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1 Endocrinology Unit, School of Molecular and Clinical Medicine, Molecular Medicine Centre, Western General Hospital, University of Edinburgh, Edinburgh, United Kingdom
* To whom correspondence should be addressed. E-mail: mandy.drake{at}ed.ac.uk.
Epidemiological studies linking low birth weight and subsequent cardio-metabolic disease have given rise to the hypothesis that events in fetal life permanently programme 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 hyperinsulinaemia and hyperglycaemia underpinned by increased activity of the key hepatic gluconeogenic enzyme, phosphoenolpyruvate carboxykinase (PEPCK). We found that the male offspring of female rats which 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 ± 0.06g, p<0.001), glucose intolerance and elevated hepatic PEPCK activity (5.7 ± 0.6 vs. 3.3 ± 0.2 nmol/min/mg protein, 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.
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