Can intracellular signalling pathways predict developmental abnormalities?

Abstract

Sensitivity of the adenylyl cyclase/c-fos protooncogene cascade to β-adrenergic agonists and glucocorticoids in foetal rat

We examined whether measurements of adenylyl cyclase and its control of c-fos protooncogene mRNA expression in mid-gestation foetal rat could be used to detect developmental effects of apparently unrelated compounds: terbutaline, a β-adrenergic receptor stimulant, and dexamethasone, a glucocorticoid hormone. On gestational day 14, acute administration of terbutaline to pregnant rats resulted in sixfold induction of c-fos mRNA within 1 h; the same increase was obtained when a membrane-permeable analogue of cAMP was given. Treatment with dexamethasone on gestational days 11,12 and 13 produced the same increase in c-fos mRNA on gestational day 14 as had been seen with acute terbutaline or CAMP; no further increase could be obtained with acute CAMP treatment in the dexamethasone-pretreated animals. Adenylyl cyclase activity was evaluated on gestational day 14. Animals treated with dexamethasone showed a 50% enhancement of basal enzyme activity that reflected a parallel increase in total catalytic activity as measured with forskolin-Mn²⁺. Dexamethasone also increased adenylyl cyclase activity in the presence of a β-agonist but to a lesser extent than the increase in total catalytic activity. These results indicate that cell signalling pathways mediating the expression of the genes that control cell differentiation are a likely target for structurally and mechanistically unrelated drugs and chemicals and may therefore be useful as early biomarkers of abnormal development.

Key Words :

• adenylyl cyclase
• β-adrenergic receptors
• c-fos
• dexamethasone
• terbutaline
• foetal development