Prenatal Exposure to Interleukin-6 Results in Hypertension and Increased Hypothalamic-Pituitary-Adrenal Axis Activity in Adult Rats

Abstract

During pregnancy, systemic inflammatory responses induce cytokines that may stress the fetus and contribute to cardiovascular and neuroendocrine dysfunction in adulthood. We evaluated the effects of early and late prenatal exposure to IL-6 on mean systolic arterial pressure (MSAP) and hypothalamic-pituitary-adrenal (HPA) axis regulation in male and female rats at 5-24 wk of age. MSAP and ACTH and corticosterone levels were measured basally and in response to a novel environment, immobilization stress, and stimulation with corticotropin-releasing factor (CRF) and ACTH. In addition, mRNA expression and protein levels of glucocorticoid receptor, mineralocorticoid receptor, CRF receptor type 1, and CRF were estimated in brain areas thought to mediate central effects of corticosteroids on the HPA axis and on central neuroendocrine regulation of MSAP. Both early and late prenatal IL-6 exposure led to hypertension, which was evident in females at 5 wk of age. In adult rats, basal ACTH and corticosterone levels were elevated, the responses to stress and stimulation tests were of extended duration, and circadian rhythm during the light period was flattened and reversed. Mineralocorticoid receptor and glucocorticoid receptor mRNA expression was reduced in the hippocampus, the CRF level was increased in the hypothalamus, and CRF receptor type 1 mRNA expression was increased in the pituitary. These findings suggest that fetal stress induced by prenatal exposure to IL-6 leads to hypertension and dysregulation of HPA axis activity during adulthood.

Prenatal high-salt diet in the Sprague-Dawley rat programs blood pressure and heart rate hyperresponsiveness to stress in adult female offspring

“…Lard feeding during pregnancy has been reported to produce hypertension in female offspring, but not male offspring (21). Prenatal administration of interleukin-6 (IL-6) programmed hypertension in both male and female offspring, but the effect occurred earlier in the females (33). Likewise, fetal programming of the cardiovascular response to stress has been reported to be sexually dimorphic.…”

“…Adult female offspring of mothers subjected to prenatal stress showed an enhanced pressor response to one-time restraint compared with their male counterparts (17). Prenatal administration of IL-6 also produced a greater pressor response in females (33). In humans, low-birth weight adult females were shown to have an enhanced pressor response to psychological stress compared with males (42).…”

Maternal influences on epigenetic programming of the developing hypothalamic‐pituitary‐adrenal axis

“…Animals prenatally exposed to maternal stress, high fat diet, or both were obese and showed impaired glucose tolerance as adults (Tamashiro et al, 2009). Further, induction of a systemic inflammatory response by IL-6 exposure during pregnancy increased maternal CORT and ACTH 4 hours after exposure; offspring were hypertensive and had altered stress reactivity as adults (Samuelsson et al, 2004).…”

33. Longitudinal changes in serum proinflammatory markers across pregnancy and postpartum: Effects of maternal body mass index

“…IL-6 is a key cytokine associated with adverse perinatal health outcomes [39][40][41][42][43][44]. Notably, IL-6 is secreted by adipose tissue [35].…”