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ToxSci Advance Access originally published online on February 23, 2009
Toxicological Sciences 2009 109(1):143-151; doi:10.1093/toxsci/kfp041
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© The Author 2009. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org

Mono-(2-ethylhexyl) phthalate Targets Glycogen Debranching Enzyme and Affects Glycogen Metabolism in Rat Testis

Chikanori Kuramori*,1, Yasuyoshi Hase*,1, Koichi Hoshikawa{dagger}, Keiko Watanabe*, Takeyuki Nishi*, Takako Hishiki{ddagger}, Tomoyoshi Soga§, Akihiro Nashimoto*, Yasuaki Kabe{ddagger}, Yuki Yamaguchi*, Hajime Watanabe, Kohsuke Kataoka||, Makoto Suematsu{ddagger} and Hiroshi Handa*,|||,2

* Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, 226-8501 Yokohama, Japan {dagger} Department of Surgery, Iwate Medical University School of Medicine, 020-8505 Morioka, Japan {ddagger} Department of Biochemistry and Integrative Medical Biology, School of Medicine, Keio University, 160-8582 Tokyo, Japan § Institute for Advanced Biosciences, Keio University, 997-0017 Tsuruoka, Japan Center for Integrative Bioscience, Okazaki National Research Institutes, 444-8787 Okazaki, Japan || Graduate School of Bioscience, Nara Institute of Science and Technology, 630-0192 Ikoma, Japan ||| Integrated Research Institute, Tokyo Institute of Technology, 226-8501 Yokohama, Japan

2 To whom corresponding should be addressed at Integrated Research Institute, Tokyo Institute of Technology, 4259 Nagatsuta-cho, Yokohama, 226-8501 Japan. Fax: +81-45-924-5145. E-mail: hhanda{at}bio.titech.ac.jp.

Received December 15, 2008; accepted February 17, 2009


  Abstract

Phthalate esters are commonly used plasticizers; however, some are suspected to cause reproductive toxicity. Administration of high doses of di-(2-ethylhexyl) phthalate (DEHP) induces germ cell death in male rodents. Mono-(2-ethylhexyl) phthalate (MEHP), a hydrolyzed metabolite of DEHP, appears to be responsible for this testicular toxicity; however, the underlying mechanism of this chemical's action remains unknown. Here, using a one-step affinity purification procedure, we identified glycogen debranching enzyme (GDE) as a phthalate-binding protein. GDE has oligo-1,4-1,4-glucanotransferase and amylo-1,6-glucosidase activities, which are responsible for the complete degradation of glycogen to glucose. Our findings demonstrate that MEHP inhibits the activity of oligo-1,4-1,4-glucanotransferase, but not of amylo-1,6-glucosidase. Among various phthalate esters tested, MEHP specifically binds to and inhibits GDE. We also show that DEHP administration affects glycogen metabolism in rat testis. Thus, inhibition of GDE by MEHP may play a role in germ cell apoptosis in the testis.

Key Words: phthalate esters; glycogen metabolism; metabolome analysis; germ cell; glycogen debranching enzyme.

1 These authors contributed equally to the work.


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