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~10D) SPACE FLIGHT-DISRUPTED OVARIAN FUNCTION IS DUE TO A DIRECT EFFECT AT THE OVARIAN LEVEL. THE WORKING HYPOTHESIS, BASED ON OUR PRELIMINARY DATA IS THAT DISRUPTED OVARIAN FUNCTION IS DUE TO A FAILURE OF THE PERIOVULATORY FOLLICLE TO OVULATE AND FORM A FUNCTIONAL CORPUS LUTEUM. TO TEST THIS HYPOTHESIS, MICE WILL UNDERGO A TIMED FOLLICULAR STIMULATION PROTOCOL FOLLOWED BY EVALUATION OF ESTABLISHED TEMPORALLY EXPRESSED OVARIAN MARKERS, OVULATION, AND LUTEAL DEVELOPMENT. THIS STUDY WILL FOR THE FIRST TIME DETERMINE IF SPACE INDUCED LOSS OF OVARIAN FUNCTION IS DUE TO AN INTRINSIC OVARIAN DEFECT OR IS A PROBLEM WITH HYPOTHALAMIC/ PITUITARY SUPPORT. AIM 2. DETERMINE IF ADULT FEMALE MICE RECOVER OVARIAN FUNCTION DURING EXTENDED (~60D) FLIGHT TIME. CURRENTLY, IT IS UNKNOWN WHETHER FEMALES WILL RECOVER FERTILITY FOLLOWING LONG-TERM (I.E., ~60D) ACCLIMATION TO SPACE FLIGHT, OR WILL THEY REMAIN INFERTILE OR EXHIBIT MORE PRONOUNCED DEFECTS IN OVARIAN/UTERINE FUNCTION. TO ADDRESS THIS QUESTION, MICE WILL UNDERGO A SIMILAR FOLLICULAR STIMULATION AND OVULATORY PROTOCOL IN FLIGHT BUT AFTER ~60D, AS DESCRIBED IN AIM 1, AND FERTILITY AND TISSUE BIOMARKERS WILL BE EVALUATED. AIM 3. DETERMINE IF ADULT FEMALE MICE EXPOSED TO SPACE FLIGHT ARE FERTILE UPON RETURN TO EARTH. THE WORKING HYPOTHESIS FOR THIS AIM IS THAT UPON RETURN TO EARTH, FERTILITY WILL RETURN. TO TEST THIS HYPOTHESIS, FLIGHT MICE WILL BE EXPOSED TO MALE MICE DURING A RECOVERY PERIOD UPON RETURN TO EARTH, AND REGAIN OF MATING REPRODUCTIVE BEHAVIOR, ESTROUS CYCLICITY, EARLY EMBRYO IMPLANTATION, AND HEALTH AND DEVELOPMENT OF F1 OFFSPRING WILL BE EVALUATED. THESE STUDIES WILL PROVIDE THE FIRST EVER EXAMINATION OF LONG-TERM SPACE EXPOSURE ON THE FEMALE REPRODUCTIVE BEHAVIOR/PHYSIOLOGY, AND GERM-LINE STABILITY. IN ALL 3 SPECIFIC AIMS, COLLECTION OF UTERINE AND BONE (FEMUR) TISSUES WILL ALLOW US TO ADDRESS OUR SECONDARY HYPOTHESIS BY DETERMINING LONG-TERM SPACE FLIGHT EFFECTS ON ESTROGEN RECEPTOR EXPRESSION. ULTIMATELY, FINDINGS OF THE PROPOSED STUDIES WILL PROVIDE CRITICAL FOUNDATIONAL DATA TO SUPPORT MULTIGENERATIONAL MAMMALIAN STUDIES IN SPA