Effect of natural pre-luteolytic prostaglandin F2a pulses on the bovine luteal transcriptome during spontaneous luteal regression

Authors: MEZERA, MEGAN - University Of Wisconsin; Li, Wenli; LIU, LIHE - University Of Wisconsin; MEIDAN, RINA - Hebrew University Of Jerusalem; PENAGARICANO, FRANCISCO - University Of Wisconsin; WILTBANK, MILO - University Of Wisconsin

Submitted to: Biology of Reproduction
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 6/20/2021
Publication Date: 6/25/2021
Citation: Mezera, M., Li, W., Liu, L., Meidan, R., Penagaricano, F., Wiltbank, M. 2021. Effect of natural pre-luteolytic prostaglandin F2a pulses on the bovine luteal transcriptome during spontaneous luteal regression. Biology of Reproduction. 104(5):1016-1029. https://doi.org/10.1093/biolre/ioab123.
DOI: https://doi.org/10.1093/biolre/ioab123

Interpretive Summary: Luteal regression is the structural and functional degradation of the corpus luteum (CL). In cattle, timely and complete CL regression is vital to continued reproductive cycling since it provides another opportunity for conception, while incomplete regression may cause decreased fertility. CL regression is initiated by uterine-derived prostaglandin F2alpha (PGF). Though the PGF pulses secreted during spontaneous CL regression is well-documented, it's not clear what, if any, role these early PGF pulses have during early physiologic regression. Additionally, significant variation in the timing of onset of CL regression among animals makes the early regression a particularly difficult period to study since it’s hard to find a specific time point to sample all animals that are at the same stage of regression. The objective of this study is to investigate the potential physiological roles of early stage PGF pulses in the process of a complete spontaneous CL regression. In this study, we first performed bi-hourly blood sampling to measure the PGF metabolite, which was used to confidently categorize the adult dairy cattle into early or late regression groups. We then employed a whole transcriptome RNA sequencing approach to study the transcriptomic impact of these small PGF pulses using CL biopsies collected from these two groups throughout natural CL regression. Our study provided the earliest characterization of the effect of small pulses of PGF on the CL transcriptome during spontaneous luteal regression. Such knowledge enabled us to devise a speculative model of the effects of early pulses of PGF, in which the small PGF pulses were necessary during the very early stages of CL regression to make the CL more susceptible to cell death required for subsequent spontaneous CL regression.

Technical Abstract: The pulsatile pattern of prostaglandin F2alpha (PGF) secretion during spontaneous luteolysis is well-documented, with multiple pulses of exogenous PGF necessary to induce regression using physiologic concentrations of PGF. However, during spontaneous regression, the earliest pulses of PGF are small and not associated with detectable changes in circulating progesterone (P4), bringing into question what, if any, role these early, subluteolytic PGF pulses have during physiologic regression. To investigate the effect of small PGF pulses, luteal biopsies were collected throughout natural luteolysis in conjunction with bihourly blood samples to determine circulating P4 and PGF metabolite to retrospectively assign biopsies to early and later regression. Whole transcriptome analysis was conducted on corpus luteum (CL) biopsies. Early PGF pulses altered the luteal transcriptome, inducing differential expression of 210 genes (Q<0.05) during early regression, compared to 4615 differentially expressed genes during later regression. In early regression, few of these differentially expressed genes were directly associated with luteolysis, rather there were changes in local steroid and glutathione metabolism. Most (94%) differentially expressed genes from early regression were also differentially expressed during later regression, with 98% of these continuing to be altered in the same direction compared to CL at a similar stage of the cycle that had not yet been exposed to PGF. Thus, early, subluteolytic PGF pulses impact the luteal transcriptome, though not by altering steroidogenesis or causing direct inhibition of cellular function. Rather, small pulses alter pathways resulting in removal of cellular support systems, which may sensitize the CL to later pulses of PGF.