Fetal lung mRNA levels of Hox genes are differentially altered by maternal diabetes and butyrate in rats.
Diabetes is known to be associated with delayed lung development in humans and in experimental animals. This includes delayed expression of surfactant apoproteins. An important component of the metabolic abnormalities in diabetes is elevated levels of analogs of butyric acid, and the effects of diabetes on surfactant apoproteins can be reproduced by exposure of fetal rat lung explants to butyrate. Dexamethasone has the opposite effects on lung development. In humans, antenatal exposure to dexamethasone results in a lower incidence of RDS, whereas in experimental animals, dexamethasone increases the expression of surfactant apoproteins. A subset of Hox genes are expressed in developing lung, and their level of expression decreases with advancing gestation. We hypothesized that: 1) lungs of fetuses of rats with streptozotocin-induced diabetes would have altered levels of expression of Hox genes, 2) the effect would be mediated in part through elevated levels of butyrate, and 3) dexamethasone would reverse the effect. We tested our hypotheses in vivo using fetuses from streptozotocin-treated rats and in vitro by treating lung explants from normal rats with sodium butyrate. Streptozotocin treatment increased expression of Hoxb-5 at 18 d of gestation, but did not affect Hoxa-5 expression. This was associated with a 20-fold increase in alpha-aminobutyrate levels. Dexamethasone tended to reverse this effect. In contrast, butyrate treatment of explants decreased the expression of Hoxa-5 and Hoxb-5. We conclude that diabetes alters expression of Hox genes, but that the effect of butyrate on lung development, and in particular on surfactant apoprotein expression, is independent of its effects on Hox genes.
Jacobs
H C
HC
Yale University, Department of Pediatrics, New Haven, Connecticut 06520-8064, USA.
Bogue
C W
CW
Pinter
E
E
Wilson
C M
CM
Warshaw
J B
JB
Gross
I
I
D000818:Animals; D002087:Butyrates / Q000494:pharmacology*; D020148:Butyric Acid; D003921:Diabetes Mellitus, Experimental; D005314:Embryonic and Fetal Development; D005260:Female; D018507:Gene Expression Regulation, Developmental; D005801:Genes, Homeobox / Q000187:drug effects; D005865:Gestational Age; D056572:Histone Deacetylase Inhibitors; D008168:Lung / Q000187:drug effects / Q000196:embryology*; D009924:Organ Culture Techniques; D011247:Pregnancy; D011254:Pregnancy in Diabetics; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D014158:Transcription, Genetic / Q000187:drug effects
D002087:Butyrates; D056572:Histone Deacetylase Inhibitors; D012333:RNA, Messenger; D020148:Butyric Acid