Prenatal Glucocorticoid Exposure Modifies Endocrine Function and Behaviour for 3 Generations Following Maternal and Paternal Transmission

Abstract

Fetal exposure to high levels of glucocorticoids programs long-term changes in the physiologic stress response and behaviours. However, it is not known whether effects manifest in subsequent generations of offspring following maternal (MT) or paternal (PT) transmission. We treated pregnant guinea pigs with three courses of saline or synthetic glucocorticoid (sGC) at a clinically relevant dose. Altered cortisol response to stress and behaviours transmitted to juvenile female and male F2 and F3 offspring from both parental lines. Behavioural effects of sGC in F1-F3 PT females associated with altered expression of genes in the prefrontal cortex and hypothalamic paraventricular nucleus (PVN). Exposure to sGC programmed large transgenerational changes in PVN gene expression, including type II diabetes, thermoregulation, and collagen formation gene networks. We demonstrate transgenerational programming to F3 following antenatal sGC. Transmission is sex- and generation-dependent, occurring through both parental lines. Paternal transmission to F3 females strongly implicates epigenetic mechanisms of transmission.

Prenatal programming of stress responsiveness and behaviours: Progress and perspectives

“…53 In a more recent study, prenatal treatment in early gestation resulted in decreased basal cortisol in females. 55 Multiple courses of prenatal sGC reduced HPA responsiveness in male juvenile 56 and adult offspring. A single course of prenatal sGC treatment in late gestation increased basal cortisol in juvenile male offspring but reduced HPA responsiveness in females.…”

“…54 Guinea pigs are relatively glucocorticoid resistant and have a longer gestation compared to rats and mice. 56 In adult female offspring, prenatal sGC exposure resulted in reduced basal HPA activity, although this effect was confined to the luteal phase of the reproductive cycle. 55 Multiple courses of prenatal sGC reduced HPA responsiveness in male juvenile 56 and adult offspring.…”

“…48,49 Interestingly, the anxiety-like behaviour was not observed after cross-fostering. 56 Relatively few studies have considered the impact of sGC on brain structure in humans. 56 Relatively few studies have considered the impact of sGC on brain structure in humans.…”

“…Although transgenerational effects of sGC exposure during pregnancy on behaviours have been reported, 56 the mechanisms involved are less clear. In a recent study, prenatal sGC treatment of pregnant rats resulted in reduced birthweight in F 1 and F 2 offspring.…”

“…Corticosterone treatment of adult male mice resulted in F 1 and F 2 male offspring that exhibited increased anxiety-associated behaviours; effects were not observed in female offspring 95. Furthermore, a recent study in guinea pigs demonstrated that prenatal sGC treatment in late gestation (F 0 ) resulted in increased adrenocortical responsiveness in F 1 and F 2 juvenile female offspring, and F 3 adult males, as well as hyperactivity in F 1 , F 2 and F 3 juvenile females, following paternal transmission 56. Furthermore, a recent study in guinea pigs demonstrated that prenatal sGC treatment in late gestation (F 0 ) resulted in increased adrenocortical responsiveness in F 1 and F 2 juvenile female offspring, and F 3 adult males, as well as hyperactivity in F 1 , F 2 and F 3 juvenile females, following paternal transmission 56.…”