Effects of early- and late-gestational maternal stress and synthetic glucocorticoid on development of the fetal hypothalamus–pituitary–adrenal axis in sheep

Abstract

Prenatal maternal stress (PMS) programs dysregulation of the hypothalamus-pituitary-adrenal axis (HPAA) in postnatal life, though time periods vulnerable to PMS, are still unclear. We evaluated in pregnant sheep the effect of PMS during early gestation [30-100 days of gestation (dGA); term is 150 dGA] or late gestation (100-120 dGA) on development of fetal HPAA function. We compared the effects of endogenous cortisol with synthetic glucocorticoid (GC) exposure, as used clinically to enhance fetal lung maturation. Pregnant sheep were exposed to repeated isolation stress twice per week for 3 h in a separate box with no visual, tactile, or auditory contact with their flock-mates either during early (n = 7) or late (n = 7) gestation. Additional groups received two courses of betamethasone (BM; n = 7; 2 × 110 μg kg(- 1) body weight, 24 h apart) during late gestation (106/107 and 112/113 dGA, n = 7) or acted as controls (n = 7). Fetal cortisol responses to hypotensive challenge, a physiological fetal stressor, were measured at 112 and 129 dGA, i.e. before and during maturation of the HPAA. Hypotension was induced by fetal infusion of sodium nitroprusside, a potent vasodilator. At 112 dGA, neither PMS nor BM altered fetal cortisol responses. PMS, during early or late gestation, and BM treatment increased fetal cortisol responses at 129 dGA with the greatest increase achieved in stressed early pregnant sheep. Thus, development of the HPAA is vulnerable to inappropriate levels of GCs during long periods of fetal life, whereas early gestation is most vulnerable to PMS.

Non-invasive biomarkers of fetal brain development reflecting prenatal stress: An integrative multi-scale multi-species perspective on data collection and analysis

“…Such approach results in acute and chronic stress-induced adaptations and represents the most comprehensive animal experimental model of human fetal stress exposure. (Rakers et al, 2013) Taken together, these results suggest that PS insults are critical in the development of biochemical responses and behavior in adults, and that maternal care is crucial both during pregnancy and in the first weeks of life. (Fontein-Kuipers et al, 2014) (Nolvi et al, 2016) It has been postulated that several psychiatric disorders that manifest themselves in the adult human, such as schizophrenia, depression, anxiety and drug abuse, are imbalances of dopaminergic, glutamatergic and GABAergic systems as a consequence, among other reasons, of alterations in the early development of the corticostriatal pathway.…”

Yenidoğanlarda Fetal Nütrisyonel Durum ve HPA Ekseni İlişkisi

“…In the study conducted by Rakers et al in which the effect of prenatal maternal stress on the HPA axis and fetal cortisol level in the early and late period of pregnancy was evaluated, blood cortisol levels were measured in pregnant mice by exposing them to regular stress in the early and late period of pregnancy (17). Blood cortisol levels were also measured in the same mice following administration of betamethasone which is a synthetic glucocorticoid and is used to induce fetal lung maturation in clinical practice.…”

Role of the hypothalamic–pituitary–adrenal axis in developmental programming of health and disease

“…It is in part for this reason that dexamethasone is extensively used in investigating programming by glucocorticoids. In rat models, the treatment with dexamethasone for the final week of gestation results in elevated basal and stress-induced plasma corticosterone levels in adult male offspring, indicating that HPA function is altered [153,226,257]. …”

“…In sheep, although the HPA axis shows vulnerability to inappropriate levels of glucocorticoids during long periods of fetal life, the early part of gestation appears to be the time of greatest vulnerability to maternal stress [226]. In pregnant rats treated with oral glucocorticoids, the β- and α-cell mass was reduced in the fetus by mechanisms that differed according to the stage of fetal development.…”