We tested the hypothesis that estradiol modifies respiratory control in pregnant rats and participates in the development of respiratory chemoreflexes in fetuses. Pregnant rats (n=12) received daily subcutaneous injections of vehicle (Veh, n=6) or 4 androsten-4-ol-3,17dioneacetate (inhibitor of estradiol synthesis, ATD, n=6 - 5 mg/day in vehicle) from gestational day 16 to delivery. Baseline ventilation (whole body plethysmography) and metabolic rate (VO₂) were determined at gestational days 14 and 20, in pups (3- and 20-day-old, P3 and P20) and in adult rats (P70) born to Veh or ATD treated mothers. Hypoxic chemoreflex was assessed in P3 rats by acute exposure to 60% O₂ and in P20 or P70 rats by moderate hypoxia (12 % O₂ - 30 minutes). ATD treatment reduced circulating E2 in pregnant dams at G20 without producing changes in the circulating level of estradiol precursors (testosterone and androstendione). ATD treated dams showed impaired respiratory adjustment to late gestation. Pups born to ATD mothers had higher resting VO₂ (+23% at P3, +21% at P20), respiratory frequency (+15% at P3, +12% at P20) and minute ventilation (+11% at P3, +18% at P20) than pups from Veh mothers. Respiratory decrease during acute hyperoxic exposure at P3 was -9.7% in Veh (p<0.05 vs. room air) and only -2.6% (p=ns) in ATD pups. In P20 ATD rats, hypoxic ventilatory response was attenuated compared to Veh. In P20 and P70 rats, the drop of VO₂ in hypoxia (-31 % in P70, p<0.0001) was not observed in ATD rats. We conclude that estradiol secreted during late gestation is necessary for respiratory adjustment to pregnancy, and is required for adequate development of respiratory and metabolic control in the offspring.