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Early pregnancy loss continues to be problematic in the cattle industry. A large proportion of the pregnancy loss occurs during the maternal recognition of pregnancy (MRP) phase of gestation. During the MRP, a developing conceptus must secrete sufficient interferon tau to inhibit release of the uterine- derived and luteolytic mediator, prostaglandin F2 alpha (PGF2𝛼). If successful, the progesterone- secreting corpus luteum (CL) will be maintained, which is necessary for establishment and maintenance of pregnancy. Pregnancy loss at the point of MRP may be due to a slow developing conceptus that does not effectively block PGF2𝛼. Therefore, reducing the influence of PGF2𝛼 on the CL may lengthen the window of time to establish pregnancy. Fish meal (FM) supplementation, rich in the omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), serves as a luteoprotective agent following PGF2𝛼 exposure; an effect we repeated here. However, the mechanistic actions of FM supplementation are not yet apparent. Here, we postulated two mechanisms by which FM supplementation (and components) reduces rates of luteal regression: 1) EPA and DHA protect cells against the cytotoxic effects of TNF𝛼 and IFN𝛾 and (or) 2) FM supplementation maintains luteal blood flow in functional CL 48 hrs following exposure to PGF2𝛼. We found that EPA and DHA did not protect cells from the cytotoxic effects of TNF𝛼 and IFN𝛾 exposure, although omega-3 fatty acids altered transcriptional regulation of necroptotic cell death in cells of an early and middle-stage CL. Moreover, we demonstrated that cells of a middle stage CL are less sensitive to the cytotoxic effects of TNF𝛼 and IFN𝛾, which may be due to reduced expression of TNFRI. Exposure to TNF𝛼 and IFN𝛾 increased expression of TNF𝛼 and NFkB, and reduced expression of steroidogenic genes STARD1 and CYP11A1. With respect to our second postulated mechanism, we found no change in luteal blood flow 48 hrs following PGF2𝛼 exposures, as detected with power Doppler ultrasonography. However, we did find that FM-PGF2𝛼 infused cows had a significant reduction in luteal hyperemia when compared to the control supplementation, indicating FM supplementation may be altering the acute blood flow response. In conclusion, the differing micro-environments of each luteal stage pre-conditions cellular sensitivity to TNF𝛼 and IFN𝛾 exposure. Moreover, FM supplementation may maintain functional CL by blunting the acute changes in luteal blood flow during luteal regression.