The Effects And Mechanism Of N-3 Polyunsaturated Fatty Acids On The Adult Offspring Of Gestational Diabetes Mellitus Rats Based On Metabolomics

Background: Gestational diabetes mellitus(GDM)seriously impairs maternal and child health and increases disease risks for offspring.However,the long-term influence and mechanism of GDM on offspring are poorly understood.N-3polyunsaturated fatty acids(PUFA)has many physiological functions and plays an important role in preventing some disease risks.Nevertheless,the effect of n-3 PUFA on GDM offspring remains unclear.The long-term risk and mechanism of developing diabetes in GDM offspring,as well as the effect of n-3 PUFA on the diabetic risk of GDM offspring,need to be confirmed.Moreover,it is worth studying whether GDM can cause a long-term influence on the brain of offspring and the effect of n-3 PUFA on the brain of GDM offspring.Metabolomics can find the relationship between metabolites and physiological and pathological changes,and it play an important role in understanding disease progress and early clinic diagnosis.At present,most studies with metabolomics have focused on GDM women,with only a few study on GDM offspring.The long-term effect of GDM on the metabolism of offspring have been poorly understood.It is of practical significance to investigate the long-term metabolic changes on GDM offspring,analyze the offspring's potential disease risk and explore the effect of n-3 PUFA on GDM offspring.Aim:(1)To study the long-term risk of developing diabetes in GDM offspring,even the GDM offspring grow to an old age,and to investigate the intervention effect of n-3 PUFA on the offspring's diabetes risk.(2)To study whether GDM can cause a long-term influence on the brain of offspring,and to explore the effect and mechanism of n-3 PUFA on the brain of GDM offspring.(3)To study the overall metabolism changes in the serum of GDM offspring to explore the potential disease risk when GDM offspring grow to an old age,and to investigate the modulating effect of n-3 PUFA on the serum metabolism of GDM offspring.Methods: Female Wistar rats were selected to induce GDM model by an intraperitoneal injection of streptozotocin(30 mg/kg)at the fifth day of gestation.The control group were injected with citrate buffer alone.After weaning,the offspring rats from normal female rats were fed with standard diet(7 % soybean oil)to 11 months of age.The offspring from GDM rats were divided into three groups,GDM offspring(7 % soybean oil),n-3 Adq-GDM offspring(3 % soybean oil + 4 % fish oil)and n-3Def-GDM offspring(7 % safflower,high n-6 PUFA group),fed with respective diet to11 months old.All offspring rats were sacrificed at 11 months old.Results:(1)The birth weight of GDM offspring was decreased,and they exhibited a lifetime growth restriction,which was improved by the intervention of n-3PUFA.The risk of developing diabetes in GDM offspring was gradually increased with month age from no obvious risk at weaning to an obvious diabetes risk at 11 months old,whereas n-3 PUFA lowered the offspring's diabetes risk by improving the pancreatic fat infiltration,decreasing the hepatic TG and TC level and lowering the oxidative stress and inflammation of liver and pancreas.The telomere shortening of liver and pancreas were also improved by n-3 PUFA.GDM caused the obvious metabolism alteration of liver and pancreas of offspring at 11 months old.Seventy-three metabolites were altered in the liver of GDM offspring,and many metabolites and metabolic pathways were closely related to diabetes risk,such as ceramide,hexadecenoic acid,oxalacetic acid,cortisol,?-linolenic acid,niacinamide and tocotrienol.N-3 PUFA modulated twenty-seven metabolites.In the n-3 Def-GDM offspring,however,only seven metabolites were improved,and twenty-one metabolites were even aggravated.S ixty-eight metabolites were changed in the pancreas of GDM offspring,whereas thirty metabolites were improved by n-3 PUFA.In the n-3 Def-GDM offspring,thirty-five metabolites were even aggravated.(2)GDM caused a long-term influence on the brain of offspring.Firstly,the hippocampus and cortex of GDM offspring exhibited oxidative stress at 11 months old.N-3 PUFA improved the oxidative stress by increasing the hippocampal activity of SO D and CAT,decreasing the cortical MDA level,enhancing the cortical level of GSH and activity of SOD and CAT.Secondly,inflammation were also enhanced in the brain of GDM offspring at 11 months old.N-3 PUFA improved the enhanced inflammation by decreasing the hippocampal level of IL-1? and IL-6,increasing the IL-10 level,and lowering the cortical leve l of IL-1??IL-6 as well as TNF-?,whereas the n-3 Def-GDM offspring exhibited the highest inflammatory state.Moreover,the hippocampal telomere length of GDM offspring was shortened at weaning,and it was more obviously shortened at 11 months of age.So d id the cortical telomere length of GDM offspring at 11 months old.N-3 PUFA postponed the hippocampal and cortical telomere shortening.However,the telomere shortening were not improved in the n-3Def-GDM offspring,and this group exhibited the shortest hippocampal telomere length.Finally,GDM caused long-term metabolic changes in the offspring's brain.Many altered metabolites were closely with brain function,neurotransmitter transmission,cognitive function and nervous system disease,such as phosphatidylserine,ceramide,sphingosine,glutamic acid,indole,histamine,cortisol and galactocerebroside.Fifty-two metabolites were altered in the hippocampus of GDM offspring at 11 months old,whereas n-3 PUFA improved the thirty metabolites.In the n-3 Def-GDM offspring,twenty-one metabolites were even aggravated.Forty metabolites were changed in the cortex of GDM offspring,whereas twenty-two of them were modulated by n-3 PUFA.However,twenty-one metabolites were even aggravated in the n-3 Def-GDM offspring.(3)Forty metabolites were changed in the serum of GDM offspring at 11 months of age.These altered metabolites and the involved metabolic pathways indicated a variety of potential disease risks in GDM offspring,such as increased oxidative stress and inflammation,aging,diabetes risk,cardiovascular disease and other metabolic diseases,liver dysfunction,declined cognitive function,abnormal gut microbiota,as well as fertility reduction.N-3 PUFA modulated 21 metabolites in the serum.In the n-3 Def-GDM group,only 4 metabolites were improved,but other 23 ones were even aggravated.Conclusion:(1)The risk of developing diabetes in GDM offspring was increased with month age.The GDM offspring exhibited an obvious diabetes risk when they grew to 11 months old,whereas n-3 PUFA lowered the diabetes risk.(2)GDM can cause long-term adverse effects on the brain of GDM offspring,which increases the risk of developing brain and related nervous system diseases at old age,whereas n-3PUFA has a protective effect on the brain of GDM offspring.The result of this part is a strong evidence that the occurrence of brain and related nervous system diseases after adulthood is related to an adverse uterine environment early in life.(3)N-3PUFA plays a modulating effect on the serum metabolism of GDM offspring.It is feasible to predict the potential disease risk in GDM offspring and observe the effect of nutritional intervention as well as other treatments on the GDM offspring via searching for related biomarkers by using metabolomics.