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ToxSci Advance Access published online on December 7, 2005
Toxicological Sciences, doi:10.1093/toxsci/kfj066
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© The Author 2005. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
Received August 19, 2005
Accepted November 23, 2005

Reproductive and Developmental Toxicology

A High Inorganic Phosphate Diet Perturbs Brain Growth, Alters Akt-ERK Signaling and Results in Changes in Cap-dependent Translation

Hua Jin 1, Soon-Kyung Hwang 1, Kyungnam Yu 1, Hanjo K. Anderson 1, Yeon-Sook Lee 2, Kee Ho Lee 3, Anne-Catherine Prats 4, Dominique Morello 5, George R. Beck Jr 6, and Myung-Haing Cho 1 *

1 Laboratory of Toxicology, College of Veterinary Medicine and School of Agricultural Biotechnology, Seoul National University, Seoul 151-742, Korea
2 Department of Food and Nutrition, College of Human Ecology, Seoul National University, Seoul 151-742, Korea
3 Laboratory of Molecular Oncology, Korea Institute of Radiological & Medical Sciences, Seoul 139-240, Korea
4 INSERM U397, Endocrinologie et Communication Cellulaire, C.H.U. Rangueil, Avenue Jean Poulhès, 31403 Toulouse Cedex 04, France
5 Centre de Biologie du Développement, CNRS-UMR5547, IFR 109, Université Paul Sabatier, 118 Route de Narbonne, 31062 Toulouse, France
6 Emory University School of Medicine, Division of Endocrinology, Metabolism and Lipids, Atlanta GA. 30322, USA

* To whom correspondence should be addressed.
Myung-Haing Cho, E-mail: mchotox{at}snu.ac.kr


  Abstract

Inorganic phosphate (Pi) plays a key role in diverse physiological functions. Recently, considerable progress has been made in our understanding of the function and regulation of the brain-specific sodium-dependent inorganic phosphate transporter 1 (NPT1) which is found to exist principally in cerebrum and cerebellum. The potential importance of Pi as a novel signaling molecule and the poor prognosis of diverse neurodegenerative diseases that involve brain-specific NPT1 have prompted us to define the pathways by which Pi affects mouse brain growth. A high phosphate diet caused an increase in serum Pi accompanied by a decrease in calcium, and a decrease in body weight coupled with a decreased relative weight of cerebellum. A high phosphate diet caused a significant increase in protein expression of NPT1, both in cerebrum and cerebellum. Additionally, the high phosphate diet increased Akt phosphorylation at Ser473 in cerebrum and cerebellum, whereas suppression of Akt phosphorylation at Thr308 was observed only in cerebellum. Selective suppression of eukaryotic translation initiation factor-binding protein (eIF4E-BP1) in cerebrum was induced by high levels of Pi, which induced cap-dependent and cap-independent protein translation in cerebrum and cerebellum, respectively. Phosphorylation of ERK1 in comparison with that of ERK2 was significantly reduced in both cerebrum and cerebellum. High levels of Pi reduced protein expressions of PCNA and cyclin D1 in cerebrum and cerebellum. In conclusion, the results indicate that high dietary Pi can perturb normal brain growth possibly through Akt-ERK signaling in developing mice.


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