Overexpression of Thioredoxin-1 Reduces Oxidative Stress in the Placenta of Transgenic Mice and Promotes Fetal Growth via Glucose Metabolism

Abstract

Oxidative stress occurs where there is an imbalance between the production and scavenging of free radicals. Pregnancy per se is a state of oxidative stress due to the increased metabolic activity of placental mitochondria and reduced scavenging ability of antioxidant systems. Overproduction of reactive oxygen species may be associated with impaired fetal growth. However, the physiological influence of antioxidant systems on fetal growth is not well understood. In this study we assessed the effects of antioxidant systems on fetal growth using human thioredoxin (hTRX)-1 overexpressing transgenic (Tg) mice. Tg or C57BL/6 [wild-type (WT)] male mice were mated with WT female mice, and dams were killed to obtain the fetuses and placentas on gestational d 15. Tg fetuses were significantly heavier than WT fetuses, whereas placental weight did not differ significantly between the two groups. Immunohistochemically, hTRX-1 was localized to the nuclei of labyrinthine trophoblasts in Tg mice. In addition, placental expression of 8-hydroxy-2'-deoxyguanosine, which reflects DNA damage caused by oxidative stress, was reduced in Tg mice compared with WT mice. Placental expression of glucose transporter-1 mRNA and protein was significantly higher in Tg mice than WT mice, whereas no significant differences were observed for glucose transporter-3, IGF, and IGF-binding protein mRNA expression. These results suggest that placental and/or systemic antioxidant systems can influence fetal growth. In particular, increased hTRX-1 activity and the resulting modified placental redox state may play an important role in fetal growth by increasing the availability of glucose.

Hypoxanthine–xanthine oxidase down-regulates GLUT1 transcription via SIRT1 resulting in decreased glucose uptake in human placenta

“…It is possible that the concentration of antioxidants used in this study was not optimal or that a combination of various antioxidants is required to see an effect. A previous study has, however, reported that the overexpression of antioxidant thioredoxin increases placental GLUT1 in mice (Umekawa et al 2008). Previous studies from our laboratory have shown that cytokine response to HX/XO may be mediated by the oxidant-responsive transcription factor NF-kB (Coughlan et al 2004).…”

Maternal omega-3 fatty acid intake increases placental labyrinthine antioxidant capacity but does not protect against fetal growth restriction induced by placental ischaemia–reperfusion injury

“…The importance of limiting placental oxidative stress during normal gestation has recently been shown by two studies. First, Umekawa et al (2008) demonstrated that global TXN1 overexpression reduced oxidative damage and enhanced fetal growth in a mouse model. Similarly, we recently reported reduced placental oxidative damage and increased fetal and placental growth with maternal dietary n-3 PUFA supplementation (Jones et al 2013b).…”

Hyperglycemia perturbs biochemical networks in human trophoblast BeWo cells

“…This down- observed gene expression changes in HG conditions. Pregnancy per se can be regarded as a state of oxidative stress due to the increased metabolic activity of placental mitochondria and reduced scavenging activity of antioxidant systems [35]. Thus, diabetic states may enhance the oxidative stress in pregnancy that may accelerate the abnormalities in trophoblast function.…”