Homeobox transcription factors influence the expression of multiple genes, thereby regulating patterns of differentiation and cell fate. The Hoxa5, b5 and Hex homeobox genes are actively expressed in fetal rat lung, but little is known of their regulation.

Circulating levels of analogues of butyric acid, a known modulator of gene expression, are elevated in fetuses in diabetic pregnancies. We hypothesized that butyric acid may play a role in the delayed fetal lung maturation which is induced by maternal diabetes and that this effect may, in part, be mediated by homeobox genes. The effects of Na butyrate on morphologic development and homeobox gene expression were examined in explants of fetal rat lung.

Marked, dose dependent, inhibition of both growth and budding was detectable after 48 h in culture. Exposure of explants of 16 day fetal rat lung to Na butyrate resulted in a dose dependent decrease in Hoxa5, b5 and Hex mRNA to 42 ± 5% (p<0.01), 23 ± 2% (p<0.001), and 71± 2% (p<0.05) of control, respectively. This inhibition occurred after 6 h in culture and was maximal with 5 mM butyrate, consistent with findings in other culture systems. There was no decrease in γ actin mRNA. Similar effects of butyrate were also observed at 18 days gestation, when Hoxa5 and b5 expression is starting to decline.

We speculate that the interaction between butyrate and homeobox genes may play a role in the pathogenesis of the delayed fetal lung maturation in diabetes.