Adriamycin disruption of the Shh-Gli pathway is associated with abnormalities of foregut development.
BACKGROUND
The hedgehog signalling pathway appears to have a crucial role in the embryogenesis of the foregut in vertebrates. Sonic hedgehog (Shh) protein and gene are involved in the differentiation of many organ systems such as notochord, floor plate, and limbs; development of the left-right axis in vertebrates; and differentiation of trachea and esophagus from the primitive foregut.


METHODS
The prenatal exposure of Sprague-Dawley fetal rats to Adriamycin between days 6 and 9 of gestation was used to induce esophageal atresia and tracheoesophageal fistula. Embryos were harvested by cesarean section on gestational days 11 to 15. Embryos were examined by microscopy, dissection, and serial histology. In situ hybridization was used to study Shh gene expression in the rat embryos.


RESULTS
In situ hybridization showed that the pattern and level of Shh gene expression are affected by Adriamycin. Adriamycin-treated rats have deformed notochord and undivided foregut, and some of the embryos had a lack of the dorso-ventral patterning of Shh expression seen in control embryos.


CONCLUSIONS
These results are consistent with the hypothesis that Adriamycin influences the Shh signalling pathway, resulting in disruption of normal development of the foregut.
Arsic
Dejan
D
Department of Paediatric Surgery, Christchurch School of Medicine, Christchurch, New Zealand.
Cameron
Vicky
V
Ellmers
Leigh
L
Quan
Qi Bao
QB
Keenan
Jacqui
J
Beasley
Spencer
S
D000818:Animals; D004317:Doxorubicin / Q000494:pharmacology*; D004947:Esophagus / Q000187:drug effects* / Q000196:embryology*; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects*; D005865:Gestational Age; D053823:Hedgehog Proteins; D051379:Mice; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects*; D014132:Trachea / Q000187:drug effects* / Q000196:embryology*; D015534:Trans-Activators / Q000096:biosynthesis* / Q000187:drug effects* / Q000235:genetics
D053823:Hedgehog Proteins; D012333:RNA, Messenger; D015534:Trans-Activators; D004317:Doxorubicin