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Published on: November 27, 2019
Analysis of Gene Expression in 4,4'-Methylenedianiline-induced Acute Hepatotoxicity
Jung-Hwa Oh1, Hea-Jin Yoon1, Jung-Sun Lim1
114Toxicogenomics Team, Korea Institute of Toxicology, 19 Shinsung-ro, Yuseoung, Daejeon, 305-343 Korea.
Abstract:
4,4'-Methylenedianiline (MDA) is an aromatic amine that is widely used in the industrial synthetic process. Genotoxic MDA forms DNA adducts in the liver and is known to induce liver damage in human and rats. To elucidate the molecular mechanisms associated with MDA-induced hepatotoxicity, we have identified genes differentially expressed by microarray approach. BALB/c male mice were treated once daily with MDA (20 mg/kg) up to 7 days via intraperitoneal injection (i.p.) and hepatic damages were revealed by histopathological observation and elevation of serum marker enzymes such as AST, ALT, ALP, cholesterol, DBIL, and TBIL. Microarray analysis showed that 952 genes were differentially expressed in the liver of MDA-treated mice and their biological functions and canonical pathways were further analyzed using Ingenuity Pathways Analysis (IPA). Toxicological functional analysis showed that genes related to hepatotoxicity such hyperplasia/hyperproliferation (Timpl), necrosis/cell death (Cd14, Mt1f, Timpl, and Pmaipl), hemorrhaging (Mt1f), cholestasis (Akr1c3, Hpx, and Slc10a2), and inflammation (Cd14 and Hpx) were differentially expressed in MDA-treated group. This gene expression profiling should be useful for elucidating the genetic events associated with aromatic amine-induced hepatotoxicity and for discovering the potential biomarkers for hepatotoxicity.
Insights
4,4'-Methylenedianiline (MDA) causes liver damage by forming DNA adducts. Gene expression profiling in mice revealed significant changes in genes related to liver injury, offering potential biomarkers for aromatic amine-induced hepatotoxicity.
Area of Science:
- Toxicology
- Molecular Biology
- Genomics
Background:
- 4,4 '-Methylenedianiline (MDA) is an industrial aromatic amine known to cause genotoxicity and liver damage.
- MDA forms DNA adducts in the liver, leading to observed toxicity in humans and rats.
Purpose of the Study:
- To elucidate molecular mechanisms of MDA-induced hepatotoxicity.
- To identify differentially expressed genes and potential biomarkers using microarray analysis.
Main Methods:
- BALB/c male mice were treated with MDA (20 mg/kg/day) for 7 days.
- Hepatic damage assessed via histopathology and serum marker enzymes (AST, ALT, ALP, cholesterol, DBIL, TBIL).
- Gene expression profiling using microarray analysis, followed by Ingenuity Pathway Analysis (IPA).
Main Results:
- MDA treatment induced significant hepatic damage and altered serum enzyme levels.
- Microarray analysis identified 952 differentially expressed genes in the liver.
- Genes associated with hepatotoxicity, including hyperplasia, necrosis, hemorrhage, cholestasis, and inflammation, were significantly altered.
Conclusions:
- Gene expression profiling provides insights into the genetic events underlying aromatic amine-induced hepatotoxicity.
- The identified differentially expressed genes may serve as potential biomarkers for MDA-induced liver injury.
