Superfund Research Program

TCDD-Elicited Steatosis: The Role of Aryl Hydrocarbon Receptor Regulation in Lipid Uptake, Metabolism, and Transport

Project Leader: Timothy R. Zacharewski
Grant Number: P42ES004911
Funding Period: 2006-2021

Project-Specific Links

Publications

2022

• 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
• 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
• 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

2021

• Cholico G, Fling RR, Zacharewski TR, Zacharewski N, Fader KA, Nault R. 2021. Thioesterase induction by 2,3,7,8-tetrachlorodibenzo-p-dioxin results in a futile cycle that inhibits hepatic beta-oxidation. Sci Rep 11:15689. doi:10.1038/s41598-021-95214-0 PMID:34344994 PMCID:PMC8333094
• Fling RR, Zacharewski TR. 2021. Aryl hydrocarbon receptor (AhR) activation by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) dose-dependently shifts the gut microbiome consistent with the progression of non-alcoholic fatty liver disease. Int J Mol Sci 22(22):12431. doi:10.3390/ijms222212431 PMID:34830313 PMCID:PMC8625315
• Nault R, Fader KA, Zacharewski TR. 2021. Single-nuclei RNA sequencing assessment of the hepatic effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin. Cell Mol Gastroenterol Hepatol 11:147-159. doi:10.1016/j.jcmgh.2020.07.012 PMID:32791302 PMCID:PMC7674514

2020

• 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

2019

• 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

2018

• 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

2017

• 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
• Li J, Bhattacharya S, Zhou J, Phadnis-Moghe AS, Crawford RB, Kaminski NE. 2017. Aryl hydrocarbon receptor activation suppresses EBF1 and PAX5 and impairs human B lymphopoiesis. J Immunol 199:3504-3515. doi:10.4049/jimmunol.1700289 PMID:28978690 PMCID:PMC5679724
• 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
• Williams MR, Stedtfeld RD, Tiedje JM, Hashsham SA. 2017. MicroRNAs-based inter-domain communication between the host and members of the gut microbiome. Front Microbiol 8:10. doi:10.3389/fmicb.2017.01896 PMID:29021788 PMCID:PMC5624305

2016

• 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

2015

• 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

2013

• Angrish MM, Dominici CY, Zacharewski TR. 2013. TCDD-elicited effects on liver, serum, and adipose lipid composition in C57BL/6 mice. Toxicol Sci 131(1):108-115. doi:10.1093/toxsci/kfs277 PMID:22977169 PMCID:PMC3537129
• Forgacs AL, Dere E, Angrish MM, Zacharewski TR. 2013. Comparative analysis of temporal and dose-dependent TCDD-elicited gene expression in human, mouse, and rat primary hepatocytes. Toxicol Sci 133(1):54-66. doi:10.1093/toxsci/kft028 PMID:23418086 PMCID:PMC3627554
• Kopec AK, Boverhof DR, Nault R, Harkema JR, Tashiro C, Potter D, Sharratt B, Chittim B, Zacharewski TR. 2013. Toxicogenomic evaluation of long-term hepatic effects of TCDD in immature, ovariectomized C57BL/6 mice. Toxicol Sci 135(2):465-475. doi:10.1093/toxsci/kft156 PMID:23864506 PMCID:PMC3807621
• Nault R, Forgacs AL, Dere E, Zacharewski TR. 2013. Comparisons of differential gene expression elicited by TCDD, PCB126, βNF, or ICZ in mouse hepatoma Hepa1c1c7 cells and C57BL/6 mouse liver. Toxicol Lett 223(1):52-59. doi:10.1016/j.toxlet.2013.08.013 PMID:23994337 PMCID:PMC4096832
• Nault R, Kim S, Zacharewski TR. 2013. Comparison of TCDD-elicited genome-wide hepatic gene expression in Sprague-Dawley rats and C57BL/6 mice. Toxicol Appl Pharmacol 267(2):184-191. doi:10.1016/j.taap.2012.11.028 PMID:23238561 PMCID:PMC4104405

2011

• 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

2010

• 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

2008

• 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