Stress during pregnancy alters hepatic renin-angiotensin system and redox homeostasis in a sex- and age-specific manner.

The hypothesis of the development and origin of health and disease (DOHaD) highlights the relationship between exposure to harmful stimuli during pregnancy and the increased cardiometabolic risk in the offspring's adulthood. It is believed that the renin-angiotensin system (RAS) plays a central role in stress-induced hepatic programming. To determine the effects of prenatal stress, sex, and age on hepatic RAS of the offspring, pregnant Wistar rats were divided into control and stress groups. The unpredictable stress protocol was performed in the last week of pregnancy. The offspring were divided according to sex, age, and intervention. At 90 and 120 days, the offspring's blood and liver were collected to measure hepatic enzyme activity, isoprostane levels, and protein expression of the RAS and redox balance. At 90 days old, stress similarly reduced NOX4 in both sexes, whereas NOX2, NOX2/NOX4 ratio, and isoprostane were increased only in female offspring. Stress responses of NOX2 were still higher in females when compared with males. At 120 days, prenatal stress increased the activity of aspartate transaminase (AST) and alanine transaminase (ALT) in females, whereas it decreased AST in males. Furthermore, stress enhances the expression of angiotensin II type 1 receptor, ACE, and Mas receptor in males, whereas reducing NOX2/NOX4 ratio. Still, stress reduced ACE2 expression and continued to increase NOX2/NOX4 ratio in females at 120 days. Prenatal stress induces hepatic programming in offspring in a sex- and age-specific way, altering the RAS and NOX4 pathways at 120-day-old males while inducing early redox changes in females at 90 days and remaining at 120 days.NEW & NOTEWORTHY Prenatal stress may contribute to sex- and age-specific programming of the liver in adult offspring. Our results showed that stress during pregnancy alters the hepatic renin-angiotensin system only at 120-days old and specially in male offspring. Furthermore, the prenatal stress leads to redox imbalances in females at 90 days and remaining at 120 days old independently of the renin-angiotensin system.