Vinblastine and doxorubicin administration to pregnant mice affects brain development and behaviour in the offspring.
BACKGROUND
Administration of chemotherapy during the fetal phase of pregnancy may put late-developing organs like the central nervous system at risk.


METHODS
Transplacental transfer of doxorubicin and vinblastine was measured in C57/BJ mice by high-performance liquid chromatographic detection of the drugs in maternal and fetal plasma, 90 min after intravenous injection. Further, doxorubicin, vinblastine or saline were administered to pregnant C57/6J mouse dams on gestational day 17.5. Effects on brain morphology of the offspring were examined at 24h p.i. (immediate phase) and at 4-5 months p.i. (residual phase), using light- and electron microscopy. At the age of 3 months, offspring performed a behavioural test battery addressing neuromotor performance, exploration and anxiety, and learning and memory.


RESULTS
Fetal plasma levels of doxorubicin and vinblastine reached respectively 5.0+/-0.2% and 13.9+/-2.4% of the maternal plasma levels. In the immediate phase, pathological examination revealed endothelial and perivascular parenchymal damage to the neocortical subventricular zone and a less constant thickening of the leptomeninx, in some cases also cortical lamination defects were noted. Brain histology was within normal limits in the mice of the residual phase group. Behavioural testing revealed subtle differences between drug-exposed and control mice. Grip strength was reduced in drug-exposed mice, but other tests for motor performance were normal. Several exploratory measures were altered, and there were some indications of increased anxiety in the drug-exposed mice. In the passive avoidance task, step-through latency was shorter in the drug-exposed mice, but their normal performance in the Morris water maze indicated that this was probably not due to impaired memory.


CONCLUSIONS
The current preclinical data reveal subtle changes in behaviour and transiently also in brain morphology in the mice that were prenatally exposed to vinblastine or doxorubicin.
Department of Obstetrics & Gynecology, University Hospital Gasthuisberg, Katholieke Universiteit Leuven, Herestraat 49, 3000 Leuven, Belgium.
Kristel
K
Van Calsteren
Dieter
D
Hartmann
Leen
L
Van Aerschot
Rene
R
Verbesselt
Rieta
R
Van Bree
Rudi
R
D'Hooge
Frédéric
F
Amant
D000367:Age Factors; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D001362:Avoidance Learning / Q000187:drug effects; D001522:Behavior, Animal / Q000187:drug effects*; D001921:Brain / Q000187:drug effects* / Q000196:embryology / Q000254:growth & development / Q000648:ultrastructure; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D004317:Doxorubicin / Q000008:administration & dosage* / Q000097:blood; D004622:Embryo, Mammalian; D005106:Exploratory Behavior / Q000187:drug effects; D005260:Female; D018737:Hand Strength / Q000502:physiology; D019394:Ki-67 Antigen / Q000378:metabolism; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D046529:Microscopy, Electron, Transmission / Q000379:methods; D009043:Motor Activity / Q000187:drug effects; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology; D013037:Spatial Behavior / Q000187:drug effects; D014747:Vinblastine / Q000008:administration & dosage* / Q000097:blood
D000970:Antineoplastic Agents; D019394:Ki-67 Antigen; D014747:Vinblastine; D004317:Doxorubicin