Neonatal dexamethasone treatment leads to alterations in cell signaling cascades controlling hepatic and cardiac function in adulthood

Abstract

Increasing evidence indicates that early-life glucocorticoid exposure, either involving stress or the therapy of preterm labor, contributes to metabolic and cardiovascular disorders in adulthood. We investigated cellular mechanisms underlying these effects by administering dexamethasone (DEX) to neonatal rats on postnatal (PN) days 1-3 or 7-9, using doses spanning the threshold for somatic growth impairment: 0.05, 0.2 and 0.8 mg/kg. In adulthood, we assessed the effects on hepatic and cardiac cell function mediated through the adenylyl cyclase (AC) signaling cascade, which controls neuronal and hormonal inputs that regulate hepatic glucose metabolism and cardiac contractility. Treatment on PN1-3 produced heterologous sensitization of hepatic signaling, with upregulation of AC itself leading to parallel increases in the responses to beta-adrenergic or glucagon receptor stimulation, or to activation of G-proteins by fluoride. The effects were seen at the lowest dose but increasing DEX past the point of somatic growth impairment led to loss of the effect in females. Nonmonotonic effects were also present in the heart, where males showed AC sensitization at the lowest dose, with decreasing effects as the dose was raised; females showed progressive deficits of cardiac AC activity. Shifting the exposure to PN7-9 still elicited AC sensitization but with a greater offsetting contribution at the higher doses. Our findings show that, in contrast to growth restriction, the glucocorticoids associated with stress or the therapy of preterm labor are more sensitive and more important contributors to the cellular abnormalities underlying subsequent metabolic and cardiovascular dysfunction.

Figure 1

Mechanisms controlling AC activity, showing probes for each step in the pathway: isoproterenol for the βAR, glucagon for the glucagon receptor, NaF for the G-proteins, and forskolin for AC itself. Both βARs and glucagon receptors enhance AC activity through the stimulatory G-protein, G_s, whereas m₂AChRs inhibit AC through mediation of the inhibitory protein, G_i.

Figure 2

Effects of neonatal DEX treatment on body and tissue weights. Data represent means and standard errors obtained from 6 animals in each group, presented as the percent change from the corresponding control values (Table 1). ANOVA appears at the top and asterisks denote values that differ from the control.

Figure 3

Liver AC activity in animals given DEX on PN1-3 (A, B) or PN7-9 (C, D). Data represent means and standard errors obtained from 6 animals in each group, presented as the percent change from the corresponding control values (Table 1). ANOVA appears at the top of each panel and lower-order tests are shown within the panels. Where there was a significant treatment × stimulant interaction, asterisks denote specific responses that differ from the control. Abbreviations: Iso, isoproterenol; Glu, glucagon; NaF, sodium fluoride; Fsk, forskolin; NS, not significant.

Figure 4

Heart AC activity in animals given DEX on PN1-3. Data represent means and standard errors obtained from 6 animals in each group, presented as the percent change from the corresponding control values (Table 1). ANOVA appears at the top of each panel and lower-order tests are shown within the panels. Where there was a significant treatment × stimulant interaction, asterisks denote specific responses that differ from the control. Abbreviations: Iso, isoproterenol; Glu, glucagon; NaF, sodium fluoride; Fsk, forskolin; NS, not significant.

Figure 5

Effects of neonatal DEX treatment on liver βAR binding and on heart βARs and m₂AChRs. Data represent means and standard errors obtained from 6 animals in each group, presented as the percent change from the corresponding control values (Table 1). ANOVA appears at the top and asterisks denote values that differ from the control.