Intergenerational consequences of fetal programming by in utero exposure to glucocorticoids in rats

TLDR

Epidemiological studies linking low birth weight to later cardiometabolic disease suggest fetal life events permanently program cardiovascular risk, and this programming may extend beyond the first generation. The study used a dexamethasone‑programmed rat model where fetal glucocorticoid exposure causes low birth weight and adult hyperinsulinemia/hyperglycemia driven by increased hepatic PEPCK activity. Male offspring of dexamethasone‑exposed rats exhibited reduced birth weight, glucose intolerance, and higher hepatic PEPCK activity, with these effects persisting through several generations via maternal or paternal lines but resolving by the third generation, underscoring epigenetic inheritance of the programming phenotype and its link to cardiovascular risk.

Abstract

Epidemiological studies linking low birth weight and subsequent cardiometabolic disease have given rise to the hypothesis that events in fetal life permanently program subsequent cardiovascular risk. The effects of fetal programming may not be limited to the first-generation offspring. We have explored intergenerational effects in the dexamethasone-programmed rat, a model in which fetal exposure to excess glucocorticoid results in low birth weight with subsequent adult hyperinsulinemia and hyperglycemia underpinned by increased activity of the key hepatic gluconeogenic enzyme, phospho enolpyruvate carboxykinase (PEPCK). We found that the male offspring of female rats that had been exposed prenatally to dexamethasone, but were not manipulated in their own pregnancy, also had reduced birth weight (5.66 ± 0.06 vs. 6.12 ± 0.06 g, P < 0.001), glucose intolerance, and elevated hepatic PEPCK activity (5.7 ± 0.6 vs. 3.3 ± 0.2 nmol·min −1 ·mg protein −1 , P < 0.001). These effects resolved in a third generation. Similar intergenerational programming was observed in offspring of male rats exposed prenatally to dexamethasone mated with control females. The persistence of such programming effects through several generations, transmitted by either maternal or paternal lines, indicates the potential importance of epigenetic factors in the intergenerational inheritance of the “programming phenotype” and provides a basis for the inherited association between low birth weight and cardiovascular risk factors.