HPA axis programming by maternal undernutrition in the male rat offspring

SummaryEpidemiological and experimental studies have demonstrated that perinatal alterations such as maternal undernutrition are frequently associated with the onset of several chronic adult diseases. Although the physiological mechanisms involved in this “fetal programming” remain largely unknown, it has been shown that early exposure to undernutrition programs hypothalamic–pituitary–adrenal (HPA) axis throughout lifespan. However, the wide spectrum of experimental paradigms used (species, sex, age of the animals, and duration and severity of undernutrition exposure) has given rise to variable results that are difficult to interpret. To circumvent this problem, we used the same experimental protocol of maternal food restriction to study the effects of a severe maternal undernutrition on the HPA axis activity in the male rat offspring throughout the life, namely from fetal stage to adulthood. Mothers exposed to food restriction received 50% (FR50) of the daily intake of pregnant dams during the last week of gestation and lactation. In FR50 fetuses, HPA axis function was reduced and associated with a decreased placental 11β-HSD2 activity and a greater transplacental transfer of glucocorticoids. At weaning, maternal food restriction reduced HPA axis activity in response to an ether inhalation stress. In young adults (4-month-old), only fine HPA axis alterations were observed, whereas in older ones (8-month-old), maternal undernutrition was associated with chronic hyperactivity of this neuroendocrine axis. Interestingly, excessive glucocorticoids production is observed in a growing number of pathologies such as metabolic, cognitive, immune and inflammatory diseases, suggesting that they could, at least in part, result from fetal undernutrition and thus have a neurodevelopmental origin.