Bromodeoxyuridine leaves evidence of prenatal exposure in the postnatal skeleton in CD-1 mice

Abstract

Mice from two series of experiments (S1, S2) involving intraperitoneal (ip) injection of dams with 300 (High or H), 60 (Low or L), or 0 (VEH) mg 5′-bromodeoxyuridine (BUDR) per kilogram body weight (mg/ kg) in water (15 mL/kg) on day seven (D7), day eight (D8), or in S2 only, day nine (D9) of gestation (9DPC), and untreated (UNTD) controls, were examined between 60 and 65 days postnatal (DPN) for 88 variations of the skeleton. In S1, 65 variants occurred, and in S2 there were 58 variants that occurred. Substantial numbers of significant differences ( P < 0.01) in frequency of occurrence (%) were seen in High dose only. The number of variants that differed from UNTD were 13, 13, 12, 15, and 11 in S1-D7H, S2-D7H, S1-D8H, S2-D8H, and S2-D9H, respectively; the average absolute difference in frequency among significantly affected variants was 16% to 20%. In the same order as above, 13, 12, 8, 10, and 9 variants differed significantly from VEH, and 9, 8, 7, 8, and 8 variants differed significantly from both UNTD and VEH. In contrast, 0, 0, 1, 1, and 0 variants differed from both UNTD and VEH in S1-D7L, S2-D7L, S1-D8L, S2-D8L, and S2-D9L, respectively. Agreement between the two series was good; 11 traits were affected in High dose litters in both series in at least 3 or 4 comparisons (compared with UNTD, VEH, in S1, S2). These important indicators were #14-Interfrontal, #26-Preoptic Sutures, #48-Dyssymphysis of the Axis, #59-Malformations (Dyssymphysis or Fusions) of C3-C7, #68-Reduced Articular Processes of Thoracic Vertebrae, #70-Fourteen Ribs, #71-Malformed Ribs, #73-Malformed Sternebrae, #74-Fossa Olecrani (Humerus) Perforata, #75-Carpal Fusions, #78-27 Presacral Vertebrae. Unusually large increases in frequency among High-dose animals were seen for Interfrontal bone, Preoptic Sutures, and 14 Ribs. A 9DPC treatment regime in S2 confirms a posteriad shift in variants affected over time, though the thoracic region is the most heavily and consistently affected throughout. Reproducible demonstration of cryptic variation in the absence of malformations allows detection of prenatal BUDR exposure by detection of subtle biologic effects among a population of apparently normal survivors of prenatal teratogen exposure.