Integrated analysis of pesticides induced liver toxicity in human hepatoma cell line

Abstract

Environmental chemicals that have wide usage in human life are known to induce hepatotoxicity and reproductive toxicity. Growing concerns over environmental hazardous chemicals and their effects on human health have promoted research into the understanding molecular mechanisms of environmental chemicals. Pesticides are a wide class of environmental contaminants and cause both acute and chronic health effects in exposed organism. But it still under investigates about molecular mechanisms of them. The analysis of toxicogenomic and epigenomic profiles by bioinformatics elucidates molecular mechanisms involved in pesticide induced toxicity. Toxicogenomics is the study of the genomic response of an intact biology system to a chemical compounds and used to develop biomarkers that can be used as templates for measuring unknowns. For the epigenomic study, we researched microRNA, which is a small non-coding RNA molecule (18-22 nucleotides). In light of the mechanism of action of miRNAs in cells undergoing stress, the action and localization of miRNA-mRNA complexes may be of equal importance as their level of expression in toxicology. In this study, as a part of the ToxCast project, the toxicity of 14 pesticide chemicals was assessed. In order to screen and predict environmental toxicity of the pesticides, we compared microRNA and gene expression using two type of microarray, Agilent Human Whole Genome Array for mRNA and Agilent Human microRNA Array V13 for microRNA. And we analyzed integrated data from ToxCast project for underlying the alteration of pesticide on the liver. 1. We investigated the xenobiotic effect of pesticides at the genome and epigenome level. Some of significantly expressed genes and microRNAs can be a bio-indicator of pesticides. GnRH signaling pathway was affected pathway by pesticide microRNA and mRNA same as mRNA analysis. This alteration can cause infertility in human. 2. In the analysis of comparison between endocrine disrupting chemicals (EDCs, bisphenol A, dibutylphthalate, vinclozolin) and pesticides, atrazine and permethrin were similar with EDCs. Wnt signaling pathway was affected by EDCs and it was also found in common analysis with EDCs-pesticides. Wnt signaling pathway causes liver injury and liver oncogenesis. In the different case, ubiquitin mediated proteolysis and axon guidance related genes were regulated by pesticide versus EDCs. Axon guidance pathway changes started from receptor and ligand coding gene expression changed and it affects to neurodegenerative disorder, finally. 3. Triazole fungicides (myclobutanil, propiconazole, triadimefon) induced expression of cytochrome P450 family genes and regulate metabolism related pathways, such as Glutathion metabolism, Biosynthesis of unsaturated fatty acid. Myclobutanil is known as a nontumorigenic compound, and propiconazole and triadimefon are known as tumorigenic compounds. Tumorigenic compounds have a tumorigenic characteristic that affects to cancer related pathways, Focal adhesion, MAPK signaling pathway, Prostate cancer, Non-small cell lung cancer, Glioma and Melanoma. 4. Drug based pesticide classification was a new methodology for anchoring clinical phenotype data and in vitro genomic data. Using this analysis, we classified the pesticides by how much causing liver injury. The group that having potential severe liver injury affected to telomere maintenance that related to common mechanism of liver injury including p53 activation, oxidative stress. This integrated data analysis approach could be promising way to study pesticides induced liver injury.