Notable Sequential Alterations in Notochord Volume During Development in the Adriamycin Rat Model

Background/purpose: The Adriamycin rat model (ARM) is a well-established model of the vertebral, anorectal, cardiac, tracheoesophageal, renal, and limb association. An important finding in the ARM is that Adriamycin induces abnormal notochord morphology in the region of the foregut. Having recently demonstrated notochord hypertrophy in ARM embryos, the authors designed this study to assess notochord volume sequentially from gestational days 10 to 14 (E10-E14) to test the hypothesis that notochord hypertrophy occurs maximally soon after Adriamycin administration.

Methods: Adriamycin (1.75 mg/kg) was administered intraperitoneally to pregnant rats on E7, E8, and E9. Control animals were given saline. Embryos were recovered at E10, E11, E12, E13, and E14 and embedded in paraffin. Quantitative morphology using the Cavalieri technique was performed on hematoxylin and eosin-stained transverse serial sections to determine total embryo and total notochord volume.

Results: The percentage volume of notochord per embryo was significantly increased (P < .05) in Adriamycin-treated embryos at all gestational time frames from E10 to E14 when compared with equivalent controls. This increased volume of notochord was found to be maximal at E11.

Conclusions: These data support the authors' previous finding that Adriamycin induces notochord hypertrophy and suggest that notochord volume is increased relative to embryo volume soon after Adriamycin administration and is maximal on E11. The abnormal increase in notochord volume during the critical phase of development may interfere with organogenesis, resulting in the vertebral, anorectal, cardiac, tracheoesophageal, renal, and limb association.