Oxidative Stress And Fetal Metabolic Health

There is a rising incidence of metabolic syndrome in recent years.Incresingly more evidence suggests that the fetal development period could determine an individual’s capacity in adapting to energy metabolic burdens and this maybe affected by adverse intrauterine environment.Oxidative stress has been related to energy metabolism and multiple intrauterine adverse factors.Oxidative stress may play a critical role in fetal programming of the risk of metabolic syndrome.Our study will explore the effects and possible mechnisms of oxidative stress on fetal metabolic health from three dimensions.1.This part aim to explore whether maternal smoking affects metabolic health biomarkers in fetuses/newborns directly.In a prospective singleton pregnancy cohort(n=248),it showed that independent of maternal(glucose tolerance,age,ethnicity,parity,education,body mass index,alcohol use)and infant(sex,gestational age,birth weight z score,mode of delivery,cord blood glucose concentration)characteristics,the newborns of smoking mothers had lower IGF-I concentrations(mean: 6.7 vs.8.4 nmol/L,adjusted p=0.006),and marginally higher proinsulin-to-insulin ratios(0.94 vs.0.72,adjusted p=0.06)than the newborns of non-smoking mothers.Cord plasma insulin,proinsulin,IGF-II,leptin and adiponectin concentrations and glucose-to-insulin ratios were similar in the newborns of smoking and non-smoking mothers.In conclusion,maternal smoking was associated with decreased fetal IGF-I levels,and borderline lower fetal β-cell function.2.In a prospective singleton pregnancy cohort(n=248),assess the associations of OxLDL concentration and OxLDL/total LDL ratio in cord blood with fetal insulin sensitivity and beta-cell function biomarkers.Our study showed that OxLDL/LDL ratios were strongly correlated in cord and maternal plasma(r=0.47,p<0.001),and were substantially higher in cord plasma(1278.0±141.2 vs.591.4±29.2 U/mmol,p<0.001).Cord plasma OxLDL concentration was negatively correlated with insulin/glucose ratio(r=-0.24,p<0.001),and positively correlated with proinsulin/insulin ratio(r=0.20,p<0.001)and QUICKI(r=0.16,p<0.01),but not correlated to leptin or adiponectin concentration.Adjusting for maternal and delivery characteristics,each log unit increase in cord plasma OxLDL concentration was associated with a 10.5%(95% CI: 5.5%-15.8%)decrease in cord plasma insulin/glucose ratio,a 3.1%(0.9%-5.2%)increase in QUICKI and a 7.8%(5.5%-15.8%)increase in proinsulin/insulin ratio,respectively.Similar associations were observed for cord plasma OxLDL/LDL ratio.In conclusions,higher OxLDL concentrations were associated with lower beta cell function with a possibly compensatory increase in insulin sensitivity to maintain glucose homeostasis in fetuses/newborns.OxLDL may be one of the mechanisms which fetal “programming” effect on metabolic syndrome in adulthood.3.The present study sought to explore the effect of GDM on placental expression levels of proteins related to oxidative stress and metabolic health.In a nested case-control study(GDM 51,Control 50)using the Shanghai Birth corhort,our study showed that there was no differenc in concentrations of SOD,OxLDL,glucose,insulin,IGF-1,insulin/glucose ratio,OxLDL/LDL ratio,QUICKI in cord blood between GDM and healthy preganancies.There were 207 differentially expressed placental proteins in GDM vs.normal pregnancies,including 119 up-regulated proteins and 88 down-regulatied proteins(P<0.05).GO enrichment analysis showed that these differentially expressed proteins mainly participate in the organic hydroxy compound metabolic process,anion transport and sterol metabolic process.A total of 9 differentially expressd proteins were found in the oxidative phosphorylation pathway that all were up-regulated(relative expression levels range from 1.26 to 1.69,p<0.05)in the placentas of GDM pregnancies including Nicotinamide Adenine Dinucleotide Hydrogen(NADH)dehydrogenase 1 and Cytochrome c1.In the insulin secretion pathway,facilitated glucose transporter member 1(GLUT1)was up-regulated in the placentas of GDM vs.normal pregnancies(relative expression level: 1.43,p=0.017);In phosphatidyl inositol triphosphate-protein kinase B(PIP3-AKT)signaling pathway,Expression of Ras-related C3 botulinum toxin substrate 1(RAC1-which could impair beta cell function)was up-regulated in the placentas of GDM vs.normal pregnancies(relative expression level:1.25,p=0.002).In conclusions,placental protein expression levels of oxidative phosphoralation and RAC1 are increased in GDM.Oxidative stress may impair fetal beta cell function by up-reglulating(RAC1)expression.This may be a mechanism in oxidative stress fetal “programming” the risk of metabolic syndrome in adulthood.