Molecular and Microbial Mechanisms Leading to Triclosan Induced Liver Fibrosis

Project 3

Molecular and Microbial Mechanisms Leading to Triclosan Induced Liver Fibrosis

Project Summary/Abstract
Triclosan (TCS) is a synthetic antimicrobial agent that has been widely used in the U.S. and globally for more than 40 years. First invented in the early 1970s to be employed as an antiseptic and disinfectant in healthcare environments, TCS now comes into direct contact with humans in household settings through a large number of consumer products ranging from personal care products to food packaging materials. Consequently, its rising environmental release causes serious contamination in the environment, and it is now known as an Emerging Contaminant (EC) - a detectable but currently unregulated and frequently untreated environmental contaminant. While there have been numerous health concerns associated with TCS, our recent findings provide compelling evidence that long-term TCS exposure promotes liver carcinogenesis in mice. Using a carcinogen-induced animal model, we demonstrate that TCS causes toxicant-associated steatohepatitis (TASH) manifested by hepatic steatosis, inflammatory cell infiltration, and liver fibrosis, resulting in enhanced hepatocellular carcinoma (HCC). Similar to TCS, obesity and metabolic syndrome are also major etiologic factors causing steatohepatitis, termed nonalcoholic steatohepatitis (NASH). The rising prevalence of TASH and NASH – mirroring the increase in environmental toxicant exposure and obesity – is tightly linked to a growing epidemic of advanced liver disease. Recent animal studies have revealed that the disrupted gut microbiota (dysbiosis) plays a causative role in the pathogenesis of TASH and NASH, and patients with several types of chronic liver diseases show impairment of the gut microflora and intestinal barrier, highlighting a primary etiologic role of intestinal dysbiosis in liver disease. To explore the pathogenic mechanism underlying TCS-induced TASH, we hypothesize that “persistent TCS exposure causes a structurally disrupted intestinal microbiota that is a driving force of TASH development, and chronic overnutrition by a high-fat diet (HFD) is synergistic with TCS-induced TASH, leading to end-stage liver disease and HCC.” We propose to examine the following aims: 1) We will identify the gut microbiota composition following long-term TCS exposure using 16S rRNA sequencing and metatranscriptomics. We will also employ germ-free (GF) and humanized NASH mice to determine the role of gut flora in TCS-induced liver disease. 2) We will investigate regulatory roles of toll-like receptor (TLR) signaling in intestinal permeability and tight junctions responding to TCS treatment. We have rationalized that, reacting to TCS toxic insult, gut microbes releasing bacterial products and metabolites activate TLR signaling and initiate innate immune responses, stimulating profibrogenic and proinflammatory events in the liver. These experiments will use Myd88 liver conditional knockout mice to compare TCS and CCl4-induced liver toxicity. 3) We will evaluate whether TCS combined with a HFD confers greater susceptibility to the progression of TASH into tumorigenesis by using a diabetes animal model that displays signs of NASH following a HFD feeding. We postulate that autophagy status and IL-17A signaling underlines enhanced induction of HCC by TCS together with HFD.

Publication

PubMed Central ID: 

Fujiwara R., Mitsugi R., Uemura A., Itoh T., Tukey R.H. (2017) Severe Neonatal Hyperbilirubinemia in Crigler-Najjar Syndrome Model Mice Can Be Reversed With Zinc Protoporphyrin. Hepatol Commun. 1(8):792-802. doi: 10.1002/hep4.1082. Epub 2017 Aug 10.

PubMedID: 29399656
PubMed Central ID: 

Fujiwara R., Yoda E., Tukey R.H. (2018) Species differences in drug glucuronidation: Humanized UDP-glucuronosyltransferase 1 mice and their application for predicting drug glucuronidation and drug-induced toxicity in humans. Drug Metab Pharmacokinet. 33(1):9-16. doi: 10.1016/j.dmpk.2017.10.002. Epub 2017 Oct 7.

PubMedID: 29079228
PubMed Central ID: 

Yoda E., Paszek M., Konopnicki C., Fujiwara R., Chen S., Tukey R.H. (2017) Isothiocyanates induce UGT1A1 in humanized UGT1 mice in a CAR dependent fashion that is highly dependent upon oxidative stress. Sci Rep. 7:46489. doi: 10.1038/srep46489

PubMedID: 28422158
PubMed Central ID: 

Yueh M.F., Chen S., Nguyen N., Tukey R.H. (2017) Developmental, Genetic, Dietary, and Xenobiotic Influences on Neonatal Hyperbilirubinemia. Mol Pharmacol. 91(5):545-553. doi: 10.1124/mol.116.107524. Epub 2017 Mar 10.

PubMedID: 2823555

Chen S., Lu W., Yueh M.-F., Rettenmeier E., Liu M., Auwerx J., Yu R.T., Evans R.M., Wang K., Karin M., Tukey R.H. (2017) Intestinal NCoR1, a newly discovered regulator of epithelial cell maturation, controls neonatal hyperbilirubinemia.  Proc. Nat. Acad. Sci. USA.114:E1432-E1440. doi: 10.1073/pnas.1700232114.

PubMedID: 28167773

Hirashima R., Itoh T., Tukey R.H., Fujiwara R. (2017) Prediction of drug-induced liver injury using keratinocytes. J Appl Toxicol. doi: 10.1002/jat.3435.

PubMedID: 28138970
PubMed Central ID: 

Hinds T.D. Jr., Hosick P.A., Chen S., Tukey R.H., Hankins M.W., Nestor-Kalinoski A., Stec D.E. (2017) Mice with hyperbilirubinemia due to Gilbert's syndrome polymorphism are resistant to hepatic steatosis by decreased serine 73 phosphorylation of PPARα. Am J Physiol Endocrinol Metab. 312(4):E244-E252. doi: 10.1152/ajpendo.00396.2016.

PubMedID: 28096081
PubMed Central ID: 

Mitsugi R., Sumida K., Fujie Y., Tukey R.H., Itoh T., Fujiwara R. Acyl-glucuronide as a Possible Cause of Trovafloxacin-Induced Liver Toxicity: Induction of Chemokine (C-X-C Motif) Ligand 2 by Trovafloxacin Acyl-glucuronide. (2016) Biol Pharm Bull. 39(10):1604-1610. doi: 10.1248/bpb.b16-00195.

PubMedID: 27725437
PubMed Central ID: 

Hirashima R., Michimae H., Takemoto H., Sasaki A., Kobayashi Y., Itoh T., Tukey R.H., Fujiwara R. (2016) Induction of the UDP-Glucuronosyltransferase 1A1 during the Perinatal Period Can Cause Neurodevelopmental Toxicity. Mol Pharmacol. 90:265-74. doi: 10.1124/mol.116.104174.

PubMedID: 27413119
PubMed Central ID: 

Liu M., Chen S., Yueh M.F., Fujiwara R., Konopnicki C., Hao H., Tukey R.H. (2016) Cadmium and arsenic override NF-κB developmental regulation of the intestinal UGT1A1 gene and control of hyperbilirubinemia. Biochem Pharmacol. 110-111:37-46. doi:10.1016/j.bcp.2016.04.003.

PubMedID: 27060662

Touboul, T., Chen, S., To, C.C., Mora-Castilla, S., Sabatini, K., Tukey, R.H., Laurent, L.C. (2016) Stage-specific regulation of the WNT/β-catenin pathway results in improved differentiation of hESCs to functional hepatocytes. J Hepatol. pii: S0168-8278(16)00162-8. doi: 10.1016/j.jhep.2016.02.028.

PubMedID: 26921690
PubMed Central ID: 

Liu M., Chen S., Yueh M.F., Want G., Hao H., Tukey R.H. (2016) Reduction of p53 by knockout of the UGT1 locus in colon epithelial cells causes an increase in tumorigenesis. Cellular and Molecular Gastro and Hepatology. 2:63-76. doi: 10.1016/j.jcmgh.2015.08.008.

 

PubMedID: 26807433

Yueh, M. F., Tukey, R. H. (2016) Triclosan: A Widespread Environmental Toxicant with Many Biological Effects. (2016) Annu Rev Pharmacol Toxicol. 56, 251-72. doi: 10.1146/annurev-pharmtox-010715-103417.

PubMedID: 26738475

Barateiro, A., Chen, S., Yueh, M. F., Fernandes, A., Domingues, H. S., Relvas, J., Barbier, O., Nguyen, N., Tukey, R. H., Brites, D. (2016) Reduced Myelination and Increased Glia Reactivity Resulting from Severe Neonatal Hyperbilirubinemia. Mol Pharmacol. 84-93. doi: 10.1124/mol.115.098228.

PubMedID: 26480925

Fujiwara, R., Maruo, Y., Chen, S., Tukey, R. H. (2015) Role of extrahepatic UDP-glucuronosyltransferase 1A1: Advances in understanding breast milk-induced neonatal hyperbilirubinemia. Toxicol Appl Pharmacol. doi: 10.1016/j.taap.2015.08.018.

PubMedID: 26342858

Sakamoto, M., Itoh, T., Tukey, R. H., Fujiwara, R. (2015) Nicotine regulates the expression of UDP-glucuronosyltransferase (UGT) in humanized UGT1 mouse brain. Drug Metab Pharmacokinet. 30(4), 269-75.

PubMedID: 26210671
PubMed Central ID: 

Landrigan, P. J., Wright, R. O., Cordero, J. F., Eaton, D. L., Goldstein, B. D., Hennig, B., Maier, R. M., Ozonoff, D. M., Smith, M. T., Tukey, R. H. (2015) The NIEHS Superfund Research Program: 25 Years of Translational Research for Public Health. Environ Health Perspect. 123(10), 909-18. doi: 10.1289/ehp.1409247.

PubMedID: 25978799
PubMed Central ID: 

Kutsuno, Y., Hirashima, R., Sakamoto, M., Ushikubo, H., Michimae, H., Itoh, T., Tukey, R. H., Fujiwara, R. (2015) Expression of UDP-Glucuronosyltransferase 1 (UGT1) and Glucuronidation Activity toward Endogenous Substances in Humanized UGT1 Mouse Brain. Drug Metab Dispos. 43(7),1071-6.

PubMedID: 25953521
PubMed Central ID: 

Yueh, M. F., Taniguchi, K., Chen, S., Evans, R. M., Hammock, B. D., Karin, M., Tukey, R. H. (2014) The commonly used antimicrobial additive triclosan is a liver tumor promoter. Proc Natl Acad Sci USA. 111(48), 17200-5.

PubMedID: 25404284
PubMed Central ID: 

Aoshima, N., Fujie, Y., Itoh, T., Tukey, R. H., Fujiwara, R. (2014) Glucose induces intestinal human UDP-glucuronosyltransferase (UGT) 1A1 to prevent neonatal hyperbilirubinemia. Sci Rep. 4, 6343.

PubMedID: 25209391
PubMed Central ID: 

Kutsuno, Y., Itoh, T., Tukey, R. H., Fujiwara, R. (2014) Glucuronidation of drugs and drug-induced toxicity in humanized UDP-glucuronosyltransferase 1 mice. Drug Metab Dispos 42(7), 1146-52.

PubMedID: 24764149
PubMed Central ID: 

Maruo, Y., Morioka, Y., Fujito, H., Nakahara, S., Yanagi, T., Matsui, K., Mori, A., Sato, H., Tukey, R. H., Takeuchi, Y. (2014) Bilirubin Uridine Diphosphate-Glucuronosyltransferase Variation Is a Genetic Basis of Breast Milk Jaundice. J Pediatr. doi: 10.1016/j.jpeds.2014.01.060.

PubMedID: 24650397
PubMed Central ID: 

Yueh, M. F., Chen, S., Nguyen, N., Tukey, R. H. (2014) Developmental onset of bilirubin-induced neurotoxicity involves Toll-like receptor 2-dependent signaling in humanized UDP-glucuronosyltransferase1 mice. J Biol Chem. 289(8), 4699-709.

PubMedID: 24403077
PubMed Central ID: 

Chen, S., Yueh, M. F., Bigo, C., Barbier, O., Wang, K., Karin, M., Nguyen, N., Tukey, R. H. (2013) Intestinal glucuronidation protects against chemotherapy-induced toxicity by irinotecan (CPT-11). Proc Natl Acad Sci USA. 110,19143-19148. 

PubMedID: 24191041
PubMed Central ID: 

Shibuya, A., Itoh, T., Tukey, R. H., Fujiwara, R. (2013)  Impact of fatty acids on human UDP-glucuronosyltransferase 1A1 activity and its expression in neonatal hyperbilirubinemia. Sci Rep. doi: 10.1038/srep02903.

 

PubMedID: 24104695
PubMed Central ID: 

Sumida, K., Kawana, M., Kouno, E., Itoh, T., Takano, S., Narawa, T., Tukey, R. H., Fujiwara, R. (2013) Importance of UDP-glucuronosyltransferase 1A1 expression in skin and its induction by UVB in neonatal hyperbilirubinemia. Mol Pharmacol. 84, 679-686.

PubMedID: 23950218
PubMed Central ID: 

Konopnicki, C. M., Dickmann, L. J., Tracy, J. M., Tukey, R. H., Wienkers, L. C., Foti, R. S. (2013) Evaluation of UGT protein interactions in human hepatocytes: effect of siRNA down regulation of UGT1A9 and UGT2B7 on propofol glucuronidation in human hepatocytes. Arch Biochem Biophys. 535(2), 143-9.

PubMedID: 23562620

Li, T., Yu, R. T., Atkins, A. R., Downes, M., Tukey, R. H., Evans, R. M. (2012) Targeting the pregnane X receptor in liver injury. Expert Opin Ther Targets. 16(11), 1075-83.

PubMedID: 22913318
PubMed Central ID: 

Chen, S., Yueh, M. F., Evans, R. M., Tukey, R. H. (2012) Pregnane-x-receptor controls hepatic glucuronidation during pregnancy and neonatal development in humanized UGT1 mice. Hepatology. 56, 658-667.

PubMedID: 22371261
PubMed Central ID: 

Fujiwara, R., Chen, S., Karin, M., Tukey, R.H. (2012) Reduced expression of UGT1A1 in intestines of humanized UGT1 mice via inactivation of NF-κB leads to hyperbilirubinemia. Gastroenterology. 142(1), 109-118.

PubMedID: 21983082
PubMed Central ID: 

Yueh, M. F., Mellon, P. L., Tukey, R. H. (2011) Inhibition of human UGT2B7 gene expression in transgenic mice by the constitutive androstane receptor. Mol Pharmacol. 79(6),1053-60.

PubMedID: 21415305
PubMed Central ID: 

Fujiwara, R., Nguyen, N., Chen, S., Tukey, R. H. (2010) Developmental hyperbilirubinemia and CNS toxicity in mice humanized with the UDP-glucuronosyltransferase 1 (UGT1) locus. Proc Natl Acad Sci USA. 107(11), 5024-5029.

PubMedID: 20194756
PubMed Central ID: 

Cai, H., Nguyen, N., Peterkin, V., Young-Sun, Y., Hotz, K., Beaton-La Placa, D., Chen, S., Tukey, R. H., and Stevens, J. C. (2010) A humanized UGT1 mouse model expressing the UGT1A1*28 allele for assessing drug clearance by UGT1A1 dependent glucuronidation. Drug Metabol Dispos. 38(5), 879-86.

PubMedID: 20124398
PubMed Central ID: 

Argikar, U.A., Senekeo-Effenberger, K., Larson, E.E., Tukey, R.H., Remmel, R.P. (2009) Studies on induction of lamotrigine metabolism in transgenic UGT1 mice. Xenobiotica. 39, 826-835.

PubMedID: 19845433

Nguyen, N., Bonzo, J. A., Chen, S., Chouinard, S., Kelner, M., Hardiman, G., Belanger, A., and Tukey, R. H. (2008) Disruption of the Ugt1 locus in mice resembles human Crigler-Najjar type I disease. J Biol Chem. 283. 7901-7911.

PubMedID: 18180294
PubMed Central ID: 

Pezzoli, K., Tukey, R., Sarabia, H., Zaslavsky, I., Miranda, M. L., Suk, W. A., Lin, A., Ellisman, M. (2007) The NIEHS Environmental Health Sciences Data Resource Portal: placing advanced technologies in service to vulnerable communities. Environ Health Perspect. 115(4), 564-71.

PubMedID: 17450225

Yueh, M. F., and Tukey, R. H. (2007) Nrf2-Keap1 signaling pathway regulates human UGT1A1 expression in vitro and in transgenic UGT1 mice. J Biol Chem. 282, 8749-8758.

PubMedID: 17259171

Bonzo, J. A., Belanger, A., and Tukey, R. H. (2007) The role of chrysin and the Ah receptor in induction of the human UGT1A1 gene in vitro and in transgenic UGT1 mice. Hepatology. 45, 349-360.

PubMedID: 17256720

Senekeo-Effenberger, K., Chen, S., Yueh, M-F., Erace-Sinnokrak, E., Bonzo, J. A., Argikar, U., Kaeding, J., Trottier, T., Remmel, R. P., Ritter, J. K., Barbier, O., and Tukey, R. H. (2007) Expression of the human UGT1 locus in transgenic mice by 4-chloro-6-(2,3-xylidino)-2-pyrimidinylthioacetic acid (WY-14643) and implications on drug metabolism through peroxisome proliferator-activated receptor alpha activation. Drug Met Disp. 35, 419-427.

PubMedID: 17151188

Operaña, T. N., Nguyen, N., Chen, S., Beaton, D. and Tukey, R. H. (2007) Human CYP1A1GFP expression in transgenic mice serves as a biomarker for environmental toxicant exposure. Toxicol Sci. 95, 98-107.

PubMedID: 17065433

Chen, S., Beaton, D., Nguyen, N., Senekeo-Effenberger, K., Brace-Sinnokrak, E., Argikar, U., Remmel, R. P., Trottier, J., Barbier, O., Ritter, J., Tukey, R. H. (2005) Tissue-specific, inducible, and hormonal control of the human UDP-glucuronosyltranserase-1 (UGT1) locus. J Biol Chem. 280, 37547-37557.

PubMedID: 16155002

Machemer D. E. W., and Tukey R. H. (2005) The role of protein kinase C in regulation of TCDD-mediated CYP1A1 gene expression. Toxicol Sci. 87, 27-37.

PubMedID: 15947024

Bonzo, J. A., Chen, S., Galijatovic, A., Tukey, R. H. (2005) Arsenite inihibition of CYP1A1 induction by TCDD is independent of cell cycle arrest. Mol Pharmacol. 67, 1247-1256.

PubMedID: 15630080

Chen, S., Operana, T., Bonzo, J., Nguyen, N., Tukey R. H. (2005) Erk kinase inhibition stabilizes the aryl hydrocarbon receptor. J Biol Chem. 280, 4350-4359.

PubMedID: 15572374

Galijatovic, A., Beaton, D., Nguyen, N., Chen, S., Bonzo, J., Johnson, R., Maeda, S., Karin, M., Guengerich, F. P., Tukey, R. H. (2004) The human CYP1A1 gene is regulated in a developmental and tissue-specific fashion in transgenic mice. J Biol Chem. 279(23), 23969-76.

PubMedID: 15037607

Chen, S., Nguyen, N., Tamura, K., Karin, M., Tukey, R. H. (2003) The role of the Ah receptor and p38 in benzo[a]pyrene-7,8-dihydrodiol and benzo[a]pyrene-7,8-dihydrodiol-9,10-epoxide-induced apoptosis. J Biol Chem. 278(21), 19526-33.

PubMedID: 12637498

Yueh, M. F., Huang, Y. H., Hiller, A., Chen, S., Nguyen, N., Tukey, R. H. (2003) Involvement of the xenobiotic response element (XRE) in Ah receptor-mediated induction of human UDP-glucuronosyltransferase 1A1. J Biol Chem. 278(17), 15001-6.

PubMedID: 12566446

Huang, Y. H., Galijatovic, A., Nguyen, N., Geske, D., Beaton, D., Green, J., Green, M., Peters, W. H., Tukey, R. H. (2002) Identification and functional characterization of UDP-glucuronosyltransferases UGT1A8*1, UGT1A8*2 and UGT1A8*3. Pharmacogenetics.12(4), 287-97.

PubMedID: 12042666

Main Contact Information

Dr. Robert H. Tukey (Professor, Departments of Pharmacology and Chemistry & Biochemistry-UCSD) 

Contact

UCSD Superfund Research Center
University of California, San Diego
Pharmacology Department
9500 Gilman Drive, Mail Code 0722
La Jolla, CA 92093-0722