Transgenerational effects of prenatal nutrient restriction on cardiovascular and hypothalamic-pituitary-adrenal function

Abstract

The perinatal environment is a powerful determinant of risk for developing disease in later life. Here, we have shown that maternal undernutrition causes dramatic changes in heart structure and hypothalamo-pituitary-adrenal (HPA) function across two generations. Pregnant guinea pigs were fed 70% of normal intake from gestational days 1-35 (early restriction; ER), or 36-70 (late restriction; LR). Female offspring (F(1)) were mated and fed ad libitum to create second generation (F(2)) offspring. Heart morphology, blood pressure, baroreceptor and HPA function were assessed in male F(1) and F(2) offspring. ER(F1) males exhibited elevated blood pressure, increased left ventricular (LV) wall thickness and LV mass. These LV effects were maintained in the ER(F2) offspring. Maternal undernutrition increased basal cortisol and altered HPA responsiveness to challenge in both generations; effects were greatest in LR groups. In conclusion, moderate maternal undernutrition profoundly modifies heart structure and HPA function in adult male offspring for two generations.

Figure 1. Birth weight and growth

Animal weights at birth and at 21 and 40 days (mean ±s.e.m.) in F₁ females (A) and at birth and 21, 40 and 90 days of age in F₁ male (B), F₂ female (C) and F₂ male (D) offspring born to control mothers (male F₁n = 9, F₂n = 9; female F₁n = 10, F₂n = 10) or mothers that had been nutritionally restricted (30%) during early (ER; gestational days 1–35; male F₁n = 18, F₂n = 10; female F₁n = 15, F₂n = 7) or late (LR; gestational days 36–70; male F₁n = 18, F₂n = 22; female F₁n = 22, F₂n = 18) pregnancy. *P < 0.05, **P < 0.01 denote significant differences compared with controls. N/A, data not available as F₁ females were mated after day 40.

Figure 2. Cardiovascular function

A, mean arterial pressure (mean ±s.e.m.) in adult F₁ and F₂ male offspring whose mothers (F₁) or grandmothers (F₂) had been subjected to 30% reduction in total food intake during early (ER; black bars; F₁n = 7, F₂n = 6) or late (LR; grey bars; F₁n = 8, F₂n = 6) pregnancy or in offspring from control mothers (C; white bars; F₁n = 8, F₂n = 6). Echocardiography: interventricular septal wall thickness, anterior left ventricular wall thickness and mean left ventricular (LV) wall thickness (mean ±s.e.m.) in adult F₁ (B) and F₂ (C) male offspring in the same groups of animals. *P < 0.05, **P < 0.01 denote significant differences compared with controls of same generation.

Figure 3. Basal HPA function

ACTH (A and B) and cortisol (C and D) concentrations (mean ±s.e.m.) in adult F₁ and F₂ male offspring whose mothers or grandmothers had been subjected to 30% reduction in total food intake during early (ER; gestational days 1–35; F₁n = 7, F₂n = 6) or late (LR; gestational days 36–70; F₁n = 8, F₂n = 6) pregnancy or in controls (C; F₁n = 8, F₂n = 6). **P < 0.01 denotes significant differences compared with controls of same generation.

Figure 4. Dexamethasone suppression and corticotrophin-releasing hormone challenge (ACTH)

Plasma ACTH concentrations (mean ±s.e.m.) following dexamethasone (DEX, 1 mg kg⁻¹) and corticotrophin-releasing hormone (CRH, 0.5 μg kg⁻¹) challenge in adult male offspring whose mothers (A, F₁) or grandmothers (B, F₂) had been subjected to 30% reduction in total food intake during early (ER; gestational days 1–35; F₁n = 7, F₂n = 6) or late (LR; gestational days 36–70; F₁n = 8, F₂n = 6) pregnancy or in controls (C; F₁n = 8, F₂n = 6). **P < 0.01 denotes significant differences compared with controls of the same generation. Histograms represent net area above the curve (AAC) of plasma ACTH concentrations after suppression by DEX and incremental area under the curve (AUC) plasma ACTH after activation with CRH.

Figure 5. Dexamethasone suppression and corticotrophin-releasing hormone challenge (cortisol)

Plasma cortisol concentrations (mean ±s.e.m.) following dexamethasone (DEX, 1 mg kg⁻¹) and corticotrophin-releasing hormone (CRH, 0.5 μg kg⁻¹) challenge in adult male offspring whose mothers (A, F₁) or grandmothers (B, F₂) had been subjected to 30% reduction in total food intake during early (ER; gestational days 1–35; F₁n = 7, F₂n = 6) or late (LR; gestational days 36–70; F₁n = 8, F₂n = 6) pregnancy or in controls (C; F₁n = 8, F₂n = 6). **P < 0.01 denotes significant differences compared with controls of the same generation. Histograms represent net area above the curve (AAC) of plasma cortisol concentrations after suppression by DEX and incremental area under the curve (AUC) plasma cortisol after activation with CRH.