The intergenerational consequences of fetal programming

• Main Author: Drake, Amanda J.
• Published: University of Edinburgh 2004
• Subjects: 618.92
• Online Access: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.649710

One proposed mechanism to explain the early life origins of disease is fetal overexposure to glucocorticoids. We have explored intergenerational effects in the dexamethasone-programmed rat, a model of fetal programming in which <i>in utero</i> exposure to excess glucocorticoid results in low birth weight offspring, which develop glucose intolerance in adulthood, thought to be secondary to an increase in the activity of a key gluconeogenic enzyme, phosphoenolpyruvate carboxykinase (PEPCK). Using this model we have demonstrated programming effects in a second generation of animals, which also showed reduced birth weight, elevated PEPCK and glucose intolerance; effects which had resolved by the third generation. Although the persistence of such programming effects in subsequent generations may be secondary to programmed alterations in maternal physiology, resulting in an adverse environment for the developing fetus, we also demonstrate a clear effect of paternal phenotype on offspring birth weight and PEPCK, suggesting that the father also has an effect on the intergenerational transfer of disease risk. The association between low birth weight and later disease is amplified by the development of obesity in humans and in animal models of maternal undernutrition. We have developed a model of high fat feeding in Wistar rats and used this to explore the effect of obesity in the dexamethasone-programmed rat. After 20 weeks on a high fat diet, there were no differences in body weight and insulin resistance between rats exposed to dexamethasone <i>in utero</i> and control animals; however there was a marked increase in hepatic triglyceride content in the programmed group. These observations demonstrate intergenerational effects of fetal programming by flucocorticoids, which cannot be explained entirely by the exposure of the fetus to a programmed adverse maternal environment and indicate the potential importance of epigenetic factors in the intergenerational inheritance of the ‘programming effect’.