2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) increases necroinflammation and hepatic stellate cell activation but does not exacerbate experimental liver fibrosis in mice.
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a persistent environmental contaminant and high-affinity ligand for the aryl hydrocarbon receptor (AhR). Increasing evidence indicates that AhR signaling contributes to wound healing, which involves the coordinated deposition and remodeling of the extracellular matrix. In the liver, wound healing is attributed to the activation of hepatic stellate cells (HSCs), which mediate fibrogenesis through the production of soluble mediators and collagen type I. We recently reported that TCDD treatment increases the activation of human HSCs in vitro. The goal of this study was to determine how TCDD impacts HSC activation in vivo using a mouse model of experimental liver fibrosis. To elicit fibrosis, C57BL6/male mice were treated twice weekly for 8weeks with 0.5ml/kg carbon tetrachloride (CCl4). TCDD (20μg/kg) or peanut oil (vehicle) was administered once a week during the last 2weeks. Results indicate that TCDD increased liver-body-weight ratios, serum alanine aminotransferase activity, and hepatic necroinflammation in CCl4-treated mice. Likewise, TCDD treatment increased mRNA expression of HSC activation and fibrogenesis genes, namely α-smooth muscle actin, desmin, delta-like homolog-1, TGF-β1, and collagen type I. However, TCDD treatment did not exacerbate fibrosis, nor did it increase the collagen content of the liver. Instead, TCDD increased hepatic collagenase activity and increased expression of matrix metalloproteinase (MMP)-13 and the matrix regulatory proteins, TIMP-1 and PAI-1. These results support the conclusion that TCDD increases CCl4-induced liver damage and exacerbates HSC activation, yet collagen deposition and the development of fibrosis may be limited by TCDD-mediated changes in extracellular matrix remodeling.
Biomolecular Sciences Graduate Program, Boise State University, Boise, ID 83725, United States.
Cheri L
CL
Lamb
Biomolecular Sciences Graduate Program, Boise State University, Boise, ID 83725, United States.
Giovan N
GN
Cholico
Biomolecular Research Center, Boise State University, Boise, ID 83725, United States.
Xinzhu
X
Pu
Department of Biological Sciences, Boise State University, Boise, ID 83725, United States.
Gerald D
GD
Hagler
Biomolecular Sciences Graduate Program, Boise State University, Boise, ID 83725, United States; Biomolecular Research Center, Boise State University, Boise, ID 83725, United States; Department of Chemistry and Biochemistry, Boise State University, Boise, ID 83725, United States.
Kenneth A
KA
Cornell
Biomolecular Sciences Graduate Program, Boise State University, Boise, ID 83725, United States; Department of Biological Sciences, Boise State University, Boise, ID 83725, United States. Electronic address: kristenmitchell@boisestate.edu.
Kristen A
KA
Mitchell
D000818:Animals; D002251:Carbon Tetrachloride / Q000633:toxicity; D024042:Collagen Type I / Q000378:metabolism; D017364:Collagenases / Q000378:metabolism; D055166:Hepatic Stellate Cells / Q000187:drug effects* / Q000378:metabolism; D007249:Inflammation / Q000139:chemically induced*; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D008103:Liver Cirrhosis / Q000139:chemically induced* / Q000378:metabolism; D008297:Male; D053509:Matrix Metalloproteinase 13 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity*; D012720:Severity of Illness Index
D024042:Collagen Type I; D000072317:Polychlorinated Dibenzodioxins; D002251:Carbon Tetrachloride; D017364:Collagenases; D053509:Matrix Metalloproteinase 13
Collagen; Fibrosis; Hepatic stellate cell; Liver; TCDD
Toxicol Appl Pharmacol. 2003 Sep 15;191(3):211-26
13678654
Arch Toxicol. 1980 Oct;45(4):273-85
6778458
FEBS Lett. 2007 Jul 31;581(19):3608-15
17412325
J Nutr. 1989 Apr;119(4):573-80
2703915
Sci Rep. 2015 Nov 27;5:17327
26612465
Mol Pharmacol. 2006 Jan;69(1):257-65
16214955
Toxicol Appl Pharmacol. 2015 Jun 15;285(3):170-8
25896968
BMC Genomics. 2010 Oct 19;11:583
20959002
J Hepatol. 1995 Jun;22(6):696-9
7560864
Toxicol Sci. 2013 Nov;136(1):72-85
23970800
Toxicol Appl Pharmacol. 2006 Feb 1;210(3):212-24
15982688
PLoS One. 2014 Oct 13;9(10):e110405
25310107
Science. 1995 May 5;268(5211):722-6
7732381
Cell Prolif. 1995 Aug;28(8):437-51
7548444
Toxicol Sci. 2008 Feb;101(2):321-30
17975115
Proc Natl Acad Sci U S A. 1996 Jun 25;93(13):6731-6
8692887
Am J Physiol Lung Cell Mol Physiol. 2005 Jul;289(1):L111-24
15792965
Nat Protoc. 2008;3(6):1101-8
18546601
J Pharmacol Exp Ther. 2013 Jun;345(3):419-29
23512538
Carcinogenesis. 1996 Mar;17 (3):443-9
8631129
Mol Pharmacol. 2006 Jul;70(1):163-70
16636136
Arch Toxicol. 2002 Jun;76(5-6):360-6
12107654
J Histochem Cytochem. 2010 Jan;58(1):29-39
19755718
J Histochem Cytochem. 1994 Aug;42(8):1127-34
8027531
Sci Transl Med. 2014 Dec 3;6(265):265sr6
25473038
Toxicol Sci. 2003 Nov;76(1):151-61
12915709
Ann N Y Acad Sci. 1999 Jun 30;878:372-87
10415742
PLoS One. 2007 Nov 28;2(11):e1227
18043735
Dis Model Mech. 2014 Feb;7(2):193-203
24713275
Chem Res Toxicol. 1993 Nov-Dec;6(6):754-63
8117913
Nat Commun. 2013;4:2823
24264436
Toxicol Res (Camb). 2015 Sep 1;4(5):1143-1158
26783425
Cold Spring Harb Perspect Biol. 2011 Dec 01;3(12):null
21917992
Crit Rev Toxicol. 2003;33(2):105-36
12708612
Cancer Lett. 2005 Jul 8;225(1):159-66
15922868
Histochem J. 1979 Jul;11(4):447-55
91593
Toxicol Appl Pharmacol. 2004 Jan 1;194(1):79-89
14728982
Hepatology. 2013 Feb;57(2):786-96
22961688
Compr Physiol. 2013 Oct;3(4):1473-92
24265236
Toxicology. 2006 Sep 21;226(2-3):197-207
16920245
Toxicol Appl Pharmacol. 1998 Nov;153(1):109-18
9875305
J Cell Sci. 2004 Feb 29;117(Pt 6):849-59
14762110
Toxicol Sci. 2006 Jul;92 (1):254-69
16443690
Toxicol Sci. 2007 Jan;95(1):215-26
17003102
Electrophoresis. 2012 Jan;33(2):366-9
22222980
J Biol Chem. 2010 May 21;285(21):16239-47
20228065
Genes Dev. 1999 Jul 1;13(13):1742-53
10398686
J Clin Invest. 2015 Feb;125(2):539-50
25562324
Biochemistry. 1990 Nov 6;29(44):10261-70
2176865
Xenobiotica. 2013 Feb;43(2):161-8
22834477
Toxicol Sci. 2014 Jan;137(1):114-24
24154488
Toxicology. 2016 Feb 17;344-346:26-33
26860701
Chemosphere. 1996 Mar;32(6):1225-33
8920595
J Biol Chem. 2012 Mar 23;287(13):10355-67
22298767
Arch Toxicol. 2002 Jul;76(7):404-13
12111005
Proc Natl Acad Sci U S A. 2014 Aug 12;111(32):E3297-305
25074909
Physiol Rev. 2003 Jul;83(3):835-70
12843410
Dev Biol. 2008 Mar 1;315(1):203-16
18234181
J Biol Chem. 2000 Jan 28;275(4):2247-50
10644669
Mol Pharmacol. 1998 Aug;54(2):313-21
9687573
Natl Toxicol Program Tech Rep Ser. 2006 Apr;(521):4-232
16835633
Mol Cell Biol. 2007 Sep;27(17):6127-39
17606626
Exp Biol Med (Maywood). 2008 Feb;233(2):109-22
18222966
Annu Rev Pharmacol Toxicol. 1995;35:307-40
7598497
Gut. 2005 Jan;54(1):142-51
15591520
PLoS One. 2013 Dec 11;8(12):e82190
24349218
Hepatology. 2010 Apr;51(4):1373-82
20131405
J Biol Chem. 2004 Jun 11;279(24):25284-93
15075337