Gestational arsenite exposure augments hepatic tumors of C3H mice by promoting senescence in F1 and F2 offspring via different pathways

Previous studies showed that gestational arsenite exposure increases incidence of hepatic tumors in the F1 and F2 male offspring in C3H mice. However, the mechanisms are largely unknown. In this study, we focused on whether cellular senescence and the senescence-associated secretory phenotype (SASP) contribute to tumor formation in C3H mice, and whether gestational arsenite exposure augments hepatic tumors through enhancement of cellular senescence. Three senescence markers (p16, p21 and p15) and two SASP factors (Cxcl1 and Mmp14) were increased in hepatic tumor tissues of 74- or 100-weeks-old C3H mice without arsenite exposure, and treatment with a senolytic drug (ABT-263) diminished hepatic tumor formation. Gestational arsenite exposure enhanced the expression of p16, p21 and Mmp14 in F1 and p15 and Cxcl1 in F2, respectively. Exploring the mechanisms by which arsenite exposure promotes cellular senescence, we found that the expression of antioxidant enzymes (Sod1 and Cat) were reduced in the tumors of F1 in the arsenite group, and Tgf-beta and the receptors of Tgf-beta were increased in the tumors of F2 in the arsenite group. Furthermore, the analysis of the Cancer Genome Atlas database showed that gene expression levels of the senescence markers and SASP factors were increased and associated with poor prognosis in human hepatocellular carcinoma (HCC). These results suggest that cellular senescence and SASP have important roles in hepatic tumorigenesis in C3H mice as well as HCC in humans, and gestational arsenite exposure of C3H mice enhances senescence in F1 and F2 via oxidative stress and Tgf-beta activation, respectively.