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Time- and Dose-based Gene Expression Profiles Produced by a Bile-duct–damaging Chemical, 4,4'-methylene Dianiline, in Mouse Liver in an Acute Phase
1 School of Veterinary Medicine and Institute of Veterinary Science, Kangwon National University, Chuncheon 200-701, Republic of Korea Correspondence: Byung-IL Yoon, DVM, PhD, School of Veterinary Medicine, Kangwon National University, 192-1 Hyoja2-dong, Chuncheon, Kangwon 200-701, Republic of Korea; e-mail:byoon{at}kangwon.ac.kr
A toxicogenomics study was performed in the mouse liver after treatment of a bile-duct–damaging chemical, 4,4'-methylene dianiline (MDA), across multiple doses and sampling times in an acute phase using the AB Expression Array System. Imprinting control region (ICR) mice were given a single oral administration of a low (10 mg/kg b.w.) or high (100 mg/kg b.w.) dose of MDA. Mice were sacrificed six, twenty-four, and seventy-two hours after treatment for serum chemistry, histopathology, and mRNA preparation from liver samples. Treatment with MDA increased liver-toxicity–related enzymes in blood and induced bile-duct cell injury, followed by regeneration. To explore potential biomarker gene profiles, the altered genes were categorized into four expression patterns depending on dose and time. Numerous functionally defined and unclassified genes in each category were up- or down-regulated throughout the period from cellular injury to the recovery phase, verified by RT-PCR. Many genes associated with liver toxicity and diseases belonged to one of these categories. The chemokine-mediated Th1 pathway was implicated in the inflammatory process. The genes associated with oxidative stress, apoptosis, and cell-cycle regulation were also dynamically responsive to MDA treatment. The Wnt/β-catenin signaling pathway was likely responsible for the reconstitution process of the MDA-injured liver.
Key Words: acute liver toxicity • 4,4'-methylene dianiline • mouse • toxicogenomics Abbreviations: AB, Applied Biosystems • ALT, alanine aminotransferase • AST, aspartate aminotransferase • COA, correspondence analysis • DEA, differential expression analysis • MDA, 4, 4'-methylene dianiline • NO, nitric oxide • ROS, reactive oxygen species
The intra- and intercellular microenvironmental changes induced by a variety of toxicants are characterized by their unique gene expression profiles, which makes it possible to identify the expression signatures of altered genes following treatment with different chemicals (Hamadeh et al. 2002; Huang et al. 2004). The unique gene expression profiles produced by chemicals can therefore provide practical information to not only predict their potential toxicity in specific tissues, but also to understand the molecular mechanisms involved (Bartosiewicz et al. 2001; Walker et al. 2006). The liver is vulnerable to a variety of metabolic, toxic, microbial, circulating, and neoplastic insults. Therefore, microenvironmental changes in liver tissues will reflect the biochemical characteristics and potential toxicity of certain chemicals and compounds. Understanding such changes is important for risk assessment in humans and animals. Toxicogenomics studies have focused on identifying gene expression changes in the liver following treatment with hepatotoxicants, which induce hepatocytic cell injury (Bartosiewicz et al. 2001; Huang et al. 2004). However, very few genomics studies have examined altered gene expression profiles induced by bile-duct-cell–damaging chemicals. 4,4'-methylene dianiline (MDA) is used in the synthesis of isocyanates and polyurethane polymers and in the production of dyes, polycondensation products, copolymers, curatives for epoxy resins, and other compounds (Kanz et al. 1992). Bile-duct cells are the main target cells of this chemical, which induces cholangitis with cellular necrosis and inflammation, resulting in "epping jaundice" in humans (Kanz et al. 1992; Kopelman et al. 1966). In the present study, we performed a toxicogenomics study to identify the distinct gene expression profiles altered by MDA in an acute phase. The aim of this study is to extend our understanding of the possible mechanisms by which MDA induces bile-duct damage, followed by cellular recovery, at the level of global genes and to identify the potential target gene profiles for risk assessment and classification of the chemicals or compounds that cause liver toxicity, especially those like MDA that cause toxicity toward bile-duct cells.
Materials MDA (CAS #101-77-9), chloroform, RNase-free 75% ethanol, RNase-free distilled water (DEPC water), and iso-propyl alcohol were all purchased from Aldrich Sigma (St. Louis, MO, USA). RNAlater RNA stabilization solution was obtained from Ambion Inc. (Austin, TX, USA). TRIzol and RNeasy Mini kits for RNA isolation were purchased from Invitrogen (Carlsbad, CA, USA) and Qiazen (Valencia, CA, USA), respectively.
Animals and Chemical Treatment After one week of acclimatization, the mice were subjected to experimental treatments. Food was withdrawn for four hours before treatment (from 8:00 AM to 1:00 pm ). Thereafter the mice of each dose group, including the vehicle group, were given a single oral administration of the selected dose of chemicals and/or vehicles. Based on the data of the preliminary study, which showed that twenty-four hours post-MDA single treatment was the peak time point of MDA-induced liver injury, three sampling time points were determined to observe the altered gene expression profiles at the early (six hours post-treatment) and the recovery (seventy-two hours post-treatment) phases, as well as the injury peak time point (twenty-four hours post-treatment). Animals were provided a normal diet (Purina Inc., Korea) and tap water ad libitum throughout the experimental period.
Histopathology and Serum Chemistry Serum was prepared from the collected blood and analyzed using chemical analyses for aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase, albumin, total bilirubin, blood urea nitrogen, creatinine, and triglyceride.
RNA Preparation and Microarray Analysis Using the Applied Biosystems Expression Array System
Statistical Analysis of Microarray Data Gene expression values were manipulated and visualized using the R package (free software under the terms of the Free Software Foundation’s General Public License). For the analysis of data correlation, correspondence analysis was also performed using the AB1700 package in R. Hierarchical cluster analysis partitioned the data into discrete hierarchical groups based on data trends. The resulting gene lists were limited to genes with changes in proportions of 1.5 or more and p < .05.
Categorization of Microarray Gene Expression Profiles
Semiquantitative RT-PCR To verify whether the genes identified from the microarray results were altered by MDA treatment, RT-PCR analyses were performed for twelve genes, as described previously (Park et al. 2004) using specific primers (Table 1). Equal amounts of total mRNA from the three samples selected from each group were pooled. First-strand cDNA was generated from 2 µg of total RNA by RT with 1 µL of 50 µM oligo (dT)20 primer and 1 µL of SuperScript III Reverse Transcriptase (Life Technologies Inc., Gaithersburg, MD, USA) in a 20-µL reaction mixture, following the manufacturer’s instructions. From the 20 µL produced, PCR was performed using AccuPower PCR PreMix (Bioneer, Daejeon, Korea) and using a Mycycler (Bio-Rad, Hercules, CA, USA). The PCR products were analyzed by electrophoresis in 1.5% agarose gels containing 0.1 mg/mL ethidium bromide. Images of RT-PCR ethidium-bromide–stained agarose gels were acquired with ultraviolet illumination on a Gel Doc EQ System (Bio-Rad, Hercules, CA, USA).
Histopathology and Serum Chemistry In the low-dose group, no notable histopathological changes were observed for any of the sampling times (Figure 2). In the high-dose group, MDA-induced cellular toxicity was limited mainly to the bile duct cells (Figure 2). Six hours after treatment, bile duct epithelial cells showed hydropic degeneration and, sometimes, necrotic changes. Necrosis of bile duct cells, resulting in exfoliation of the epithelial cells from the basement membrane, was evident twenty-four hours after the high-dose treatment of MDA. Seventy-two hours after the high-dose treatment of MDA, bile duct epithelial cells were regenerative, which was characterized by large basophilic epithelial cells of tall cuboidal shape and relatively frequent mitotic figures. A periductular desmoplastic reaction was also prominent, with the infiltration of a number of mononuclear cells. Individual necrosis and multiple necrotic foci of hepatocytes were observed randomly in the liver.
Serum chemical analyses indicated significant increases in AST, ALT, and total bilirubin twenty-four hours after treatment with the high dose of MDA, followed by a return toward control values at seventy-two hours (Table 2). With the low dose of MDA, no significant changes in the parameters examined were observed for any sampling time.
Gene Expression Changes After quantile-normalization of the raw data, statistical microarray analyses were conducted. First, we verified a good correlation (> 95%) of the gene expression profile between individuals in the same group for each sampling time. Whole microarray data are found at http://www.snubi.org/publication/TGRC_MDA. The low and high doses of MDA produced differential gene expression profiles for each selected sampling time. In the hierarchical clustering, the gene expression profiles were likely to be affected by the sampling time, rather than the dose of MDA, until twenty-four hours after treatment. However, at seventy-two hours, the gene expression profiles were distinctly comparable between the low- and high-dose groups (Figure 3). Two-way ANOVA of the dose- and time-based microarray data identified 4,257 altered genes in the low-dose group and 4,534 genes in the high-dose group, all with statistically significant changes (p < .05). These microarray data were further filtered into a list of genes with changes more than 1.5 times the control level. The numbers of altered genes (p < .05, with a change of more than two times) for each sampling time in the low- and high-dose groups are shown in Figure 4. Categorization of the altered genes based on the PANTHER biological process indicated that a variety of genes were implicated in the biological processes of the liver after MDA treatment, associated with cell cycle and proliferation; cell structure and motility; developmental processes; immunity and defense; intra-cellular protein traffic; lipid, fatty acid, and steroid metabolism; protein metabolism and modification; signal transduction; transport; and so on (Figure 5). The global gene expression profiles were classified further based on the comparative gene expression patterns between the low- and high-dose groups (Figure 1). Semiquantitative RT-PCR was performed using specific primers (Table 1) to verify the gene expression profiles detected using the oligonucleotide microarray. The semiquantitative RT-PCR and microarray results were quite compatible for each sampling time: ten of twelve genes (83.3%) at six hours, nine of twelve genes (75.0%) at twenty-four hours, and ten of twelve genes (83.3%) at seventy-two hours showed the same patterns of change (Figure 6).
Class I: Genes That Showed Similar Expression Patterns at the Low and High Dose This class contains genes that were up- or down-regulated in both the low- and high-dose groups with similar patterns of expression (Supplementary Table 1: http://www.snubi.org/publication/TGRC_MDA). Various genes associated with amino acid metabolism; apoptosis; carbohydrate metabolism; the cell cycle; cell structure and motility; developmental processes; electron transport; immunity and defense; lipid, fatty acid, and steroid metabolism; nucleoside, nucleotide, and nucleic acid metabolism; oncogenesis; signal transduction; and other functions were placed in this category. In particular, the genes that were altered concomitantly with both the low and high doses were found most frequently at the peak injury time twenty-four hours after treatment with MDA. The genes associated with the induction of apoptosis, for example, Chordc1, Tnfrsf6, and Casp3, were up-regulated irrespective of dose. Several notable genes were associated with carbohydrate metabolism: Gbe1, Galk2, and Galnt11. Gbe1 is up-regulated in the hypoxic environmental conditions of the mouse liver (Zhao et al. 2004). In association with the cell cycle, cyclin D1 was concomitantly down-regulated at the late phase, whereas other cell cycle-related genes, including Cks2, Nudc, Mobk1b, and Rback, were up-regulated at twenty-four hours after MDA treatment. The alteration of cortactin, which is involved in cytoskeletal reorganization (Lua et al. 2005), was notable because it was highly up-regulated by more than ten times at twenty-four hours after MDA treatment for both dose levels. Genes associated with developmental processes and electron transport tended to be down-regulated by MDA treatment, especially at the time of peak injury at twenty-four hours. In contrast, many genes associated with intracellular protein traffic and lipid, fatty acid, and steroid metabolism were up-regulated. In particular, Copg and Sgpl1 (apoptosis-associated genes under stress) were prominently elevated and Gpx6 was affected at the peracute phase.
Class II: Genes That Showed Similar Expression Patterns at Any Sampling Time(s) at Both Dose Levels, but Showed Dose-dependent Expression at Any Other Sampling Time(s)
Class III: Genes That Showed Reverse Expression Patterns Between the Low and High Dose This class contains genes that were down-regulated for the low dose and up-regulated for the high dose, and vice versa (Supplementary Table 3: http://www.snubi.org/publication/TGRC_MDA). These genes may reflect differential responses of the liver depending on intensity and type of cellular injury. Catalase was included in this category; it was highly overexpressed at twenty-four hours for the low dose, but it significantly down-regulated at the active regenerating phase for the high dose, suggesting the importance of oxidative stress in association with toxic mechanisms and the preventive function of catalase at a low dose of MDA. Ehpb1, Map3k4, Mipep, Hsd3b7, Slc25a25, and Slc25a15 showed the same expression patterns as catalase. In contrast, Galnt7, B4galt4, and Mt1 had expression patterns opposite to that of catalase. They were down-regulated for the low dose, but they were highly over-expressed at the regenerating phase for the high dose.
Class IV: Genes That Were Separately Affected in an On/Off Pattern Dose-dependently
MDA is a selective bile duct toxicant (Kanz et al. 1992), as also indicated by our histopathological observations in an association with serum chemistry. However, the MDA-induced toxic effect is achieved not only by targeting biliary cells, but also by breaking the functional relationships with other liver cell components. In the genomic circumstances, host cell responses against chemical-inducing effects are even more dynamic and active, but very much conserved. Thus, our microarray data represented complicated and understandable expression changes in a variety of genes maintaining cellular microenvironmental homeostasis across MDA-induced toxic effects and adaptation in the liver, including the genes altered in response to bile duct cell injury by MDA.
Exploration of Potential Biomarker Gene Profiles to Discern the Toxic Endpoints of Bile Duct Cells The genes belonging to Classes I and II could be affected by chemicals similar to MDA independent of dose. In fact, several genes that are postulated to be associated with liver toxicity, including bile duct damage, were frequently found in these classes (Table 3). Class I and II genes may also represent the microenvironmental conditions associated with the toxic mechanism of MDA. Cortactin (Cttn) and catenin beta (Catnb) are functionally involved in cell mortility (Chuma et al. 2004; Lua and Low 2005) and Wnt signaling (Janssens et al. 2006), respectively, and will contribute to the remodeling of the MDA-injured liver together with cell-cycle– and apoptosis–regulating genes such as cyclin D, Rback, caspase3, sphingosine phosphate lyase 1, and so on (Supplementary Table 3: http://www.snubi.org/publication/TGRC_MDA). An iron homeostatic gene, Alas1, is also activated by MDA treatment, which is associated with heme synthesis regulated by bile acids in the liver (Peyer et al. 2007). In contrast, the genes belonging to Classes III and IV could be potential biomarker genes in predicting the level of exposure to MDA-like chemicals because their expression was dose dependent. As shown in Class III, many genes that were altered at the time of peak injury (i.e., twenty-four hours) in the low-dose group had reversed expression patterns during the recovery phase (i.e., seventy-two hours) in the high-dose group. Metallothionein-1 and catalase have been shown to be altered by some liver toxicants such as furan (Bartosiewicz et al. 2001; Huang et al. 2004). In contrast, genes belonging to Class IV were affected in an on/off dose-dependent expression pattern. Among the genes affected only by the low dose of MDA, some genes such as Sdh1 (2.5-times increase), Gck (4.1-times increase), and Hyal (2.1-times decrease followed by 3.0-times increase) have already been postulated as biochemical markers associated with liver function and toxicity, including biliary diseases (Table 3). In addition, Caveolin 2 (Cav2), which is highly expressed in the proliferating bile ductules in primary biliary cirrhosis (Yokomori et al. 2005), was significantly up-regulated at the time of peak injury at the high dose of MDA. In association with liver fibrosis, overexpression of smad 1 was noteworthy at the late stage of severely MDA-injured liver (Table 3) (Fan et al. 2006). Glypican 3, a cell-adhesion–related gene, is a useful marker for hepatocellular carcinoma (Libbrecht et al. 2006), but MDA, a bile-duct-damaging chemical, induced glypican 1 at the low dose and glypicans 4 and 5 at the high dose. Early-response genes have been an important topic in toxi-cogenomics studies. In the microarray, Egr1, Nmyc1, Cxcl1, Clrf, Hmgcs1, P2rx2, Gng2, and Dnajb4 were considered potential early biomarkers associated with biliary cell damage in liver exposed to a low dose of MDA because they were dramatically up-regulated at the early phase (six hours) in the low-dose group. In particular, Egr1 was up-regulated by approximately forty-five times in the early phase after the low dose of MDA. This gene changes rapidly at the mRNA level in the livers of mice with cholestasis (Kim et al. 2006). Galk2 (galactokinase 2), which is regulated by Egr1 (Yang et al. 2004), was subsequently up-regulated by low and high doses of MDA. More importantly, Gpx6 (+2.5 times, +2.9 times), Emid2 (+2.8, +2.8), Nr0b2 (+4.1, +3.2), Slc23a3 (+3.2, +2.3), Dio1 (+5.5, +5.0), Ard1 (–2.4, –3.0), Prss22 (–5.3, –5.8), And (–2.2, –2.5), Wbscr16 (–2.6, –3.3), Havcr1 (–4.8, –4.5), Cox10 (–2.2, –2.9), and other genes showed marked alterations at both the low and high doses in the early phase after MDA treatment. The altered expression of these genes was further verified using RT-PCR in cases (Figure 6).
Comprehensive Action Mechanisms of Altered Genes Following MDA Treatment
Immunity and Inflammation In the high-dose group, periductal inflammation characterized by lymphocyte infiltration was histopathologically evident in the acute late phase. This finding was supported by the up-regulation of numerous immunity-associated genes. Lymphocyte-related genes such as Lsp1, Ly6a, and Ly96, and chemokine-related genes such as Ccl2, Ccl9, Cxcl9, and Xcl1 were up-regulated, implying that the Th1 pathway was involved in MDA-induced inflammation. The activation of these types of proinflammatory cytokines also occurs in mice suffering from biliary atresia (Leonhardt et al. 2006). Further, regulators of cytokine signaling such as Jak1 and Map3k4 were also activated by MDA treatment.
Cell Cycle and Proliferation
Apoptosis
Oxidative Stress In summary, a single oral administration of MDA produced differential gene expression profiles in mouse liver tissues that were dependent on or independent of sampling time and dose. With regard to potential biomarker genes, we divided the altered genes into four categories, Classes I to IV. Numerous functionally defined and unclassified genes in each category were differentially up- or down-regulated throughout the period from cellular injury to the recovery phase at the examined doses, providing potential biomarker gene profiles. These gene expression profiles were also comprehensive with regard to the mechanistic responses maintaining cellular homeostasis or recovery from MDA-induced liver toxicity. Thus, our results are valuable not only for understanding the mechanisms by which MDA-like chemicals induce liver toxicity, in particular bile duct cell injury, but also for risk assessment and classification of the chemicals using biotoxchips.
This work was supported by a grant from the Korea Food and Drug Administration (KFDA-05122-TGP-584).
Sun-Bum Kwon and Joon-Suk Park contributed equally to this work.
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660-673 (2008)
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Abstract
Introduction
-glucan branching enzyme 1 up-regulation via the hypoxic signaling pathway. Toxicol Appl Pharmacol, 196, 404-9