The Role Of Thyroid Function In The Association Between Phthalate Exposure During Pregnancy And Infant Growth Trajectory:A Birth Cohort Study

ObjectivesTo describe the distribution of phthalate(PAEs)exposure level during pregnancy and assess the health risks of cumulative exposure to multiple PAEs.To explore the association between PAEs exposure during pregnancy and gestational age and premature infants,and its impact on infant growth trajectories.To analyze the mediating effects of maternal and fetal thyroid function in the association mentioned above.MethodsBased on the Ma’anshan birth cohort(n = 3 474),women were followed and serum and urine samples were obtained at three trimesters and delivery.Body weight,height/length,and head circumference were measured at 42 days,3,6,9,12,18,24,30,and 36 months of age.The concentrations of 7 PAEs metabolites in urines were analyzed by high performance liquid chromatography-tandem mass spectrometry.Four thyroid function indicators were measured by umbilical cord serum using electrochemiluminescence immunoassay at three trimesters.A total of 3 455 pregnant women with urine samples were included.The exposure levels of PAEs metabolites were described using geometric mean and 95% confidence interval(CI).A hazard index(HI)method was introduced to assess the health risks of cumulative exposure to multiple PAEs using a volume fraction model and a creatinine-adjusted model.The intragroup correlation coefficient(ICC)and its 95% CI were used to assess the temporal variability of cumulative exposure risk.A total of 3 266 live births with complete information were investigated.The association between PAEs metabolites and birth gestational age was fitted by smooth curve.Binary logistic regression was used to analyze the association between PAEs exposure and preterm infants(28-36 weeks gestation),and the dose-response relationship of which was analyzed using a restricted cubic spline(RCS)model.After excluding children with a history of premature birth,low birth weight,small for gestational age or less than 5 physical examinations received,a total of 2 600 pairs of mother and child were studied.The physical measurements were performed on age-specific body weight(WAZ),age-specific height/length(LAZ),and age-specific head circumference(HCAZ).The growth trajectory model was established by the latent category growth model,and the optimal fitting model and the number of categories were selected.With reference to the lowest growth trajectory,a multivariate logistic regression model was used to analyze the statistical association between PAEs exposure during pregnancy and different growth trajectories of infants,and to explore the gender difference and the critical window period.The linear mixed model(LMM)was used to analyze the association between exposure of di(2-ethylhexyl)phthalate(DEHP)and its three metabolites,namely mono(2-ethylhexyl)phthalate(MEHP),mono(2-ethyl-5-hydroxyhexyl)dicarboxylate(MEOHP)and mono(2-ethyl-5-oxohexyl)phthalate(MEHHP),and thyroid function of mother and infant.The mediating effect of thyroid function on DEHP exposure and WAZ growth trajectory was also examined.ResultsExcept for the monobenzyl phthalate(MBzP)which detection rate was 49.4%,over 98% of PAEs metabolites were detecTab.The highest exposure level was monobutyl phthalate(MBP),followed by monomethyl phthalate(MMP),MEOHP,MEHHP,monoethyl phthalate(MEP)and MEHP.In the creatinine-adjusted model,an HI value over 1 was observed in 1 106(11.61%)samples.The HI value calculated by the creatinine-adjusted model had moderate time variability(ICC values ≥ 0.44),while the volume fraction model had higher HI time variability(ICC values ≤ 0.14).There was a nonlinear correlation between the concentration of PAEs metabolites and the gestational age.MMP exposure increased the risk of preterm birth.Stratification analyses by gender found that MMP exposure only increased the risk of preterm infants in girls.The stratification analyses according to pregnancy trimester showed that MMP exposure during the second and third trimesters and MEHHP exposure during the third trimester increased the risk of preterm infants.RCS results showed a non-linear "J" relationship between LMWP and MEHP exposure and risk of preterm infants.WAZ’s LCGM model fits optimally to 7 categories,and its trajectory was defined from low to high as from WAZ-1 to WAZ-7.Compared with the WAZ-1 group,MEP exposure increased the risk of WAZ-4 occurrence,LMWP exposure increased the risk of the WAZ-2 occurrence,and three metabolites of DEHP(MEHP,MEOHP,and MEHHP)and HMWP exposure increased the risk of occurrence from WAZ-2 to WAZ-7.Stratification analysis based on gender found that most of the associations were still observed in girls.In addition,some kinds of PAEs affected the growth trajectory of children during the first and second trimesters,but did not influence health during the third trimester.LMM analyses showed that MEHP exposure during pregnancy was associated with decreased maternal total thyroxine(TT4)levels,and MEOHP,MEHHP,and DEHP exposure were associated with increased maternal total triiodothyronine(TT3)and TT4 ratio(T3/T4).MEHP and MEHHP exposure during pregnancy was positively correlated with thyroid stimulating hormone(TSH)concentrations in umbilical cord serum.The T3/T4 ratio in serum and TT3 level in umbilical cord serum of mothers played a negative mediating role in the association of MEOHP,MEHHP and DEHP exposure with WAZ.For MEOHP,MEHHP and DEHP,the mediating effect of maternal T3/T4 ratio was 27.55%,14.94% and 15.97%,respectively.The mediating effect of fetal TT3 was 22.73%,30.77%,and 16.56%,respectively.Conclusions1.Pregnant women are ubiquitously exposed to a variety of PAEs,and the cumulative exposure risk during pregnancy is considerable.The creatinine-adjusted model is more suitable.for assessing CRA than the volume fraction model.2.There is a non-linear correlation between PAEs and gestational age.Exposure to MMP in the second and third trimester increases the risk of preterm infants,especially among girls.There is a non-linear "J" relationship between the exposure to LMWP and MEHP and the risk of preterm infants.3.Exposure to PAEs during pregnancy increases the growth trajectory of infants,and girls are more sensitive.Early pregnancy may be a critical window period.4.Exposure to DEHP during pregnancy affects thyroid function and increases the maternal T3/T4 ratio and fetal TSH level.DEHP exposure may affect the growth trajectory of infants by interfering with maternal T3/T4 and reducing fetal TT3 level.