Abstract
Prenatal exposure to arsenic is associated with an increased risk of disease development such as liver cancer in adulthood. Increasing evidence suggests that fetal stem cells are key targets during transplacental chemical exposure. Our earlier study reported that in utero arsenic exposure caused various types of DNA damage in newborns. In this study, we further investigated the effects of prenatal arsenic exposure on mutagenic DNA damage in umbilical cord mesenchymal stem cells (MSCs) that represent fetal stem cells from the same birth cohort. DNA damage measured as 8-hydroxydeoxyguanine (8-OHdG) and 8-nitroguanine was increased in umbilical cord MSCs of newborns in relation to maternal arsenic levels in a dose-dependent manner. Levels of 8-OHdG and 8-nitroguanine were significantly (p<0.05) and positively associated with arsenic levels in cord blood and maternal toenails. In vitro studies confirmed that arsenite treatment alone (0-5µM, 24h) significantly increased the levels of 8-OHdG and 8-nitroguanine in an MSC cell line derived from umbilical cord tissue (UC-MSCs). When UC-MSCs were allowed to differentiate into hepatocytes in the presence of arsenite (0.5µM, 21 days), there were significant increases (p<0.05) in 8-OHdG and 8-nitroguanine compared to those observed in undifferentiated UC-MSCs. Moreover, in these arsenite-exposed differentiated hepatocytes, expression of inflammatory genes (CXCL6 and CXCL8) and an oxidative stress response gene (NFE2L2) was increased, while that of a DNA repair gene (OGG1) was decreased. Arsenite treatment also increased cell transformation ability of hepatocytes differentiated from UC-MSCs. These results suggest that arsenic exposure increases mutagenic DNA damage in fetal stem cells which continued when these cells differentiated to become hepatocytes which have increased cell transformation ability. This study highlights the potential risk of in utero arsenic exposure, which may lead to liver disease and cancer development later in life.
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