Hesperetin Activated SIRT1 Neutralizes Cadmium Effects on the Early Bovine Embryo Development

Cadmium (Cd) is a major environmental contaminant that has been linked to oocyte quality reduction and early embryo mortality in various in vivo studies. In this study, we investigated the mechanism of Cd-induced mitochondrial toxicity in bovine in vitro matured oocytes, primary cultured bovine cumulus cells, and in vitro developed bovine embryos. Cd significantly reduced PPARGC1A (PGC-1α) and nuclear respiratory factors, which leads to mitochondrial damage and hence reduction in oocyte maturation and embryo development. NAD-dependent deacetylase sirtuin-1 (SIRT1) is the upstream marker of PGC-1α and nuclear respiratory factors, and its activation significantly mitigated Cd-induced mitochondrial damage. For SIRT1 activation, we used Hesperetin (Hsp), a citrus flavonoid and a potent activator of SIRT1. The molecular docking approach was used to investigate the binding of hesperetin to bovine SIRT1, which revealed that hesperetin creates polar and non-polar interactions with residues that are reported essential for the activation of SIRT1. Furthermore, the SIRT1 enzymatic activity was measured in primary cultured bovine granulosa cells after hesperetin treatment. To further confirm the SIRT1-dependent effects of hesperetin we used a specific inhibitor of SIRT1 (EX527), which significantly (p < 0.05) reduced the effects of hesperetin on embryo mitochondria. Next, we treated hesperetin and Cd to early bovine embryos and discovered a significant (p 0.05) increase in PGC-1, NRF1, and NFE2L2 protein expression as well as embryo development recovery. Thus, we came to the conclusion that hesperetin can activate PGC-1 and nuclear respiratory factors via SIRT1, which can greatly reduce Cd-induced mitochondrial toxicity and promote mitochondrial biogenesis in early bovine embryos.