Effects Of Bisphenols Exposure In First Trimester On Fetal Intrauterine Development And Placental Inflammation: A Birth Cohort Study

Objective To investigate the serum bisphenols(BPs)concentrations and evaluate the associated dietary risk and health hazard in pregnant women.To explore the correlation between BPs exposure during pregnancy and impaired intrauterine development of the offspring,and to verify the scientific hypothesis that"placental inflammation induced by BPs exposure during pregnancy may mediate the impaired function of placental barrier,substance exchange and endocrine,which may be an important cause of altered intrauterine development programming of the offspring.Methods The nested case-control study design was used in the present study,and the pregnant women were recruited at their first visit to maternity and childcare hospital for prenatal health services and followed up until the end of delivery.The newborns were divided into three groups based on their sex and delivery pregnancy week,small for gestational age(SGA),appropriate for gestational age(AGA),and large for gestational age(LGA).The concentration of BPA,BPs,BPF and BPAF in maternal serum,the inflammatory factors in maternal blood,umbilical cord blood,and placenta,and the placental function indexes were detected.We also prospectively collected the basic information,prenatal examination data,laboratory test data,hospital delivery data,and so on.The statistical methods used in this study including Spearman correlation analysis,linear regression model,binomial and polynomial logistic regression model,locally weighted regression(LOESS)model,latent variable growth curve model,Bayesian kernel machine regression(BKMR)model,restricted cubic bar function,etc.Results 1)Study one:A total of 394 pregnant women were included in this study,and the concentrations of BPA,BPF,BPs,and BPAF in 477 serum samples were detected.The detection rates of BPA,BPF,BPS,BPAF and?BPS were 94.55%,98.43%,97.06%,95.60%,and 100%respectively.The median concentrations of BPA,BPF,BPS,BPAF,and?BPS were 0.3?g/m L,0.91?g/m L,0.12?g/m L,0.05?g/m L,and 1.35?g/m L respectively.The pairwise correlation coefficient between the four BPs nd?BPs ranged from 0.15 to 0.95;and the correlation coefficients between BPAF and BPF was 0.81,suggesting that they may share a common exposure pathway.All the four BPs lacked good interclass consistency,and the intraclass correlation coefficient(ICC)still failed to meet the requirements even after two specimens were collected during the same week.The results of polynomial logistic regression model showed that frequent calcium supplementation during pregnancy significantly increased the risk of high exposure to BPA(OR=2.22,95%CI=1.09?4.54),BPF(OR=2.23,95%CI=1.05?5.15),and BPS(OR=2.81,95%CI=1.3?6.06).Frequent folic acid supplementation during pregnancy significantly reduced the risk of moderate exposure(OR=0.21,95%CI=0.1?0.45)and high exposure(OR=0.2,95%CI=0.09?0.45)to BPF,as well as reduced the risk of moderate exposure(OR=0.18,95%CI=0.09?0.37)and high exposure(OR=0.2,95%CI=0.09?0.44)to BPS.Pregnant women who frequently took vitamin D supplements during pregnancy were 3.84(95%CI=1.68?8.8)times and 3.46(95%CI=1.37-8.75)times more likely to detect the moderate and high concentrations BPS in their serum respectively.The risk of moderate exposure and high exposure to BPS increased by 2.44(95%CI=1.33-4.47)times and 2.51(95%CI=1.23?5.08)times in pregnant women who occasionally ate animal offal compared with those who ate very little.The average estimated daily intake(EDI)of the four BPs in 394 pregnant women ranged from 0.02 to 0.13?g/kg/d,and the median EDI ranged from 0.01 to 0.09?g/kg/d.The maximum value of hazard index(HI)was 0.70.These data suggested that EDI in all 394 included women did not exceed the EFSA requirement of 4?g/kg/d.Study two:univariate analysis showed that there was a statistical correlation between exposure level of individual BPs during pregnancy and weight,BMI and PI of newborns,which was limited to female newborns.In female newborns,the proportion of SGA in low-exposure,medium-exposure and high-exposure groups of BPAF was 0%,11.2%and 12.2%,respectively,with statistically significant differences((?)~2=11.94,P=0.02).The proportion of high BMI in female neonates with low,medium and high PS exposure was 13.95%,29.76%,and 37.21%respectively,and the difference was statistically significant((?)~2=9.83,P=0.04).The proportion of newborns with high BMI in low,medium and high BPAF exposure was 12.5%,32.58%,and 31.71%respectively,with statistical significance((?)~2=14.69,P<0.01).The proportion of female newborns with high PI was 6.98%,16.67%and 30.23%in low,medium,and high BPS exposure groups respectively,and the difference was statistically significant((?)~2=11.32,P=0.02).The proportion of female newborns with high PI in low,medium and high BPAF exposure groups was 2.5%,22.47%,and 21.95%respectively,and the difference was statistically significant((?)~2=11.23,P=0.02).The multiple linear regression models were used to analyze the associations between prenatal BPs exposure with the development of fetal head and hip length from7 to 14 weeks of gestation,as well as with the development of double parietal diameter,head circumference,abdominal circumference,and femur length from 15 to 40 weeks of gestation.The prenatal BPs exposure exhibited a stable and sustained damage to fetal head and hip length during the 7 and 14 weeks of gestation,especially the 11 and 13weeks of gestation.The prenatal BPs exposure had a significant inhibitory effect on the parietal diameters in both male and female fetus;and the prenatal BPs exposure significantly affected the development of the fetal head circumference with significant gender differences,but the results were inconsistent.There were significant sex difference on the effect of prenatal BPs exposure on the fetal abdominal circumference,as well as the the length of femur,with the promoting effect in male fetus and the inhibiting effect in female fetus.However,there were no significant linear correlation between birth outcomes with BPA,BPF,BPS,BPAF and?BPS.The multiple linearreg ression models were used to analyze the associations of prenatal BPs exposure and maternal weight gain,glucose and lipid metabolism during pregnancy.The results showed that the higher concentration of BPS was associated with a 1.31(0.05?2.57)kg increase and a 0.04(0,0.07)kg/week growth rate of maternal eight during pregnancy compared with the low concentration groups.The higher concentrations of BPA,BPF,BPS,BPAF,and?BPS were significantly associated with the 0.2(95%CI=0.09?0.31),0.13(95%CI=0.01?0.24),0.17(95%CI=0.06?0.29),0.12(95%CI=0.01?0.24),and 0.17(95%CI=0.06?0.28)mmol/L increase of fasting blood glucose with the low concentration groups.BKMR model was used to analyze the combined effect of BPA,BPF,BPS and BPAF on fasting blood glucose in pregnant women.The combined effect of the four BPs on fasting blood glucose in pregnant women showed a trend of continuous growth.Among the four BPs,BPS made the largest contribution to the combined effect.3)Study three,the mean placental weight in the five different BPAF concentration groups(20,P₂₁-P₄₀,P₄₁-P₆₀,P₆₁-P₈₀,and>P₈₀)was(407.32±67.06)g,(452.61±84.87)g,(469.47±87.29)g,(461.44±103.46)g,and(444.21±88.29)g,and the difference was statistically significant(F=3.47,P<0.01).After adjusting for maternal age,pre-pregnancy weight and height,the placental weight in the higher BPAF concentration groups(P₂₁-P₄₀,P₄₁-P₆₀,P₆₁-P₈₀,and>P₈₀)was increased by 48.88g,61.4g,52.32g,and38.92g compared with the lowest concentration group(20)respectively.The mean concentrations of TNF-?and IL-8 in maternal and umbilical blood between different BPF groups(25,P₂₅-P₇₅,>P75)were statistically different,and exhibited a u-shaped relationship.The nonlinear relationship between prenatal BPF exposure and TNF-?and IL-8 in maternal blood and umbilical blood was simulated using the restricted cubic bar function after adjusting for maternal age and pre-pregnancy BMI,and the u-shaped nonlinear relationships were observed.The concentration of IL-6 in maternal blood and prenatal blood between different BPS concentration groups were statistically different((?)~2=7.39,P=0.03;(?)~2=6.44,P=0.04),with an inverted"U"shaped relationship.There was a significant correlation between BPF,BPS,BPAF and TNF-mRNA expression in placenta during pregnancy(r=-0.30,P<0.05;r=0.23,P=0.03;r=-0.22,P=0.04).Spearman correlation and restricted cubic bar model were used to analyze the effects of renatal BPs exposure on the substance exchange and endocrine function of placenta.It was found that BPAF firstly promoted and then inhibited mRNA expression of GLUT1and SNAT2.BPF exhibited a significant negative regulatory effect on VEGF-A.BPAF exhibited a significant negative regulatory effect on IGF2 and PGF,and?BPs exhibited a significant negative regulatory effect on VEGF-A.Conclusion Our study showed that although the concentration of BPs in pregnant women is far lower than the EFSA level of 4?g/kg/d,it still inhibited the intrauterine development of offspring,especially the head and hip length in early pregnancy.The inhibited effects on the intrauterine development of offspring were different between female and male newborns.Interestingly,prenatal exposure of BPA,BPF,BPS,BPAF and?BPS all significantly associated with the increased blood glucose levels during pregnancy,which may support the role of BPs exposure in promoting weight gain in pregnant women.Mechanism research showed that BPF and BPAF firstly inhibited the inflammatory factors and then promoted them in maternal blood,umbilical cord blood and placenta.Meanwhile,BPF and BPAF also exhibited the significant inhibitory effects on placental substance transport and endocrine function.Due to the small sample size,we needed to recruit more participators to determine the stability of the results.