Placental oxidative DNA damage and its repair in preeclamptic women with fetal growth restriction

Abstract

Preeclampsia is frequently accompanied by fetal growth restriction (FGR). Preeclampsia increases oxygen free radical production, and the resulting oxidative stress impairs placental blood flow. To determine whether placental oxidative stress is associated with FGR in preeclamptic women, we evaluated placental oxidative DNA damage and its repair in 13 preeclamptic women with FGR, 10 preeclamptic women without FGR, and 11 healthy pregnant women without complications. We measured maternal and umbilical serum derivatives of reactive oxygen metabolites (d-ROMs), as a marker of oxygen free radicals, and pulsatility index (PI) of uterine and umbilical arteries, and performed an immunohistochemical analysis to measure the proportion of nuclei in the placental trophoblast that stained positive for 8-hydroxy-2′-deoxyguanosin (8-OHdG), an indicator of oxidative DNA damage, and redox factor-1 (ref-1), indicative of the repair function towards oxidative DNA damage. D-ROMs were increased in the maternal blood of both preeclamptic groups (with FGR, 687.3 ± 50.4 CARR U, p < 0.01; without FGR, 750.4 ± 87.2 CARR U, p < 0.001) compared with controls (504.7 ± 25.0 CARR U). In contrast, d-ROM levels in the umbilical artery were elevated in preeclamptic women with FGR (134.9 ± 13.3 CARR U, p < 0.01), but not in preeclamptic women without FGR (44.0 ± 7.3 CARR U) compared with controls (38.2 ± 5.0 CARR U). Mean PI for uterine arteries was significantly increased in both preeclamptic groups, and the PI in preeclamptic women with FGR was significantly greater than that in women without FGR (0.94 ± 0.07 vs. 1.31 ± 0.07, p < 0.001). The PI for umbilical arteries was significantly increased in preeclamptic women with FGR (0.90 ± 0.05vs. 1.19 ± 0.07, p < 0.001), but not in preeclamptic women without FGR. The proportion of nuclei positive for 8-OHdG was higher in both groups of preeclamptic women than in the control group, but was higher in preeclamptic women with FGR (0.21 ± 0.05 vs. 0.87 ± 0.01, p < 0.001). The proportion of nuclei positive for ref-1 was higher in preeclamptic women without FGR (0.54 ± 0.06, p < 0.001) than in the control group, whereas the proportion did not differ significantly between normal and preeclamptic women with FGR. Our findings indicate that increased oxidative stress and disrupted compensatory reaction against placental oxidative DNA damage may be associated with FGR in preeclamptic women.