Genetic control of fertility and embryonic waste in the mouse: A role for angiotensinogen

The purpose of this study was to evaluate the impact of angiotensinogen gen e (Agt) deficiency on reproductive fitness in a rodent model. Mice with 0 ( Agt(-/-)), 1 (Agt(-/+)), and 2 (Agt(+/+)) copies of Agt were bred according to the following schemes: 1) Agt(-/-) X Agt(-/-), 2) Agt(-/+) X Agt(-/+), 3) Agt(+/+) X Agt(+/+), and 4) Agt(+/+) female X Ag-/+ male. There were 4 b reeding pairs per scheme. Breedings were time mated. Mice and litters were weighed daily. Southern blotting was used for genotyping. We found that Agt (-/-) breeding pairs had fewer litters (2 [range 1-2] vs. 4 [range 3-5]; P = 0.01), fewer pups per litter (4 [range 1-7] vs. 6 [range 1-10]; P = 0.006 ), and longer interpregnancy intervals (43 days [range 31-44] vs. 35.5 days [range 22-58]; P = 0.04) compared to wild-type controls. The ratio of post coital plugs to subsequent litters was 4.0 and 1.2 for Agt(-/-) and Agt(+/) breedings, respectively (P = 0.03). Median maternal weights during all tr imesters of pregnancy were significantly lower for Agt-deficient mice compa red to wild-type controls. Among Agt(-/+) X Agt(-/+) breedings, the proport ions of Agt(+/+) (n = 17), Agt(-/+) (n = 38), and Agt(-/-) (n = 4) offsprin g differed significantly from the expected 1:2:1 Mendelian inheritance patt ern (P = 0.03). Neonatal survival among the offspring derived from the Agt( -/-) X Agt(-/-) breeding scheme was significantly reduced (P = 0.001). We c onclude that Agt deficiency is associated with an in utero lethal effect, d ecreased fertility, and impaired neonatal survival.