Bardoxolone methyl modulates Nrf2/NF-𝜅B signaling in turkey uterovaginal junction organoids with potential use for improving reproductive longevity in breeder hens

Turkey production faces significant challenges in maintaining breeder flock fertility, due in part to increased inflammation and accelerated reproductive aging in the distal reproductive tract. These conditions are associated with chronic oxidative stress and compromised cellular function. Activation of the antioxidant nuclear factor erythroid 2-related factor 2 (Nrf2), and inhibition of the pro-inflammatory nuclear factor kappa B (NF-κB) may ameliorate these conditions. This approach remains unexplored in avian reproductive tissues, which possess distinct metabolic and physiological profiles from mammals. This study was designed to investigate the effects of Nrf2/NF-κB modulation in turkey reproductive cells using the Nrf2 activator, bardoxolone methyl (BM), in vitro and further evaluate the effects of this antioxidant in vivo. Turkey uterovaginal junction (UVJ) organoids were treated with BM and exposed to oxidant hydrogen peroxide. Treatment with 0.5 μM BM increased viability, reduced Reactive Oxygen Species production, and inhibited nuclear translocation of NF-𝜅B. Furthermore, BM promoted Nrf2 nuclear accumulation and upregulated antioxidant markers, including heme oxygenase 1 and thioredoxin reductase 1. Short-term treatment with BM in breeder hens did not adversely affect body weight, egg production, or reproductive immune cell localization. Transcriptomic analysis of vaginal tissues revealed downregulation of Oxidative Phosphorylation and inflammatory markers, including secreted phosphoprotein 1. In the UVJ, reduced redox-sensitive transcripts suggested lowered baseline physiological stress. Direct exposure of turkey spermatozoa to BM did not impair viability, morphology, or motility. These findings suggest that targeting the turkey antioxidant response via the Nrf2/NF-κB axis may serve as a safe potential strategy for enhancing reproductive longevity.