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Loss of p53 Is an Early Event in Induction of Brain Tumors in Mice by Transplacental Carcinogen Exposure¹

Department of Pathology, Faculty of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113 [H. O., S. Z., N. T., S. S., Y. N., T. I.], and Department of Morphogenesis, Institute of Molecular Embryology and Genetics, Kumamoto University School of Medicine, 4-24-1 Kushinaji, Kumamoto 860 [S. A.], Japan

Experimental carcinogenesis studies using p53-deficient mice have suggested that loss of function of this tumor suppressor gene is generally not an early event but is rather related to tumor progression. However, the biological functions of p53 and the accumulating evidence of alteration in human tumors imply a possible role for loss of p53 in the initial stages of tumorigenesis. Ethylnitrosourea administration to p53-heterozygous pregnant mice resulted in rapid development of primary brain tumors, which are extremely rare in mice, in 70% of the p53-null offspring. Brain tumors also developed later in 4% of heterozygous mice, but they had lost the wild-type allele. Thus, loss of normal p53 gene expression is of direct significance to early events in brain tumorigenesis, and this tumor suppressor gene may protect embryos from DNA damage in the brain induced by transplacental carcinogen exposure.

¹ Supported by Grants-in-Aid for Scientific Research on Priority Areas from the Ministry of Education, Science, Sports and Culture, the Smoking Research Foundation, and the Princess Takamatsu Cancer Research Fund.

² These authors contributed equally to this work.

³ To whom requests for reprints should be addressed. Phone: 03-5802-3345; Fax: 03-5802-3346.

Received 9/ 3/96. Accepted 12/20/96.

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