Craniofacial and axial skeletal defects induced by the fungicide triadimefon in the mouse.
BACKGROUND
Triadimefon is an antifungal derived from triazole. In in vitro whole-rodent embryo cultures, triazole-derivatives showed specific teratogenic effects at the branchial apparatus. The aim of the present work was to test in vivo triadimefon (FON), in order to verify a relationship between triazole exposure, embryonic abnormalities, and/or fetal malformations.


METHODS
Pregnant CD-1 mice were treated with 0-300 mg/kg FON by gavage on day 8 post coitum (p.c.) at 10:00 AM, and sacrificed on day 8 p.c. at 1:00 PM, on day 9 p.c. at 10:00 AM, on day 10 p.c. at 10:00 AM, and at term of gestation (day 18 p.c.). At midgestation, the embryos were processed for specific immunostainings to visualize the hindbrain segmentation (day 8 p.c.) and the neural crest cell migration (days 8 and 9 p.c.). Fetuses explanted at term were all processed for skeletal examination after double-staining of osseous and cartilaginous tissues.


RESULTS
At midgestation, the immunostaining of rhombomeres 3 and 5 showed a light scattering of the immunostained areas; the neural crest cell migration was unaffected, but their localization at the branchial arch level was abnormal. At term, several severe malformations were observed at the craniofacial and at the axial skeletal level. Ectopic cartilage was observed at the upper jaw.


CONCLUSIONS
Triadimefon is teratogenic. The observed craniofacial malformations could be explained by an alteration of the rhombomeric organization and neural crest migration to the branchial arches; the axial abnormalities could be explained by the abnormal segmental identity specification.
Menegola
Elena
E
Department of Biology, University of Milan, Milan, Italy. elena.menegola@unimi.it
Broccia
Maria Luisa
ML
Di Renzo
Francesca
F
Massa
Valentina
V
Giavini
Erminio
E
D000014:Abnormalities, Drug-Induced; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D001842:Bone and Bones / Q000002:abnormalities* / Q000187:drug effects / Q000378:metabolism; D019465:Craniofacial Abnormalities / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D047108:Embryonic Development / Q000187:drug effects*; D005260:Female; D047109:Fetal Development / Q000187:drug effects*; D019084:Fluorescent Antibody Technique, Indirect; D005659:Fungicides, Industrial / Q000633:toxicity*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D011247:Pregnancy; D013723:Teratogens / Q000633:toxicity*; D014230:Triazoles / Q000633:toxicity*
D015415:Biomarkers; D005659:Fungicides, Industrial; D013723:Teratogens; D014230:Triazoles; C032910:triadimefon