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

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, phosphoenolpyruvate 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.

Sex-specific, male-line transgenerational responses in humans

“…8 In rats paternal dexamethasone exposure in utero led to both a reduced birth weight and increased hepatic activity of the gluconeogenic enzyme, phosphoenolpyruvate carboxykinase, in future offspring. 19 Beyond studies of mutagenic agents, 20 we are not aware of any general male-line transgenerational studies in humans. This probably stems from two factors; residual scepticism 21 about the germline's susceptibility to environmentally-induced change and epigenetic inheritance (with its hint of Lamarkism), and the fact that human transgenerational studies are fraught with problems.…”

Sexual dimorphism in environmental epigenetic programming

“…Prenatal exposure to dexamethasone of males mated with control females lowered birth weight in their progeny of either sex. However when dexamethasone-prenatally exposed female rats were mated with control males only the male part of the offspring was affected [62].…”

“…In addition to these malprogramming epigenetic somatic processes there are now also clear examples of transmission through the germline for both sexes, with sex-specific effects [62][63][64].…”

Exposure to undernutrition in fetal life determines fat distribution, locomotor activity and food intake in ageing rats

“…The early period (days 0-7) corresponds to the embryonic phase of development in the rat and in fact embryos only implant at around day 4.5. 7 The mid-gestation period (days [8][9][10][11][12][13][14] largely corresponds to the period of organogenesis, while late gestation (days [15][16][17][18][19][20][21][22] is the period of most rapid growth and differentiation of key structures. By feeding at these targeted periods, it is possible to identify when nutritional programming occurs and this can provide important indicators of potential mechanisms.…”

“…A large number of studies in rats, mice, guinea pigs and sheep have clearly shown that exposure to relatively short periods of undernutrition or endocrine disturbance in fetal life can programme raised blood pressure, glucose intolerance and insulin resistance. [7][8][9] The range of nutritional exposures capable of eliciting programmed responses in the developing offspring is broad, including micronutrient deficiency, [10][11][12] excess of saturated fat 13 and restriction of food intake (global nutrient restriction). 14,15 In the present paper, we report findings from a model of low protein feeding in rat pregnancy.…”