PLACENTAL OXIDATIVE DNA DAMAGE MARKERS AND EPIGENETIC AGING OF PLACENTA

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Altered placental aging is increasingly recognized to be a potential mechanism in the pathophysiology of a scope of pregnancy complications related to placental dysfunction. Several studies have found that premature aging of the placenta is associated with preeclampsia, low birth weight, stillbirth, and preterm birth. The field of biological aging has recently been revolutionized by Steve Horvath’s molecular methods that estimate the biological age of a tissue with high accuracy using DNA methylation markers. This “clock” is particularly valuable in studies of placental aging because traditional histopathological examination and telomerase homeostasis markers may not capture subtle aging alterations and premature cellular senescence caused by DNA damage due to oxidative stress. Placenta-specific epigenetic clocks have been developed. The difference between epigenetic age and gestational age of the placenta, namely placental age acceleration (PAA), indicates whether the “biological age” of the placenta is older than its chronological age. Higher PAA has been associated with increased risk for early-onset preeclampsia in an earlier study, and with low birthweight in male neonates in the NICHD Fetal Growth Studies cohort. The clinical utility of the placental epigenetic clock as a novel preventative and therapeutic target in adverse pregnancy outcomes can be facilitated by identifying non-invasive markers of PAA during gestation. PAA has been found to be under substantial genetic control with heritability of 57%. Moreover, the rate of epigenetic aging is developmentally adjusted, suggesting that the epigenetic aging rate is primarily set in early gestation. Cellular oxidative stress within the placenta leads to increased release of several factors into the maternal circulation. Therefore, biomarkers that the placenta excretes into the maternal circulation may give early signals of pathological changes in a prematurely aging placenta. Markers of oxidative DNA damage that are elevated in placentas from advanced gestational ages similarly to maternal blood of pregnancies with adverse outcomes related to placental insufficiency can be primary candidates. Prior studies have demonstrated that at advanced gestational ages, placentas show high levels of the oxidative DNA damage marker 8OHdG (8-hydroxydeoxyguanosine) accompanied by decreased levels of the antioxidant marker TAC (total antioxidant capacity). 8OHdG is a byproduct generated from oxygen free radical-induced DNA damage either spontaneously or induced by other agents. Similar patterns have been found in maternal plasma levels of these biomarkers in pregnancies complicated by preeclampsia, stillbirth, and fetal growth restriction. Collectively, similarities in the patterns of these biomarkers in late/post-term placentas and in pregnancy complications related to placental aging suggests that placental oxidative DNA damage markers may be potential early signals of premature aging of the placenta.