Journal Article

Prenatal Exposure to TCDD Triggers Significant Modulation of microRNA Expression Profile in the Thymus That Affects Consequent Gene Expression

Singh, Udai P., Guan, Hongbing, Nagarkatti, Mitzi, Singh, Narendra P., Nagarkatti, Prakash

2012

Overview

MicroRNAs (miRs) are a class of small RNAs that regulate gene expression. There are over 700 miRs encoded in the mouse genome and modulate most of the cellular pathways and functions by controlling gene expression. However, there is not much known about the pathophysiological role of miRs. TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin), an environmental contaminant is well known to induce severe toxicity (acute and chronic) with long-term effects. Also, in utero exposure of fetus to TCDD has been shown to cause thymic atrophy and alterations in T cell differentiation. It is also relevant to understand \"the fetal basis of adult disease\" hypothesis, which proposes that prenatal exposure to certain forms of nutritional and environmental stress can cause increased susceptibility to clinical disorders later in life. In the current study, therefore, we investigated the effects of prenatal exposure to TCDD on miR profile in fetal thymocytes and searched for their possible role in causing thymic atrophy and alterations in the expression of apoptotic genes. miR arrays of fetal thymocytes post exposure to TCDD and vehicle were performed. Of the 608 mouse miRs screened, 78 miRs were altered more than 1.5 fold and 28 miRs were changed more than 2 fold in fetal thymocytes post-TCDD exposure when compared to vehicle controls. We validated the expression of several of the miRs using RT-PCR. Furthermore, several of the miRs that were downregulated contained highly complementary sequence to the 3'-UTR region of AhR, CYP1A1, Fas and FasL. Also, the Ingenuity Pathway Analysis software and database was used to analyze the 78 miRs that exhibited significant expression changes and revealed that as many as 15 pathways may be affected. These studies revealed that TCDD-mediated alterations in miR expression may be involved in the regulation of its toxicity including cancer, hepatic injury, apoptosis, and cellular development.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: 3' Untranslated regions / Analysis / Animal genetics / Animals / Apoptosis / Apoptosis - drug effects / Apoptosis - genetics / Atrophy / Biology / Biomarkers / Cancer / Cell cycle / Cell differentiation / Cluster Analysis / Contaminants / Cytochrome P-450 CYP1A1 - genetics / Cytochrome P-450 CYP1A1 - metabolism / Cytochrome P450 / Differentiation (biology) / Dioxins / Disease susceptibility / Environmental stress / Enzymes / Exposure / Fas Ligand Protein - genetics / Fas Ligand Protein - metabolism / fas Receptor - genetics / fas Receptor - metabolism / FasL protein / Female / Fetal alcohol syndrome / Fetuses / Gene expression / Gene Expression Profiling / Gene Expression Regulation, Developmental - drug effects / Gene Regulatory Networks / Genes / Genomes / Genomics / Herbicides / Hydrocarbons / Immunology / Intrauterine exposure / Long-term effects / Lymphocytes T / Maternal Exposure / Medicine / Mice / MicroRNA / MicroRNAs / MicroRNAs - genetics / miRNA / Neoplasms - genetics / Nutrient deficiency / Pathology / Pathways / Polychlorinated Dibenzodioxins - pharmacology / Polychlorinated Dibenzodioxins - toxicity / Polymerase chain reaction / Pregnancy / Pregnant women / Prenatal experience / Prenatal exposure / Prostate cancer / Receptors, Aryl Hydrocarbon - genetics / Receptors, Aryl Hydrocarbon - metabolism / Reproducibility of Results / Ribonucleic acid / RNA / Rodents / Signal Transduction - drug effects / T cells / TCDD / Thymocytes / Thymocytes - drug effects / Thymocytes - metabolism / Thymus / Thymus Gland - drug effects / Thymus Gland - embryology / Thymus Gland - metabolism / Toxicity