Effect of the natural NRF2 modulators sulforaphane and brusatol on the transcriptome of immortalized bovine mammary cells

Changes during the production cycle of dairy cattle can leave these animals susceptible to oxidative stress and reduced antioxidant health. In particular, the periparturient period, when dairy cows must rapidly adapt to the sudden metabolic demands of lactation, is a period when the production of damaging free radicals can overwhelm the natural antioxidant systems, potentially leading to tissue damage and reduced milk production. Central in protection against free radical damage and antioxidant defense, is the transcription factor NRF2, which activates an array of genes associated with antioxidant functions as well as cell survival. The objective of this study was to evaluate the effect that two natural NRF2 modulators, the NRF2 agonist sulforaphane (SFN) and the antagonist brusatol (BRU) have on the transcriptome of immortalized bovine mammary alveolar cells (MACT) using both RT-qPCR of putative NRF2 target genes, as well as RNA sequencing approaches. Treatment of cells with SFN resulted in the activation of many putative NRF2 target genes and upregulation of genes associated with pathways involved in cell survival, metabolism, and antioxidant function, while suppressing the expression of genes associated with the cellular senescence and DNA repair. In contrast, treatment of cells with BRU resulted in upregulation of genes associated with inflammation, cellular stress, and apoptosis, while suppressing the transcription of genes involved in various metabolic processes. Together, these data indicate that treatment of cells with SFN and BRU may be effective at modulating the NRF2 transcriptional network, but that additional effects associated with cellular stress and metabolism may complicate the effectiveness of these compounds to improve antioxidant health in dairy cattle via nutrigenomic approaches