The Transgenerational Impact of Maternal Dexamethasone Administration on Female Offspring Growth and Insulin and Glucose Dynamics. (2011)

The intrauterine environment has a profound effect on fetal growth and subsequent risk of developing chronic disease postnatally. Maternal under- and over-nutrition alter fetal growth, with subsequent altered phenotype in postnatal offspring. A course of synthetic glucocorticoids (sGC) are routinely administered to women in risk of preterm birth to accelerate fetal lung maturation. There are accumulating data indicating that repeated sGC treatments result in fetal growth restriction in humans and multiple animal models. However, the presence of transgenerational effects has not been evaluated in a precocial species. F0 nulliparous ewes of similar age, weight and body condition were bred to a single ram. After natural mating, ewes were fed at NRC recommendations for maintenance and beginning at 0800h on the morning of d 103 of gestation, dexamethasone (Dex) ewes received the first of 4 injections of 2 mg Dex i.m, given 12 h apart, with control (C) ewes receiving saline. Ewes were allowed to lamb naturally. At lambing, F1 newborn female lambs (n = 10 Dex and 12 C) body weights (BW) were recorded and again weekly until 1 month of age and then monthly thereafter. At 22 ± 4 months of age, F1 ewes were naturally mated to a single ram to produce an F2 generation. At birth, BW was recorded for each F2 lamb (n = 9 females per treatment group) and determined again at similar times as the F1 offspring. A randomly chosen subsample of 6 per treatment group female F1 offspring (3 ± 0.5 years of age) and F2 females (~ 0.5 years of age) underwent an intravenous glucose tolerance test (IVGGT). Offspring weights and plasma glucose and insulin were analyzed using SAS. Birth weight was lower (P < 0.05) in both F1 and F2 Dex female offspring compared to C offspring (5.03 ± 0.18 vs 5.59 ± 0.17; 5.72 ± 0.26 vs. 6.62 ± 0.26, F1 and F2 respectively). BW of the F1 Dex animals was less (P < 0.05) than the C offspring from 21 days of age until 12 months of age. In the F2 generation BW was reduced in the Dex F2 offspring from 14 days of age until 5 months of age. Dex F1 ewes were hypoglycemic (P = 0.03) during baseline sampling, however, there was no difference in insulin compared to C F1 ewes (62 ± 3 vs 54 ± 3 mg/dl and 6.6 ± 1.2 vs 7.7 ± 1.2 µIU/mL, respectively). Dex F2 offspring were hyperglycemic (P = 0.04) and tended to be hypoinsulinemic (P = 0.06) during the baseline sampling compared to C F2 offspring (75 ± 2 vs 68 ± 2 mg/dl, and 4.4 ± 0.6 vs 5.8 ± 0.6 µIU/mL, respectively). The F1 female offspring had increased (P < 0.01) plasma glucose and decreased (P = 0.04) plasma insulin compared to C offspring during the IVGTT. In the F2 offspring, plasma glucose was increased (P < 0.05) throughout the IVGTT and plasma insulin was decreased (P < 0.05) at 10 to 45 min post glucose infusion. sGC treatment in sheep reduced birth weights and postnatal growth and resulted in hyperglycemia and hypoinsulinemia during IVGTT in female F1 offspring; it further lead to a similar reduction in birth weight and postnatal growth, and alteration in glucose and insulin homeostasis in Female F2 offspring. In conclusion, the negative effects of sGC administration not only affect female offspring but carry over into their female offspring, the F2 generation. Supported in part by NIH INBRE #P20RR016474.