Fetal Lung mRNA Levels of Hox Genes Are Differentially Altered by Maternal Diabetes and Butyrate in Rats

Abstract

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.

Position‐specific expression of Hox genes along the gastrointestinal tract

“…In conclusion, we demonstrated that Hox genes are expressed in a region‐specific manner along the adult GI tract. Considering the critical role of Hox genes in morphogenesis and their abnormal expression pattern after various teratogen exposures (Jacobs et al . 1998; Li et al .…”

“…Li & Shiota 1999) showed that heat treatment induced embryonic day‐specific vertebral transformations accompanied by altered expression of Hox genes. Jacobs et al . (1998) demonstrated abnormal Hox expression in the lungs of fetuses from streptozotocin‐treated rats.…”

Caudal Regression Syndrome in Twin Pregnancy With Type II Diabetes

“…30 Although the link between homeobox genes and diabetes-induced CRS has not yet been reported in the literature, maternal diabetes has been shown to alter expression of Hox genes in fetal rat lungs. 31 The teratogenic insult in diabetic embryopathy occurs from the third to seventh week of gestation at the initiation of organogenesis. 32 In rats, uncontrolled diabetes produced lumbosacral malformations only during the period of organ differentiation.…”

Homeobox genes in normal and malignant cells

“…Rats fetuses, with streptozoticin-induced diabetes, display altered Hox gene expression in the lung. This effect is mediated by butyrate and reversed by dexamethasone (Jacobs et al, 1998).…”