC et al (2015) Proteomic analysis of the palmitoyl protein thioesterase 1 interactome in SH-SY5Y human neuroblastoma cells. J Proteom 123:42–53CrossRefGoogle Scholar
  53. Shen ES, Whitlock JP Jr (1992) Protein-DNA interactions at a dioxin-responsive enhancer. Mutational analysis of the DNA-binding site for the liganded Ah receptor. J Biol Chem 267:6815–6819Google Scholar
  54. Smyth GK (2004) Linear models and empirical bayes methods for assessing differential expression in microarray experiments. Stat Appl Genet Mol Biol. Google Scholar
  55. Sogawa K, Numayama-Tsuruta K, Takahashi T, Matsushita N, Miura C, Nikawa J, Gotoh O, Kikuchi Y, Fujii-Kuriyama Y (2004) A novel induction mechanism of the rat CYP1A2 gene mediated by Ah receptor-Arnt heterodimer. Biochem Biophys Res Commun 318:746–755CrossRefGoogle Scholar
  56. Storey JD, Tibshirani R (2003) Statistical significance for genomewide studies. Proc Natl Acad Sci USA 100:9440–9445CrossRefGoogle Scholar
  57. Sun RX, Chong LC, Simmons TT, Houlahan KE, Prokopec SD, Watson JD, Moffat ID, Lensu S, Linden J, P’ng C et al (2014) Cross-species transcriptomic analysis elucidates constitutive aryl hydrocarbon receptor activity. BMC Genom 15:1053CrossRefGoogle Scholar
  58. Swanson HI, Chan WK, Bradfield CA (1995) DNA binding specificities and pairing rules of the Ah receptor, ARNT, and SIM proteins. J Biol Chem 270:26292–26302CrossRefGoogle Scholar
  59. Tijet N, Boutros PC, Moffat ID, Okey AB, Tuomisto J, Pohjanvirta R (2006) Aryl hydrocarbon receptor regulates distinct dioxin-dependent and dioxin-independent gene batteries. Mol Pharmacol 69:140–153CrossRefGoogle Scholar
  60. Tuomisto JT, Viluksela M, Pohjanvirta R, Tuomisto J (1999) The AH receptor and a novel gene determine acute toxic responses to TCDD: segregation of the resistant alleles to different rat lines. Toxicol Appl Pharmacol 155:71–81CrossRefGoogle Scholar
  61. Von Burg R (1988) Tcdd. J Appl Toxicol 8:145–148CrossRefGoogle Scholar
  62. Watson JD, Prokopec SD, Smith AB, Okey AB, Pohjanvirta R, Boutros PC (2014) TCDD dysregulation of 13 AHR-target genes in rat liver. Toxicol Appl Pharmacol 274:445–454CrossRefGoogle Scholar
  63. Wisniewski JR, Zougman A, Nagaraj N, Mann M (2009) Universal sample preparation method for proteome analysis. Nat Methods 6:359–362CrossRefGoogle Scholar
  64. Yao CQ, Prokopec SD, Watson JD, Pang R, P’ng C, Chong LC, Harding NJ, Pohjanvirta R, Okey AB, Boutros PC (2012) Inter-strain heterogeneity in rat hepatic transcriptomic responses to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Toxicol Appl Pharmacol 260:135–145CrossRefGoogle Scholar
  65. Yeager RL, Reisman SA, Aleksunes LM, Klaassen CD (2009) Introducing the “TCDD-inducible AhR-Nrf2 gene battery”. Toxicol Sci 111:238–246CrossRefGoogle Scholar
  66. Zeeberg BR, Qin H, Narasimhan S, Sunshine M, Cao H, Kane DW, Reimers M, Stephens RM, Bryant D, Burt SK et al (2005) High-Throughput GoMiner, an ‘industrial-strength’ integrative gene ontology tool for interpretation of multiple-microarray experiments, with application to studies of Common Variable Immune Deficiency (CVID). BMC Bioinform 6:168CrossRefGoogle Scholar
  67. Zhang B, Duan S, Shi J, Jiang S, Feng F, Shi B, Jia Z (2018) Family-based study of association between MAFB gene polymorphisms and NSCL/P among Western Han Chinese population. Adv Clin Exp Med 27:1109–1116CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Stephenie D. Prokopec
    • 1
  • Aileen Lu
    • 1
    • 2
  • Sandy Che-Eun S. Lee
    • 1
  • Cindy Q. Yao
    • 1
  • Ren X. Sun
    • 1
  • John D. Watson
    • 1
  • Rabah Soliymani
    • 3
  • Richard de Borja
    • 1
  • Ada Wong
    • 4
  • Michelle Sam
    • 4
  • Philip Zuzarte
    • 4
  • John D. McPherson
    • 4
  • Allan B. Okey
    • 2
    Email author
  • Raimo Pohjanvirta
    • 5
    • 6
    Email author
  • Paul C. Boutros
    • 1
    • 2
    • 7
    • 8
    • 9
    • 10
    • 11
    Email author
  1. 1.Computational BiologyOntario Institute for Cancer ResearchTorontoCanada
  2. 2.Department of Pharmacology and ToxicologyUniversity of TorontoTorontoCanada
  3. 3.Department of Biochemistry and Developmental Biology, Meilahti Clinical and Basic Proteomics Core FacilityUniversity of HelsinkiHelsinkiFinland
  4. 4.Genome Technologies ProgramOntario Institute for Cancer ResearchTorontoCanada
  5. 5.Laboratory of ToxicologyNational Institute for Health and WelfareKuopioFinland
  6. 6.Department of Food Hygiene and Environmental HealthUniversity of HelsinkiHelsinkiFinland
  7. 7.Department of Medical BiophysicsUniversity of TorontoTorontoCanada
  8. 8.Department of Human GeneticsUniversity of CaliforniaLos AngelesUSA
  9. 9.Department of UrologyUniversity of CaliforniaLos AngelesUSA
  10. 10.Institute for Precision HealthUniversity of CaliforniaLos AngelesUSA
  11. 11.Jonsson Comprehensive Cancer CenterUniversity of CaliforniaLos AngelesUSA

Personalised recommendations