IMPACT OF FERTILITY-BASED SELECTION ON KEY PHYSIOLOGICAL PATHWAYS THAT CONTROL REPRODUCTION IN DAIRY CATTLE

Our long-term goal is to expand current understanding of biological and physiological mechanisms that control reproduction in cattle, so that better strategies to improve genetic gain and maximize reproductive efficiency can be developed. Incorporation of fertility traits into programs for dairy cattle selection has helped halt a longstanding decline in reproductive performance. Nonetheless, specific biological mechanisms underlying such improvement remain largely unexplored. Considerable effort has been devoted to characterize phenotypes based on relevant reproductive outcomes and identify genomic markers that allow for selection of superior individuals. For instance, daughter pregnancy rate (DPR) measures the percentage of lactating cows that become pregnant every 21 days past the voluntary wait period and heifer conception rate (HCR) is calculated as the proportion of heifers that become pregnant at every service, both of which are of vital importance for economic success of dairy herds. These traits are based on curated epidemiological data representative of a large population of U.S. dairy animals. What remains essentially unknown, however, is how physiological mechanisms that control reproductive function differs among females with different genomic predicted transmitting ability (GPTA) for these traits. Previous studies strongly suggest that expression of behavioral estrus, ovarian responsiveness to gonadotropins, hypothalamic sensitivity to steroid hormones, and insulin-like growth factor (IGF) system are controlled by genetic factors and have been affected by selection practices. More importantly, our preliminary data suggest that selecting towards conception-based traits such as HCR, despite increasing IGF-1 concentrations and pregnancy outcomes, may have unintended consequences on expression of estrus behavior. In times when the dairy industry is under constant scrutiny regarding blanket therapies and use of reproductive hormones, understanding how our selection efforts are shaping endocrine axes and establishment of pregnancy is of utmost importance. There is, therefore, a critical need to understand the physiological mechanisms controlling reproductive outcomes in dairy cattle with different GPTA for fertility traits and elucidate how these processes are altered with onset of lactation. In the absence of such knowledge, it is likely that key interactions among genetic, physiological, and management factors will be overlooked, limiting the progress of animal improvement programs.The overall objective in this proposal is to determine changes related to hypothalamus-pituitary-gonad (HPG) axis, reproductive behavior, and markers of early embryonic development in dairy females with different GPTA values for DPR and HCR. A unique feature of our experimental approach is that responses of interest will be evaluated in the same animals during two very distinct physiological states, namely non-lactating heifers and lactating cows. Our central hypothesis is that improved embryo development and establishment of pregnancy associated with high values for DPR and HCR have distinct underlying mechanisms. Specifically, (1) females with high DPR have greater hypothalamic responsiveness to estradiol's positive feedback and increased ovarian sensitivity to luteinizing hormone (LH), whereas (2) females with high HCR have increased IGF-1 availability. These hypotheses will be evaluated via four specific aims:Objective #1: Determine changes in reproductive behavior and spontaneous ovulatory capacity in Holstein heifers and first lactation cows with different GPTA for DPR and HCR. We hypothesize that heifers and cows with high DPR will have longer and more intense estrus behavior compared with herdmates with low DPR, whereas the opposite will be observed regarding HCR. We anticipate that females with high DPR and HCR are more likely to ovulate spontaneously after estrus.Objective #2: Compare the risk of pregnancy, markers for early embryonic development, and pregnancy loss in Holstein heifers and first lactation cows with different GPTA for DPR and HCR. We hypothesize that females with high DPR and HCR have greater pregnancy risk, increased expression of interferon-stimulated genes and concentrations of pregnancy-specific protein B during early stages of gestation, and smaller incidence of pregnancy loss compared with counterparts with low GPTA values.Objective #3: Determine changes in hormonal profiles and ovarian structures in Holstein heifers with different GPTA for DPR and HCR. We hypothesize that concentrations of progesterone, estradiol, LH pulse frequency, corpus luteum (CL) and follicle growth, and expression of key transcripts in luteal and granulosa cells are greater in heifers with high vs. low DPR, whereas IGF-1 concentrations are greater in heifers with high vs. low HCR.Objective #4: Compare GnRH- and estradiol-induced release of LH in Holstein heifers with different GPTA for DPR and HCR. We anticipate that responsiveness to steroid hormones is a major difference between females with extreme GPTA for fertility traits. Therefore, we anticipate that estradiol-induced LH release but not GnRH-induced LH release is smaller in heifers with low DPR and HCR than in heifers with high GPTA values.This proposal is based on the rationale that reproductive performance is paramount to ensure sustainability of the U.S. dairy herd and that genetic selection practices will undoubtedly shape how reproduction is managed in the near future. Because successful management of reproduction relies on our understanding of biological mechanisms that orchestrate reproductive function, it is vital that we recognize the changes in reproductive biology derived from animal improvement programs as we select for superior individuals based on fertility. For instance, our preliminary results indicate that increasing focus on traits associated with insemination risk and pregnancy establishment improves estrus expression, whereas focus on traits associated with conception only may unintendedly impair estrus expression. Upon conclusion of these studies, we will have determined the main physiological mechanisms underlying the differences in reproductive performance associated with genetic merit for fertility traits extensively used by U.S. dairy producers. Our expected outcomes will generate novel information on reproductive biology of modern dairy cattle and elucidate biological consequences of genetic selection based on DPR and HCR. Furthermore, these results will have immediate impact on management practices. Characterizing specific changes in reproductive behavior that are controlled genetically will allow dairymen to fine-tune estrus detection systems for increased efficiency and accuracy. Identifying low-fertility cohorts based on genomic information will also allow for implementation of targeted fertility programs - a strategy that will reduce management costs and diminish public scrutiny over blanket use of reproductive hormones in commercial U.S. dairies.