Based On The DOHaD Theory, This Paper Explores The Effect Of Obesity Before And During Pregnancy On The Respiratory Diseases Of The Offspring And Its Mechanism

Objectives:1.Through feeding maternal mice with high fat before and during pregnancy,the offspring were given by bleomycin to induce lung injury,and the effects of exposure to high fat environment before and during pregnancy on lung injury and repair of offspring were observed.The roles of insulin-like growth factor 1(IGF-1)and insulin-like growth factor binding protein 3(IGFBP3)were also explored in this study,aiming to provide experimental support for the study of the developmental origin of respiratory diseases in children.2.Through prospective clinical observational studies,the effects of pregnant obese women and their TCM constitutions on respiratory system diseases in their offspring were evaluated,and the roles of surfactant protein B(SPB),1 surfactant protein C(SPC),IGF-1 and IGFBP3 were explored to provide clinical basis for preventive medicine and policy of eugenics.3.A comprehensive meta-analysis was conducted to evaluate the association of pre-pregnancy maternal obesity or overweight and high GWG with the risk for childhood asthma and wheeze with the purpose of providing evidence-based medical evidence for the relationship between maternal overnutrition and childhood respiratory disease.Methods:1.Eighty 3-week-old C57BL/6 female mice were raised in two batches.The first batch was fed with high fat before pregnancy.Forty 3-week-old female mice were randomly divided into a pre-pregnancy high-fat group and a pre-pregnancy control group with 20 mice in each group.The fat group was fed with 40%high-fat feed,and the control group was fed by standard feed before pregnancy.After 12 weeks of feeding,6 mice in each group were taken to observe the liver pathology of the female mice for model verification.The other female mice mated with the normal male mice in a cage with a male to female ratio of 2:1.After successful mating,they were fed with standard feed.The second batch was high-fat feeding during pregnancy.40 female mice at the age of 3 weeks were fed with common feed to 8 weeks of age.The female mice were randomly divided into a high-fat group and a control group,with 20 mice in each group.After successful mating,the high-fat group during pregnancy will be fed with 40%high-fat feed,and the control group will be fed with standard feed for 3 weeks.The male offspring born in two batches will be fed with standard feed until 6 weeks of age after 3 weeks of weaning,which were divided into normal mice control group,normal mice model group,high-fat mice control group and high-fat mice model group.All mice in the model group were given by bleomycin to induced lung injury.Samples were respectively collected at 3 weeks and 5 weeks after molding,and the following tests were conducted:(1)HE staining and Masson staining were performed on the lung tissue sections of the offspring to evaluate the degree of alveolitis and fibrosis;(2)lung function tests were carried out on the offspring before sampling;(3)Immunohistochemical(HIC)staining was performed on the lung sections of the mice to observe the expression of podoplanin(PDPN)and SPC;(4)Enzyme-linked immunosorbent assay(ELISA)was used to detect the levels of IGF-1 and IGFBP3 in the serum and alveolar perfusion of the offspring.2.We collected the pregnant women waiting for delivery in the Obstetrics and Gynecology Department of the China-Japan Friendship Hospital from March 2019 to July 2019,and included 30 obese pregnant women who met the criteria as an obese group with matching 30 normal pregnant women during the same period as a control group to evaluate the TCM constitution of pregnant women in the third trimester Situation.HIC and ELISA were used to detect the expression of SPB,SPC,IGF-1 and IGFBP3 in the placenta and the level of IGFBP3 in umbilical cord blood,and the incidence of respiratory diseases on offspring at 6 months was followed up.3.The PubMed,Excerpt Medica Database(EMBASE),Cochrane Central Register of Controlled Trials(CENTRAL),Cochrane Database of Systematic Reviews,and Google Scholar were searched from inception to July 30,2019 for observational studies that assessed the association between pre-pregnancy maternal obesity or overweight and GWG and the risk for asthma or wheeze in children.Literature search,quality assessment,and data extraction were completed independently and in duplicate.Effect-size estimates are expressed as odds ratio(OR)with 95%confidence interval(CI).Overall analysis,subgroup analysis,meta-regression analysis and publication bias were performed on the extracted data.Results:1.High-fat feeding before and during pregnancy gave similar results as follows:(1)weight of offspring:there was no significant difference in body weight between high-fat group and control group(P>0.05).(2)degree of alveolitis and fibrosis:the injury period was 3 weeks after modeling.Compared with the normal control group,the alveolar inflammation and pulmonary fibrosis scores of the normal mice model group and high-fat model group were significantly increased,indicating successful modeling(P<0.01).The recovery period was 5 weeks after the model.Compared with the normal control group,the alveolar inflammation and pulmonary fibrosis score of the normal mice model group increased slightly,indicating that the recovery was relatively good,and there was still a difference from normal lung tissue(P<0.05),and the alveolitis and pulmonary fibrosis scores of the high-fat mice model were still significantly increased,suggesting poor recovery(P<0.05).Compared with the normal mice model group,the alveolitis and pulmonary fibrosis scores of the high-fat mice model group were significantly increased,suggesting that the recovery of the high-fat mice model was worse than that of the ordinary rat model(P<0.05).(3)Lung function parameters:In 3 weeks after modeling,the lung function parameters FEV0.05,FEV0.1,FEV0.2 and FVC were significantly different between the four groups(P<0.001).Compared with the normal mice control group,FEV0.05,FEVO.1,FEV0.2 and FVC in the normal mice model group and high-fat mice model group were significantly decreased(all P<0.05),but there was no significant difference in the high-fat rat control group(P>0.05).Compared with normal mice model group,there were no significant changes in FEV0.05,FEV0.1,FEV0.2 and FVC of the high-fat mice model group(all P>0.05).In 5 weeks after the model was made,and the lung function parameter FE V0.05,FEV0.1,FEV0.2 and FVC were significantly different between the four groups(P<0.001).Compared with the normal mice control group,FEV0.05,FEV0.1,FEV0.2 and FVC in the high-fat mice model group were significantly decreased(all P<0.05),but no obvious changes were made in the normal mice model group(P>0.05).Compared with the normal mice model group,FEV0.05,FEV0.1,FEV0.2 and FVC in the high-fat mice model group were significantly reduced(P<0.05).(4)PDPN and SPC expression:the injury period was 3 weeks after modeling Compared with the normal mice control group,the expression of PDPN in the lung tissues of the normal mice model and the high-fat mice model groups was significantly reduced(P<0.05),and there was no significant difference between the two model groups(P>0.05).The recovery period was 5 weeks after modeling.Compared with the normal mice control group,the expression of PDPN in the high-fat mice model group was significantly reduced,but there was no significant change in the normal mice model.Compared with the normal mice model group,the expression of PDPN in the high fat rat model group is still significantly reduced(P<0.05)The expression of SPC in the 3-week injury period has a tendency to decrease between the two model groups and there is an increasing trend of the expression of SPC between the two model groups in the 5-week recovery period,which did not reach statistical difference(all P>0.05).(5)IGF-1 and IGFBP3 levels:there was no significant difference of IGFBP3 in serum and alveolar lavage at 3 and 5 weeks after the model was made in the study feeding with high fat before pregnancy(all P>0.05).In the study of high-fat feeding during pregnancy,no significant difference was found in serum igf-1 and IGFBP3 between 3 and 5 weeks after the model was established(all P>0.05).IGFBP3 levels in alveolar lavage fluid in the normal rat model group,the high-fat rat control group and the high-fat rat model group all increased significantly at 3 weeks after modeling(all P<0.05).2.The clinical research results are as follows:(1)baseline comparison between the two groups of children:In terms of gender,birth mode,birth length,birth weight,Apgar score,whether there is hypoxia asphyxia,feeding methods,supplementary food supplement time,length and weight of 6 months,there was no statistical difference between the two groups(all P>0.05).(2)the situation of respiratory diseases of the children of the two groups:the proportion of children in the obese group was higher than that of the control group in terms of upper respiratory tract infection and the overall incidence of respiratory diseases The offspring of the group did not reach statistical difference(P>0.05);(3)the expression of SPB,SPC,IGF-1 and IGFBP3 in the placenta of pregnant women:the expression of SPB,SPC,IGF-1 and IGFBP3 in the two groups of placenta have a decreasing trend,and of which the expression of IGFBP3 is significantly reduced(P<0.05).(4)the level of IGFBP3 in cord blood:IGFBP3 in the cord blood of obese pregnant women is significantly lower than that of the control group(P<0.05).(5)evaluation of TCM constitution of pregnant women:compared with the control group,the proportion of biased TCM constitution in the obese group increased significantly(P<0.05),and the biased constitution mainly consisted of phlegm and dampness and yang deficiency.3.Twenty-two observational studies involving 145,574 mother-child pairs were meta-analyzed.In overall analyses,maternal obesity or overweight in pre-pregnancy significantly increased the risk of both childhood asthma and wheeze(adjusted OR:1.41 and 1.13,95%CI:1.26-1.59 and 1.07-1.20,both P<0.001).Per 1 kg/m2 increment in maternal body mass index was associated with a significantly increased risk of childhood asthma and wheeze(adjusted OR:1.03,95%CI:1.02-1.03,P<0.001).Compared with normal GWG,very high GWG(adjusted OR:1.24,95%CI:1.04-1.47,P:0.018),moderate high GWG(adjusted OR:1.12,95%CI:1.04-1.21,P:0.004),and very low GWG(adjusted OR:1.26,95%Cl:1.08-1.47,P:0.004)increased the risk of childhood asthma and wheeze.There was a low probability of publication bias.Conclusion:1.From the perspective of morphology,histology and lung function,it has been confirmed that high-fat feeding before and during pregnancy does not aggravate the bleomycin-induced lung injury in the offspring,but affects the repair function of the offspring after lung injury,and IGFBP3 may play a role in lung injury in offspring fed with high fat during pregnancy.2.Obesity during pregnancy does not increase the risk of respiratory diseases in the offspring at 6 months,and IGFBP3 may play a relevant role in high birth weight of offspring during pregnant obese women.Obesity during pregnancy is more likely to have a biased TCM constitution and may be prone to respiratory diseases on offspring.3.Our findings indicate that both pre-pregnancy maternal obesity or overweight and very to moderate high or low GWG render their offspring susceptible to a significantly increased risk of having childhood asthma and wheeze.4.Obesity before and during pregnancy has a significant influence on children’s respiratory diseases,so controlling weight before and during pregnancy may be an important measure to prevent children from developing respiratory diseases in the future.