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MORPHOMETRIC ANALYSIS OF RAT HINDLIMB MALFORMATIONS DUE TO GESTATIONAL EXPOSURE TO 5-FU
Citation:
Setzer, R W., M. D. Williams, D. Litton, AND M G. Narotsky. MORPHOMETRIC ANALYSIS OF RAT HINDLIMB MALFORMATIONS DUE TO GESTATIONAL EXPOSURE TO 5-FU. Presented at Annual Meeting of Teratology Society, Scottsdale, AZ, June 22-27, 2002.
Description:
SETZER1, R. W., M. D. WILLIAMS2, D. LITTON3, M.G. NAROTSKY4, 1Experimental Toxicology Division and 4Reproductive Toxicology Division, NHEERL, ORD, USEPA, Research Triangle Park, North Carolina; 2UNC School of Medicine, Chapel Hill, North Carolina; and 3Department of Aerospace Engineering, North Carolina State University, Raleigh, North Carolina . Morphometric analysis of rat hindlimb malformations due to gestational exposure to 5-FU.
The chemotherapeutic drug 5-fluorouracil (5-FU) is a strong inducer of hindlimb malformations, largely loss (or fusion) of digit segments, in rats that have been exposed on gestation day (GD) 14. The dose-response is highly non-linear: virtually no animals are affected in doses lower than 30 mg/kg, whereas at 40 mg/kg, around 65% of the animals are affected. On the other hand, body weight at term declines gradually with increasing dose, with a somewhat accelerating dose-response as dose increases, but no clear break in the slope of the dose-response curve. In this study we address whether the hindlimb malformations are the result of a discrete, catastrophic change in the course of development, manifested in the 30-40 mg/kg range, or whether increasing doses gradually change the shape of the limb until, between 30 and 40 mg/kg, homeostatic mechanisms can no longer maintain normal development. When developing hindlimbs were measured 24 hours after exposure, the regions that would develop into digits 1 and 5 were differentially reduced in size relative to the other digits by dose, suggesting that the latter situation might be true. In this study, timed-pregnant Sprague-Dawley rats were given single doses (0-40 mg/kg) of 5-FU on GD 14, and killed on GD 20. Fore-and hindlimbs were removed from stained embryonic skeletons and imaged. The lengths, widths, and areas of digits from normal forelimbs and hindlimbs, and selected abnormal hindlimbs, were measured, and analyzed to estimate the relationship between dose and individual measurements or various measures of shape, such as ratios of digit lengths. While generally the limbs were reduced in size at higher doses, any change of shape among the normal limbs was subtle, if present at all. Thus, either the developing hindlimb is very sensitive to changes in shape induced by 5-FU, or a change in shape is not the route by which 5-FU induces limb malformations. [This abstract does not necessarily reflect EPA policy.]