The Role Of Intestinal Microflora In The Liver Lipid Metabolism Abnormalities In Adult Offspring Induced By Maternal Bisphenol A Exposure During Pregnancy

Background Bisphenol A(BPA)is a substance that we can easily contact in our daily life.It is environmental endocrine disruptors(EDCs),which can enter the human body and accumulate through many ways.Due to its wide distribution and diversity of exposure routes,the related research on the adverse effects of BPA exposure on the human body has become the current research focus.In recent years,the adverse outcomes caused by direct exposure to BPA have been widely studied.Recently,Developmental Origins of Health and Disease(DOHaD)has enabled us to advance the focus of disease risk factors to prenatal and maternal pregnancy.The previous study of the research group showed that exposure to BPA during pregnancy and childbirth would increase the susceptibility of offspring to obesity,and the obesity process was accompanied by abnormal liver lipid metabolism and inflammatory damage.However,the specific mechanism of the generation effect of abnormal lipid metabolism caused by BPA exposure is still unclear.Recent studies have proved that the mother can transmit its own intestinal flora to the newborn through the colonization of the flora,and have an impact on the metabolism of the offspring in adulthood.Other studies have shown that BPA exposure will cause intestinal flora imbalance,so we speculate that BPA exposure during pregnancy will cause the imbalance of the mother’s intestinal flora,and play a certain role in the liver damage of the offspring.According to previous studies,maternal BPA exposure has significant adverse effects on the offspring of high fat diet(HFD),but has little impact on the offspring of normal chow diet(NCD).Based on the background that the obesity rate of the population is increasing year by year and the environmental exposure is becoming increasingly serious,it is of great public health significance to study the impact of maternal exposure of environmental endocrine disruptor BPA on the health of offspring after adulthood.Method Animal experiments were used to establish a mouse model of the effect of maternal BPA exposure on the lipid metabolism of offspring in adulthood,to detect the changes of intestinal flora in pregnant mice and offspring mice,as well as liver lipid metabolism indicators after high-fat diet feeding in adulthood,and to clarify that maternal BPA exposure during pregnancy induced the imbalance of maternal intestinal flora and led to the disorder of intestinal flora in offspring,It was significantly related to the abnormal liver lipid metabolism caused by HFD in the adult of its offspring;Through the improvement of dietary fiber supplementation on the disturbance of intestinal flora in female mice induced by BPA exposure and the abnormality of liver lipid metabolism in adult offspring,the role of maternal intestinal flora in the abnormality of liver lipid metabolism in adult offspring caused by BPA exposure during pregnancy was verified.The results of this study provide a new theoretical basis for clarifying the generation effect of environmental BPA exposure,and provide a new idea for preventing the long-term harm of environmental BPA exposure.The mRNA levels of acetyl-CoA carboxylase 1(Acc1),fatty acid transporter Cd36 and fatty acid synthase(Fasn)were detected by qRT-PCR.Results1.Effects of BPA Exposure During Pregnancy on Intestinal Microflora inMothers and OffspringAfter maternal BPA exposure during pregnancy,the β diversity of intestinal microflora in both mothers and offspring was significantly changed during the third trimester of pregnancy.At the same time,it was found that the ratio of dominant Bacteroidetes to Firmicutes(F/B)was significantly altered.LEfSe analysis showed a significant difference in microflora between the DMSO and BPA exposed groups.High dietary fiber supplementation during maternal pregnancy significantly improved the imbalance of intestinal flora in both mothers and offspring caused by BPA exposure.2.The Impact of Maternal BPA Exposure During Pregnancy on the Mother and Offspring After BirthPregnancy data records showed no significant differences in weight and water consumption of female mice in each group at the same time point during pregnancy.There were no significant differences in the average litter size,sex ratio,and 21-day survival rate of offspring born to mothers in each group.The average birth weight of the maternal high-dose BPA exposure group during pregnancy was lower than that of the control group.In adult offspring,HFD-fed offspring gained significantly more weight than NCD-fed offspring,but at different time points,female weight was lower than male weight in both HFD-fed and NCD-fed offspring.There was no significant difference in body weight between offspring born after maternal exposure to different doses of BPA and fed different diets.Dietary fiber supplementation was performed on pregnant mice,and it was found that compared to the maternal high-dose BPA exposure group during pregnancy,the average birth weight of offspring born to the1000 nM BPA+HFiD group increased,but the difference was not statistically significant.3.Effects of maternal exposure to different doses of BPA during pregnancy on liver lipid metabolism in adult offspring3.1 Effects on liver function and histologyAt the 3rd week of the offspring,the liver cells of each group of mice were densely arranged,with no significant tissue damage and lipid accumulation.In adulthood,no significant damage or lipid accumulation was found in the liver cells of offspring fed with NCD,but the liver function ALT and AST of offspring exposed to maternal high dose BPA increased;In the HFD feeding group,there was no significant difference between males and females,but there was a similar trend.The size of lipid droplets and the degree of vacuolation in liver cells increased with the increase of maternal BPA exposure dose,while ALT and AST in liver function of offspring exposed to high doses of maternal BPA increased.Dietary fiber supplementation during pregnancy significantly improves liver damage in offspring caused by BPA exposure.3.2 Impact on plasma lipid metabolism indicatorsAt the third week of offspring,there was no significant difference in plasma lipid metabolism indicators among the groups;At the 19 th week,there was no significant difference between the groups of NCD fed offspring.In HFD fed offspring,HDL-C decreased with the increase of BPA exposure dose in the mother mice,while LDL-C,T-CHO,TG,and ADPN increased with the increase of BPA exposure dose in the mother mice.Maternal dietary fiber supplementation significantly improved BPA-induced lipid metabolism abnormalities in offspring.3.3 Effect on liver lipid metabolism gene expressionThere was no significant difference in the lipid metabolism related genes Acc1,Cd36,and Fasn between male and female mice at the 3rd week.At the 19 th week,there was no significant difference between NCD groups,while the liver lipid metabolism related genes of offspring fed with HFD showed a trend of increasing with the increase of maternal BPA exposure dose during pregnancy,and the differences between the maternal high-dose BPA exposure group and the control group were statistically significant.Dietary fiber supplementation during maternal pregnancy significantly improved the expression of lipid metabolism related genes in offspring during adulthood caused by BPA exposure.4.Correlation analysis between lipid metabolism phenotype and intestinal flora in adult offspring exposed to BPA during maternal pregnancyFinally,we conducted Pearson correlation analysis between the lipid metabolism indicators of offspring mice in adulthood and the relative abundance of the Top10 flora at the genus level.The results showed that the relative abundance of genus norank＿f＿＿Muribaculaceae was negatively correlated with liver lipid metabolism abnormalities,while the relative abundance of genus Ileibacterium was positively correlated with liver lipid metabolism abnormalities.Conclusion1.Maternal and offspring intestinal flora imbalance induced by BPA exposure during pregnancy is associated with adult offspring liver lipid metabolism abnormalities.2.Maternal dietary fiber supplementation regulates the intestinal flora imbalance induced by BPA exposure during pregnancy and improves adult offspring liver lipid metabolism abnormalities.