Expression and role of SIRT1 and SIRT6 in porcine conceptus and trophoblasts: relevance to early placenta development†.

Abstract

Placenta insufficiency, arising from impaired trophoblast (Tr) function, contributes to early embryo loss and fetal growth restriction. Sirtuin (SIRT) 1 and SIRT6 are redox modulators in early embryonic development, yet their roles in porcine Tr remain unclear. This study examined the expression and roles of SIRT1/6 in porcine Tr during early pregnancy. Conceptus and Tr tissues from days 12 to 30 pregnant gilts were analyzed for SIRT1/6 expression. Then, day-15 Tr cells were treated with SIRT1/6 modulators to assess gene expression, cell viability, cell-cycle proteins, cell adhesion, cytokine synthesis, and reactive oxygen species (ROS) generation under control and hydrogen peroxide (H2O2)-induced oxidative stress. SIRT1 mRNA expression increased with placenta development (days 15-30 of gestation), while its protein levels remained unchanged. SIRT6 protein abundance was greater during implantation (day-15 conceptuses) and at placentation onset (day-20 Tr) compared with day-30 Tr. SIRT1 activation stimulated mRNA expression of mitochondrial biogenesis regulators (NFE2L2, TFAM) and respiratory chain components (MT-ND1-2, MT-ATP6/8). The SIRT6 activator induced NRF1, TFAM, and all 13 mitochondrial respiratory subunit genes (MT-ND1-6, MT-CYB, MT-CO1-3, MT-ATP6/8). Both activators stimulated cell proliferation, possibly by shortening mitosis as evidenced by reduced phospho-H3-S10 levels. IL6 synthesis was upregulated, while IFNγ production was decreased in these cells. SIRT6 activation counteracted H2O2-induced oxidative stress, reducing ROS and supporting cell viability, while amplifying stress-induced mitochondrial pathways. In conclusion, SIRT1/6 may support porcine Tr development and function. SIRT6 appears to modulate the response of peri-implantation conceptuses to oxidative stress, suggesting its potential as a target for improving prenatal survival.