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Person Details: Timothy R. Zacharewski

Superfund Research Program

Timothy R. Zacharewski

Michigan State University
Department of Biochemistry and Molecular Biology
1129 Farm Lane, Room 241
Food Safety Toxicology Building
East Lansing, Michigan 48824-1319
Phone: 517-355-1607
Fax: 517-353-9334


Research Briefs



  • Cholico G, Orlowska K, Fling RR, Sink WJ, Zacharewski N, Fader KA, Nault R, Zacharewski TR. 2023. Consequences of reprogramming acetyl-CoA metabolism by 2,3,7,8-tetrachlorodibenzo-p-dioxin in the mouse liver. Sci Rep 13(1):4138. doi:10.1038/s41598-023-31087-9 PMID:36914879 PMCID:PMC1001158
  • Jurgelewicz A, Nault R, Harkema JR, Zacharewski TR, LaPres JJ. 2023. Characterizing the impact of simvastatin co-treatment of cell specific TCDD-induced gene expression and systemic toxicity. Sci Rep 13(1):16598. doi:10.1038/s41598-023-42972-8 PMID:37789023 PMCID:PMC10547718
  • Nault R, Cave MC, Ludewig G, Moseley HN, Pennell KG, Zacharewski TR. 2023. A case for accelerating standards to achieve the FAIR principles of environmental health research experimental data. Environ Health Perspect 131(6):65001. doi:10.1289/EHP11484 PMID:37352010 PMCID:PMC10289218
  • Orlowska K, Fling RR, Nault R, Schilmiller AL, Zacharewski TR. 2023. Cystine/glutamate Xc- antiprorter induction compensates for transsulfuration pathway repression by 2,3,7,8-tetrachlorodibenzo- p-dioxin (TCDD) to ensure cysteine for heptic glutathione biosynthesis. Chem Res Toxicol 36(6):900-915. doi:10.1021/acs.chemrestox.3c00017 PMID:37184393 PMCID:PMC10284067


  • Cholico G, Nault R, Zacharewski TR. 2022. Genome-wide ChIPseq analysis of AhR, COUP-TF, and HNF4 enrichment in TCDD-treated mouse liver. Int J Mol Sci 23(3):1558. doi:10.3390/ijms23031558 PMID:35163483 PMCID:PMC8836158
  • Liu R, Zacharewski TR, Conolly RB, Zhang Q. 2022. A physiologically based pharmacokinetic (PBPK) modeling framework for mixtures of dioxin-like compounds. Toxics 10(11):700. doi:10.3390/toxics10110700 PMID:36422908 PMCID:PMC9698634
  • Nault R, Saha S, Bhattacharya S, Dodson J, Sinha S, Maiti T, Zacharewski TR. 2022. Benchmarking of a Bayesian single cell RNAseq differential gene expression test for dose-response study designs. Nucleic Acids Res doi:10.1093/nar/gkac019 PMID:35061903
  • Nault R, Saha S, Bhattacharya S, Sinha S, Maiti T, Zacharewski TR. 2022. Single cell transcriptomics shows dose-dependent disruption of hepatic zonation by TCDD in mice. Toxicol Sci doi:10.1093/toxsci/kfac109 PMID:36222588
  • Orlowska K, Fling RR, Nault R, Sink WJ, Schilmiller AL, Zacharewski TR. 2022. Dioxin-elicited decrease in cobalamin redirects propionyl-CoA metabolism to the beta-oxidation-like pathway resulting in acrylyl-CoA conjugate buildup. J Biol Chem 298(9):102301. doi:10.1016/j.jbc.2022.102301 PMID:35931118 PMCID:PMC9418907



  • Doskey CM, Fader KA, Nault R, Lydic TA, Matthews J, Potter D, Sharratt B, Williams K, Zacharewski TR. 2020. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) alters hepatic polyunsaturated fatty acid metabolism and eicosanoid biosynthesis in female Sprague-Dawley rats. Toxicol Appl Pharmacol 398:14. doi:10.1016/j.taap.2020.115034 PMID:32387183 PMCID:PMC7294678
  • Fling RR, Doskey CM, Fader KA, Nault R, Zacharewski TR. 2020. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) dysregulates hepatic one carbon metabolism during the progression of steatosis to steatohepatitis with fibrosis in mice. Sci Rep 10:14831. doi:10.1038/s41598-020-71795-0 PMID:32908189 PMCID:PMC7481292


  • Dornbos P, Jurgelewicz A, Fader KA, Williams K, Zacharewski TR, LaPres JJ. 2019. Characterizing the role of HMG-CoA reductase in aryl hydrocarbon receptor-mediated liver injury in C57BL/6 mice. Sci Rep 9(1):15828. doi:10.1038/s41598-019-52001-2 PMID:31676775 PMCID:PMC6825130
  • Fader KA, Nault R, Doskey CM, Fling RR, Zacharewski TR. 2019. 2,3,7,8-Tetrachlorodibenzo-p-dioxin abolishes circadian regulation of hepatic metabolic activity in mice. Sci Rep 9:6514. doi:10.1038/s41598-019-42760-3 PMID:31015483 PMCID:PMC6478849
  • Josyula N, Andersen ME, Kaminski NE, Dere E, Zacharewski TR, Bhattacharya S. 2019. Gene co-regulation and co-expression in the aryl hydrocarbon receptor-mediated transcriptional regulatory network in the mouse liver. Arch Toxicol 94:113-126. doi:10.1007/s00204-019-02620-5 PMID:31728591


  • Fader KA, Nault R, Raehtz S, McCabe LR, Zacharewski TR. 2018. 2,3,7,8-Tetrachlorodibenzo-p-dioxin dose-dependently increases bone mass and decreases marrow adiposity in juvenile mice. Toxicol Appl Pharmacol 348:85-98. doi:10.1016/j.taap.2018.04.013 PMID:29673856 PMCID:PMC5984050
  • Nault R, Doskey CM, Fader KA, Rockwell CE, Zacharewski TR. 2018. Comparison of hepatic NRF2 and aryl hydrocarbon receptor binding in 2,3,7,8-tetrachlorodibenzo-p-dioxin-treated mice demonstrates NRF2-independent PKM2 induction. Mol Pharmacol 94(2):876-884. doi:10.1124/mol.118.112144 PMID:29752288 PMCID:6022803


  • Fader KA, Nault R, Kirby MP, Markous G, Matthews J, Zacharewski TR. 2017. Convergence of hepcidin defiency, systemic iron overloading, heme accumulation, and REV-ERBalpha/beta activation in aryl hydrocarbon receptor-elicited hepatotoxicity. Toxicol Appl Pharmacol 321:1-17. doi:10.1016/j.taap.2017.02.006 PMID:28213091
  • Fader KA, Nault R, Kumagai K, Harkema JR, Zacharewski TR, Zhang C. 2017. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD)-elicited effects on bile acid homeostasis: Alterations in biosynthesis, enterohepatic circulation, and microbial metabolism. Sci Rep 7:5921. doi:10.1038/s41598-017-05656-8 PMID:28725001 PMCID:PMC5517430
  • Fader KA, Zacharewski TR. 2017. Beyond the Aryl Hydrocarbon Receptor: Pathway Interactions in the Hepatotoxicity of 2,3,7,8-Tetrachlorodibenzo-p-dioxin and Related Compounds. Curr Opin Toxicol 2:36-41. doi:10.1016/j.cotox.2017.01.010 PMID:28948239 PMCID:PMC5609723
  • Kovalova N, Nault R, Crawford RB, Zacharewski TR, Kaminski NE. 2017. Comparative analysis of TCDD-induced AhR-mediated gene expression in human, mouse and rat primary B cells. Toxicol Appl Pharmacol 316:95-106. doi:10.1016/j.taap.2016.11.009 PMID:27913140 PMCID:PMC5292778
  • Nault R, Fader KA, Lydic TA, Zacharewski TR. 2017. Lipidomic evaluation of aryl hydrocarbon receptor-mediated hepatic steatosis in male and female mice by 2,3,7,8-tetrachlorodibenzo-p-dioxin. Chem Res Toxicol 30(4):1060-1075. doi:10.1021/acs.chemrestox.6b00430 PMID:28238261
  • Nault R, Fader KA, Zacharewski TR. 2017. Loss of liver-specific and sexually dimorphic gene expression by aryl hydrocarbon receptor activation in C57BL/6 mice. PLoS One 12:17. doi:10.1371/journal.pone.0184842 PMID:28922406 PMCID:PMC5602546
  • Stedtfeld RD, Stedtfeld TM, Fader KA, Williams MR, Bhaduri P, Quensen JF, Zacharewski TR, Tiedje JM, Hashsham SA. 2017. TCDD influences reservoir of antibiotic resistance genes in murine gut microbiome. FEMS Microbiol Ecol 93:8. doi:10.1093/femsec/fix058 PMID:28475713 PMCID:PMC5458050


  • Nault R, Fader KA, Ammendolia DA, Dornbos P, Potter D, Sharratt B, Kumagai K, Harkema JR, Lunt SY, Matthews J, Zacharewski TR. 2016. Dose-dependent metabolic reprogramming and differential gene expression in TCDD-elicited hepatic fibrosis. Toxicol Sci 154(2):253-266. doi:10.1093/toxsci/kfw163 PMID:27562557 PMCID:PMC5139066
  • Nault R, Fader KA, Kirby MP, Ahmed S, Matthews J, Jones AD, Lunt SY, Zacharewski TR. 2016. Pyruvate kinase isoform switching and hepatic metabolic reprogramming by the environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin. Toxicol Sci 149(2):358-371. doi:10.1093/toxsci/kfv245 PMID:26582802 PMCID:PMC4900217
  • Nault R, Fader KA, Kopec AK, Harkema JR, Zacharewski TR, Luyendyk J. 2016. From the cover: coagulation-driven hepatic fibrosis requires protease activated receptor-1 (PAR-1) in a mouse model of TCDD-elicited steatohepatitis. Toxicol Sci 154(2):381-391. doi:10.1093/toxsci/kfw175 PMID:27613713 PMCID:PMC5139072


  • Fader KA, Nault R, Ammendolia DA, Harkema JR, Williams KJ, Crawford RB, Kaminski NE, Potter D, Sharratt B, Zacharewski TR. 2015. 2,3,7,8-Tetrachlorodibenzo-p-dioxin alters lipid metabolism and depletes immune cell populations in the jejunum of C57BL/6 mice. Toxicol Sci 148(2):567-580. doi:10.1093/toxsci/kfv206 PMID:26377647 PMCID:PMC5009443
  • Nault R, Colbry D, Brandenberger C, Zacharewski TR, Harkema JR. 2015. Development of a computational high-throughput tool for the quantitative examination of dose-dependent histological features. Toxicol Pathol 43(3):366-375. doi:10.1177/0192623314544379 PMID:25274660 PMCID:PMC4382446
  • Nault R, Fader KA, Zacharewski TR. 2015. RNA-Seq versus oligonucleotide array assessment of dose-dependent TCDD-elicited hepatic gene expression in mice. BMC Genomics 16:373. doi:10.1186/s12864-015-1527-z PMID:25958198 PMCID:PMC4456707



  • Angrish MM, Jones AD, Harkema JR, Zacharewski TR. 2011. Aryl hydrocarbon receptor-mediated induction of stearoyl-CoA desaturase 1 alters hepatic fatty acid composition in TCDD-elicited steatosis. Toxicol Sci 124(2):299-310. doi:10.1093/toxsci/kfr226 PMID:21890736 PMCID:PMC3216411
  • Dere E, Forgacs AL, Zacharewski TR, Burgoon LD. 2011. Genome-wide computational analysis of dioxin response element location and distribution in the human, mouse, and rat genomes. Chem Res Toxicol 24:494-504. doi:10.1021/tx100328r PMID:21370876 PMCID:PMC4038167
  • Dere E, Lee AW, Burgoon LD, Zacharewski TR. 2011. Differences in TCDD-elicited gene expression profiles in human HepG2, mouse Hepa1c1c7 and rat H4IIE hepatoma cells. BMC Genomics 12:doi:10.1186/1471-2164-12-193 PMID:21496263 PMCID:PMC3089798
  • Dere E, Lo R, Celius T, Matthews J, Zacharewski TR. 2011. Integration of genome-wide computation DRE search, AhR ChIP-chip and gene expression analyses of TCDD-elicited responses in the mouse liver. BMC Genomics 12:365. doi:10.1186/1471-2164-12-365 PMID:21762485 PMCID:PMC3160422
  • Kopec AK, D'Souza ML, Mets BD, Burgoon LD, Reese SE, Archer KJ, Potter D, Tashiro C, Sharratt B, Harkema JR, Zacharewski TR. 2011. Non-additive hepatic gene expression elicited by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and 2,2 ',4,4 ',5,5 '-hexachlorobiphenyl (PCB153) co-treatment in C57BL/6 mice. Toxicol Appl Pharmacol 256:154-167. doi:10.1016/j.taap.2011.08.002 PMID:21851831 PMCID:PMC4126514
  • Lo R, Celius T, Dere E, MacPherson L, Harper PA, Zacharewski TR, Matthews J. 2011. Identification of aryl hydrocarbon receptor binding targets in mouse hepatic tissue treated with 2,3,7,8-tetrachlorodibenzo-p-dioxin. Toxicol Appl Pharmacol 257:38-47. doi:10.1016/j.taap.2011.08.016 PMID:21889950


  • Forgacs AL, Burgoon LD, Lynn SG, LaPres JJ, Zacharewski TR. 2010. Effects of TCDD on the expression of nuclear encoded mitochondrial genes. Toxicol Appl Pharmacol 246(1-2):58-65. doi:10.1016/j.taap.2010.04.006 PMID:20399798 PMCID:PMC4030424
  • Kopec AK, Burgoon LD, Ibrahim-Aibo D, Burg AR, Lee AW, Tashiro C, Sharratt B, Harkema JR, Rowlands C, Budinsky R, Zacharewski TR. 2010. Automated dose-response analysis and comparative toxicogenomic evaluation of the hepatic effects elicited by TCDD, TCDF, and PCB126 in C57BL/6 mice. Toxicol Sci 118(1):286-297. doi:10.1093/toxsci/kfq236 PMID:20702594 PMCID:PMC2955213
  • Kopec AK, Burgoon LD, Ibrahim-Aibo D, Mets BD, Tashiro C, Potter D, Sharratt B, Harkema JR, Zacharewski TR. 2010. PCB153-elicited hepatic responses in the immature, ovariectomized C57BL/6 mice: comparative toxicogenomic effects of dioxin and non-dioxin-like ligands. Toxicol Appl Pharmacol 243(3):359-371. doi:10.1016/j.taap.2009.12.003 PMID:20005886 PMCID:PMC3987113


  • Boverhof DR, Burgoon LD, Williams KJ, Zacharewski TR. 2008. Inhibition of estrogen-mediated uterine gene expression responses by dioxin. Mol Pharmacol 73(1):82-93. doi:10.1124/mol.107.040451 PMID:17942748
  • Kopec AK, Boverhof DR, Burgoon LD, Ibrahim-Aibo D, Harkema JR, Tashiro C, Chittim B, Zacharewski TR. 2008. Comparative toxicogenomic examination of the hepatic effects of PCB126 and TCDD in immature, ovariectomized C57BL/6 mice. Toxicol Sci 102(1):61-75. doi:10.1093/toxsci/kfm289 PMID:18042819


  • Burgoon LD, Boutros PC, Dere E, Zacharewski TR. 2006. dbZach: A MIAME-compliant toxicogenomic supportive relational database. Toxicol Sci 90(2):558-68. PMID:16403854
  • Cook J, Denslow ND, Iguchi T, Linney EA, Miracle A, Shaw JR, Viant MR, Zacharewski TR. 2006. "Omics" approaches in the context of environment toxicology. (In: Emerging Molecular and Computational Approaches for Cross-Species Extrapolations). Chapter 1in: Society of Environmental Toxicology and Chemistry (SETAC) Annual Meeting 2006. Washington, DC. pp.1-29.
  • Cook J, Denslow ND, Iguchi T, Linney EA, Miracle AL, Shaw JR, Viant MR, Zacharewski TR. 2006. "Omics" approaches in the context of human and environmental toxicology. Chapter 1 in: Genomic Approaches for Cross-Species Extrapolation in Toxicology. pp.1-25.
  • Lee K, Burgoon LD, Lamb L, Dere E, Zacharewski TR, Hogenesch JB, LaPres JJ. 2006. Identification and characterization of genes susceptible to transcriptional cross-talk between the hypoxia and dioxin signaling cascades. Chem Res Toxicol 19(10):1284-1293. doi:10.1021/tx060068d PMID:17040097 PMCID:PMC3152583


  • Burgoon LD, Eckel-Passow JE, Gennings C, Boverhof DR, Burt JW, Fong C, Zacharewski TR. 2005. Protocols for the assurance of microarray data quality and process control. Nucleic Acids Res 33(19):e172. PMID:16272462


  • Boverhof DR, Tam E, Harney AS, Crawford RB, Kaminski NE, Zacharewski TR. 2004. 2,3,7,8-Tetrachlorodibenzo-p-dioxin induces suppressor of cytokine signaling 2 in murine B cells. Mol Pharmacol 66(6):1662-1670. PMID:15371557
  • Boverhof DR, Tam E, Harney AS, Crawford RB, Kaminski NE, Zacharewski TR. 2004. Suppressor of cytokine signaling-2: a novel TCDD inducible gene in CH12.LX murine B-cells. Environ Health Perspect 78(1-S):(Abst.1412).


  • Burgoon LD, Boverhof DR, Eckel-Passow JE, Gennings C, Zacharewski TR. 2003. Comparison of the modeified loop and independent reference microarray designs. In: Proceedings of the 2nd Annual Great Lakes Bioinformatic Retreat - Michigan Center for Biological Information. Kellogg Center, Aug. 19-20. Michigan State University, East Lansing, MI.
  • Burgoon LD, Boverhof DR, Eckel-Passow JE, Gennings C, Zacharewski TR. 2003. Comparison of the modified loop and independent reference microarray designs. In: Proceedings of the 6th International Meeting of the Microarray Gene Expression Data Society. Sept. 3-5. Aix-en-Provence, France.
  • Zacharewski TR. 2003. Incorporation of a systems toxicology approach into mechanistic and predictive toxicology. In: Proceedings of the Biogen's First Annual Preclinical & Clinical Development Science (PCDS) Offsite Symposium. Cliff House, Oct. 23. Ogunquit, ME.
  • Zacharewski TR. 2003. Incorporation of computational approaches into mechanistic and predictive toxicology. In: Proceedings of the Center for Biological Modeling - Biological Networks Symposium, Oct. 17. Michigan State University, East Lansing, MI.
  • Zacharewski TR. 2003. Integrating toxicogenomics into predictive and mechanistic toxicology. In: Proceedings of the Lorne Genome Conference. Febuary 16-20. Lorne, Australia.


  • Trosko JE, Kwan K, Upham BL, Halgren R, Zacharewski TR, Chang C. 2001. Stem cell biology in toxicology. Toxicol Sci 60:150.


  • Ake, Jr., Connor K, Ramamoorthy K, Moore M, Wang F, Mustain M, Chen I, Zacharewski TR, Gillesby B, Joyeux A, Belaguer P, Gaido KW, Leonard LS, Maness SC, McDonnell DP. 1998. Estrogenic activity of hydroxylated polychlorinated biphenyls (PCBs) and their interaction. In: Hormonal Toxicants in Food, Proceedings. John Wiley, pp.200-207.
  • Ankley GT, Mahaich E, Stahl R, Tillitt DE, Colborn T, McMaster S, Miller R, Bantle J, Campbell P, Denslow ND, Dickerson RL, Folmar LC, Fry M, Giesy JP, Gray LE, Guiney PD, Hutchinson T, Kennedy SP, Kramer VJ, LeBlank G, Mayes M, Nimrod A, Patino R, Peterson R, Purdy R, Ringer R, Thomas P, Touart L, Van Der Kraak G, Zacharewski TR. 1998. Overview of a workshop on screening methods for detecting potential (anti-) estrogenic/androgenic chemicals in wildlife. Environ Toxicol Chem 17(1):68-87.
  • Gould JC, Leonard LS, Maness SC, Wagner BL, Connor K, Zacharewski TR, Safe SH, McDonnell DP, Gaido KW. 1998. Bisphenol A interacts with the estrogen receptor α in a distinct manner from estradiol. Mol Cell Endocrinol 142:203-214. PMID:9783916


  • Connor K, Ramamoorthy K, Moore M, Mustain M, Chen I, Safe SH, Zacharewski TR, Gillesby B, Joyeux A, Belaguer P. 1997. Hydroxylated polychlorinated biphenyls (PCBs) as estrogens and antiestrogens: structure-activity relationships. Toxicol Appl Pharmacol 145:111-123. PMID:9221830
  • Fielden MR, Chen I, Chittim B, Safe SH, Zacharewski TR. 1997. Examination of the estrogenicity of 2,4,6,2',6'-pentachlorobiphenyl (PCB 104), its hydroxylated metabolite 2,4,6,2',6'-pentachloro-4-biphenylol (HO-PCB 104), and a further chlorinated derivative, 2,4,6,2',4',6'-hexachlorobiphenyl (PCB 155). Environ Health Perspect 105(11):1238-1248. PMID:9370515 PMCID:PMC1470342
  • Gray LE, Klece WR, Wiese T, Tyl R, Gaido KW, Cook J, Klinefelter G, Desaulniers D, Wilson E, Zacharewski TR, Waller C, Foster P, Laskey J, Reel J, Giesy JP, Laws S, McLachlan JA, Breslin W, Cooper R, Di Giulio RT, Johnson R, Purdy R, Mihaich E, Safe SH, Sonnenschein C, Welshons W, Miller R, McMaster S, Colborn T. 1997. Endocrine screening methods workshop report: detection of estrogenic and androgenic hormonal and antihormonal activity for chemicals that act via receptor or steroidogenic enzyme mechanisms. Reprod Toxicol 11(5):719-750. PMID:9311581
  • Moore M, Mustain M, Daniel KD, Chen I, Safe SH, Zacharewski TR, Gillesby B, Joyeux A, Belaguer P. 1997. Antiestrogenic activity of hydroxylated polychlorinated biphenyl congeners identified in human serum. Toxicol Appl Pharmacol 142:160-168. PMID:9007045
  • Zacharewski TR, Sutter TR, Safe SH, Greenlee WF, Connolly RB. 1997. Concerns with the use of a toxic equivalency factor (TEF) approach for risk assessment of "dioxin-like" compounds. Organohalogen Compounds 34:91-94.


  • Safe SH, Washburn KS, Zacharewski TR, Phillips TD. 1995. Synthesis and characterization of hydroxylated polychlorinated biphenyls (PCBs) identified in human serum. Chemosphere 31(4):3017-3023. doi:10.1016/0045-6535(95)00162-2 PMID:7552046
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