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Relationship between in Utero Development of the Mouse Liver and Tumor Development following Transplacental Exposure to Ethylnitrosourea

Medical College of Ohio, Department of Pathology [D. G. B., G. D. S., P. B. C., P. J. G.] and Department of Physiology [C. B.], C.S. 10008, Toledo, Ohio 43614

Pregnant C3HeB/FeJ mice were treated with ethylnitrosourea (ENU) on one of gestation Days 10, 13, or 15 to determine if ENU treatment at different stages of gestation would result in morphological or quantitative differences in liver tumors induced in the offspring. Liver tumors were counted and measured 6 mo after treatment with ENU. Foci of cellular alteration were identified histologically and counted. Liver tumor number and foci of cellular alteration increased as a function of increasing dose and age at the time of ENU treatment. An inverse relationship between age at the time of treatment and the size of liver tumors was found. The mean tumor volume of male mice exposed on Day 10 of gestation was 123-fold larger than for spontaneous tumors observed in controls. The differences between mean liver tumor volume in mice which had been exposed to ENU on Days 10, 13, or 15 of gestation appeared to be associated with the exponential growth of the fetus during this period of gestation. Unique, large, multinodular foci of cellular alteration were found in mice treated on Day 10 of gestation. The relationship between the stage of gestation and the size of chemically induced liver tumors in these mice is similar to previous observations with transplacentally induced lung tumors in C3HeB/FeJ mice. This indicates that developmentally regulated cell proliferation occurring at the time of carcinogen exposure may affect the subsequent extent of tumor development in both the liver and lung. Therefore, cells transformed during early development may result in tumors that pose a greater biological hazard than those transformed in later development.

¹ To whom requests for reprints should be sent, at Pathology and Toxicology Research, The Upjohn Co., Kalamazoo, MI 49001. During part of this investigation, Dr. Branstetter was a National Service Foundation postdoctoral scholar supported by Grant 5F32AM0611.

Received 7/29/88. Revised 3/ 3/89. Accepted 3/28/89.