Adrenal, metabolic and cardio‐renal dysfunction develops after pregnancy in rats born small or stressed by physiological measurements during pregnancy

Jean N. Cheong, James S. M. Cuffe, Andrew J. Jefferies, Karen M. Moritz, Mary E. Wlodek

Women born small are at an increased risk of developing pregnancy complications. Stress may further increase a woman's likelihood for an adverse pregnancy. Adverse pregnancy adaptations can lead to long-term diseases even after her pregnancy. The current study investigated the effects of stress during pregnancy on the long-term adrenal, metabolic and cardio-renal health of female rats that were born small. Stress programmed increased adrenal Mc2r gene expression, a higher insulin secretory response to glucose during intraperitoneal glucose tolerance test (+36%) and elevated renal creatinine clearance after pregnancy. Females that were born small had increased homeostatic model assessment-insulin resistance and elevated systolic blood pressure after pregnancy, regardless of stress exposure. These findings suggest that being born small or being stressed during pregnancy programs long-term adverse health outcomes after pregnancy. However, stress in pregnancy does not exacerbate the long-term adverse health outcomes for females that were born small. Females born small are more likely to experience complications during their pregnancy, including pregnancy-induced hypertension, pre-eclampsia and gestational diabetes. The risk of developing complications is increased by stress exposure during pregnancy. In addition, pregnancy complications may predispose the mother to diseases after pregnancy. We determined whether stress during pregnancy would exacerbate the adrenal, metabolic and cardio-renal dysfunction of growth-restricted females in later life. Late gestation bilateral uterine vessel ligation was performed in Wistar Kyoto rats to induce growth restriction. At 4 months, growth-restricted and control female offspring were mated with normal males. Those allocated to the stressed group had physiological measurements [metabolic cage, tail cuff blood pressure, intraperitoneal glucose tolerance test (IPGTT)] conducted during pregnancy whilst the unstressed groups were unhandled. After the completion of pregnancy, dams were aged to 12 months and blood pressure, and metabolic and renal function were assessed. At 13 months, adrenal glands, pancreases and plasma were collected at post-mortem. Females stressed during pregnancy had increased adrenal Mc2r gene expression (+22%), higher insulin secretory response to glucose during IPGTT (+36%) and higher creatinine clearance (+29%, indicating increased estimated glomerular filtration rate). In contrast, females that were born small had increased homeostatic model assessment-insulin resistance (+54%), increased water intake (+23%), urine output (+44%) and elevated systolic blood pressure (+7%) regardless of exposure to stress. Our findings suggest that low maternal birth weight and maternal stress exposure during pregnancy are both independently detrimental for long-term adrenal, metabolic and cardio-renal health of the mother, although their effects were not exacerbated.