Evaluation of testicular toxicology of doxorubicin based on microarray analysis of testicular specific gene expression

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  • Takahashi Hikari
    Department of Hygienic Chemistry, Faculty of Pharmaceutical Sciences, Tokyo University of Science
  • Tainaka Hitoshi
    Research Center for Health Sciences of Nanoparticles, Research Institute for Science and Technology,Tokyo University of Science Research Center for Environmental Health Science of Next Generation, Research Institute for Science and Technology, Tokyo University of Science
  • Umezawa Masakazu
    Department of Hygienic Chemistry, Faculty of Pharmaceutical Sciences, Tokyo University of Science Research Center for Health Sciences of Nanoparticles, Research Institute for Science and Technology,Tokyo University of Science Research Center for Environmental Health Science of Next Generation, Research Institute for Science and Technology, Tokyo University of Science
  • Takeda Ken
    Department of Hygienic Chemistry, Faculty of Pharmaceutical Sciences, Tokyo University of Science Research Center for Health Sciences of Nanoparticles, Research Institute for Science and Technology,Tokyo University of Science Research Center for Environmental Health Science of Next Generation, Research Institute for Science and Technology, Tokyo University of Science
  • Tanaka Hiromitsu
    TANAKA Project, Center for Advanced Science and Innovation, Osaka University
  • Nishimune Yoshitake
    Animal Resource Center for Infectious Diseases, Research Institute for Microbial Diseases, Osaka University
  • Oshio Shigeru
    Department of Hygiene Chemistry, School of Pharmaceutical Sciences, Ohu University

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Abstract

Testicular toxicity of chemical substances has been generally assessed by sperm properties and histology. However, the methods can provide only a few information of the mechanism of the toxicity. The aim of this study is to show a method that can evaluate an overview of testicular toxic mechanisms using a tissue-specific microarray and classification of genes using Medical Subject Headings (MeSH). Male ICR mice (6 weeks old) were treated with doxorubicin hydrochloride (0, 0.1, 0.3 mg/kg/time, three times per week) by subcutaneous injection for 6 weeks (until 11 weeks old). Six weeks after the final administration, tissue and blood samples were obtained. Testes were subjected to gene expression analysis using quantitative RT-PCR and cDNA microarray (testis2). To interpret the microarray data, genes were classified using MeSH related to the functions of testis and sperm. Doxorubicin (both 0.1 and 0.3 mg/kg group) induced a decrease in sperm normal morphology and mortality, daily sperm production, and the number of Sertoli cells in the seminiferous tubules. Quantitative RT-PCR and microarray analysis showed dysregulation of mRNA expression levels of genes related to Sertoli cells, germ cells and spermatogenesis. Analysis of microarray data showed a significant enrichment of a total of ten MeSH categories including Spermatogenesis, Sertoli cells, Germ cells and Male infertility. This article concluded that analysis using testicular specific microarray combined with MeSH showed a more comprehensive overview of testicular toxic mechanisms than existing methods; i.e., examination of sperm properties and the histological examinations.

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