EARLY EMBRYO MORTALITY AND FAILURE TO CONCEIVE AT FIRST SERVICE CONTRIBUTES TO SUBFERTILITY COSTING THE DAIRY CATTLE INDUSTRY AN ANNUAL $1.6 BILLION LOSS IN THE UNITED STATES OF AMERICA AND $1.28 TRILLION WORLDWIDE. EMBRYO MORTALITY RATES ARE CURRENTLY 60-70% IN DAIRY COWS, 40-50% IN BEEF COWS AND 30% IN EWES AND ARE CAUSED BY IMPAIRED COMMUNICATION BETWEEN THE EMBRYO AND MOTHER, LEADING TO DEMISE OF THE OVARIAN CORPUS LUTEM (CL) AND A DECLINE IN SERUM PROGESTERONE (P4). THIS DECLINE IN SERUM P4 IS NECESSARY TO SET UP AND PREPARE FOR A NEW OVULATION AND ESTROUS CYCLE. HOWEVER, A DECLINE IN SERUM P4 FROM THE CL ON DAYS 14 TO 18 DURING PREGNANCY CAN ACTUALLY TERMINATE THE PREGNANCY AND CONTRIBUTE TO EARLY EMBRYO MORTALITY. DURING PREGNANCY, INTERFERON-TAU (IFNT) IS RELEASED BY THE CONCEPTUS (EMBRYO AND EXTRAEMBRYONIC MEMBRANES), AND ACTS ON THE UTERINE ENDOMETRIUM THROUGH PARACRINE ACTION TO ALTER ENDOMETRIAL PGF2Α PULSES SO THAT THE CL CONTINUES PRODUCTION OF P4 AND THE EMBRYO SURVIVES. THE EXPERIMENTS DESCRIBED HERE TEST THE HYPOTHESIS THAT IFNT ALSO ACTS DIRECTLY ON THE CL IN ENDOCRINE MECHANISMS TO PROTECT THE CL DURING EARLY PREGNANCY. OSMOTIC PUMPS DELIVERING EITHER BOVINE SERUM ALBUMIN (BSA; CONTROL) OR IFNT WILL BE SURGICALLY INSTALLED IN EWES WITH DELIVERY OF IFNT TO THE CL. USING THIS MODEL, THE CL PRODUCES INTERFERON STIMULATED GENES (ISGS) IN RESPONSE TO IFNT, WHEREAS THE ENDOMETRIUM DOES NOT. THE ABILITY OF EXOGENOUS IFNT TO DIRECTLY PROTECT THE CL WILL BE TESTED IN TWO IN VIVO MODELS. THE FIRST MODEL ENTAILS INSTALLING THESE OSMOTIC PUMPS WITH IFNT DELIVERY DIRECTLY TO THE CL FROM DAY 10 TO 17 OF THE ESTROUS CYCLE TO DETERMINE IF IFNT PROTECTS THE CL FROM THE ENDOGENOUS RELEASE AND LYTIC ACTION OF PGF2Α. SERUM P4 WILL BE MONITORED AS AN INDICATOR OF A FUNCTIONAL CL. THE SECOND MODEL USES OSMOTIC PUMP DELIVERY OF IFNT FROM DAY 9 TO 12 WITH EXOGENOUS PULSES OF PGF2Α DELIVERED STARTING ON DAY 10 USING A PUMP SYSTEM AT 0, 15, 22, 29 AND 36H. SERUM P4 WILL BE MONITORED TWICE PER DAY AND AT 1 H AFTER EACH PULSE OFPGF2Α. CL WILL ALSO BE COLLECTED AT 1 H FOLLOWING PGF2Α PULSES TO PROFILE GENE EXPRESSION. THIS MODEL TESTS WHETHER IFNT CAN PROTECT THE CL AGAINST AN EXOGENOUS DELIVERY OF PULSES OF PGF2Α THAT MIMIC THOSE OBSERVED DURING THE NORMAL ESTROUS CYCLE. THE FINAL MODEL STUDIES IFNT INDUCED GENES USING RT-PCR AND PROTEINS USING MASS SPECTROSCOPY APPROACHES IN THE CL DURING PREGNANCY AND THE ESTROUS CYCLE IN VIVO AND IN RESPONSE TO IFNT TREATMENTS IN VITRO.THE LONGER-TERM GOAL OF THE RESEARCH IS TO IMPROVE PREGNANCY RATES IN RUMINANTS BY UNDERSTANDING BASIC MECHANISMS OF ESTABLISHMENT AND MAINTENANCE OF PREGNANCY. THE UNDERSTANDING OF THESE MECHANISMS WILL LEAD TO DEVELOPMENT OF STRATEGIES TO REDUCE EMBRYO MORTALITY AND TO INCREASE PREGNANCY RATES IN RUMINANTS. PROTECTION OF THE CL WITH THERAPEUTIC IFNT MAY BE CONSIDERED IN FUTURE STUDIES IN CASES OF INFERTILITY SUSPECTED TO BE CAUSED BY LUTEAL INSUFFICIENCY DURING PREGNANCY IN RUMINANTS.

Colorado State University, Fort Collins CO

Investigators