Associations Of Perfluoroalkyl And Polyfluoroalkyl Substances During Pregnancy With Maternal-fetal Thyroid Hormones And Birth Weight: Potential Mediating Roles Of Thyroid Hormones

Perfluoroalkyl and polyfluoroalkyl substances(PFAS)are synthetic fluorinecontaining compounds that have been extensively used in various consumer products including surfactants,cookware,lubricants,clothing,and food packaging.Due to the strong carbon?fluorine bond,PFAS,in particular those with long-chain,can persist in the environment and human body for a long time.The persistence and widespread use of some PFAS have resulted in ubiquitous human exposure.Evidence showing that PFAS can cross the placental barrier and thus interfere fetal health.PFAS are environmental endocrine disruptors.Emerging evidence from toxicological and some epidemiological studies demonstrated that PFAS can interfere with thyroid hormones,particularly among pregnant women and children.However,results in relation to maternal exposure to PFAS are inconsistent.Further researches are warranted.Therefore,we performed our study based on two large birth cohorts.We measured the 10 PFAS and TH levels in blood samples collected among 1885 pregnant women from early pregnancy and in the cord blood of 568 prelabor caesarean deliveriers to explore the associations between PFAS and THs.Further,we also investigated the associations between cord blood PFAS and birth weight,and explored the potential mediating roles of thyroid hormones.Part 1: Perfluoroalkyl and polyfluroalkyl substances and maternal thyroid hormones in early pregnancyObjectives: We aimed to assess the relationship between PFAS and maternal thyroid hormones in early pregnancy based on a large prospective cohort study.Methods: A total of 1885 pregnant women enrolled in the Shanghai Birth Cohort were used.Ten PFAS,FT3,FT4,TSH and TPOAb were measured in maternal blood collected prior to 16 weeks of gestation.Multiple linear regression accompanied by restricted cubic spline was used to examine the association and the exposure-response relationship between each PFAS and TH in separate models.Possible effect modification by TPOAb status was also investigated.Results: In multiple linear regression model,PFOA(β= 0.118,95% CI: 0.011,0.224)and PFHx S(β= 0.123,95% CI: 0.023,0.223)were positively associated with FT4.PFNA(β=0.161,95% CI: 0.029,0.293)and PFHx S(β= 0.187,95% CI: 0.045,0.33)were positively associated with FT3,while PFHx S was negatively associated with TSH(β=-0.113,95%CI:-0.214,-0.012).The exposure-response curves show that most of the associations between PFAS and thyroid hormones were linear except for the associations between PFHx S(P-nonlinear=0.008),PFHp A(P-nonlinear=0.027)and FT4.TPOAb-positivity appeared to modify the associations between PFAS and THs.In TPOAb-positive women,several long-chain PFAS were positively associated with FT4 and/or FT3 and tended to be negatively associated with TSH.Conclusions: Exposure to several long-chain PFAS,either individually or as a mixture,was associated with disrupted TH homeostasis in Chinese pregnant women,especially among TPOAb-positive women.Part 2: Perfluoroalkyl and polyfluoroalkyl substances and fetal thyroid hormone levels in umbilical cord blood among newborns by prelabor caesarean deliveryObjectives: We aimed to examine the association between cord blood PFAS concentrations and TH levels in prelabor caesarean deliveries.Methods: We measured ten PFAS and three THs in cord blood in 568 prelabor caesarean deliveries.The associations between PFAS and TH levels were examined using multiple linear regression model and sparce partial least regression(SPLS)regression model.Results: In SPLS analyses,TSH level decreased with increasing concentrations of PFOS(β=-0.031,95%CI:-0.052,-0.013),PFNA(β=-0.030,95% CI:-0.048,-0.014),PFDA(β=-0.030,95% CI:-0.048,-0.014),PFUA(β=-0.031,95% CI:-0.049,-0.013),PFHx S(β=-0.022,95% CI:-0.047,-0.002)and PFDo A(β=-0.034,95% CI:-0.057,-0.017).Moreover,we found a positive association between PFDo A and FT4 levels(β= 0.141,95% CI: 0.064,0.221)after adjusting for potential confounders.FT3 levels were positively associated with concentrations of PFOS(β= 0.113,95% CI: 0.039,0.189),but negatively associated with PFDo A(β=-0.307,95% CI:-0.428,-0.207).When stratified by gender,we found that PFOA(β= 0.062,95% CI: 0.024,0.138),PFNA(β= 0.040,95% CI: 0.006,0.081),PFDA(β= 0.043,95% CI: 0.016,0.078),PFDo A(β= 0.054,95% CI: 0.019,0.119)and PFBS(β= 0.056,95% CI: 0.009,0.158)were positively associated with FT4 among male infants.PFDo A(β= 0.174,95% CI: 0.019,0.331)was negatively associated with FT4 and PFBS(β= 0.098,95% CI: 0.021,0.182)was positively associated with FT3 in female infants.We also observed negative associations of TSH with PFDo A(β=-0.062,95% CI:-0.108,-0.017)in male infants and PFOS(β=-0.016,95% CI:-0.032,-0.002)in female infants.Conclusion: Our results suggest that prenatal exposure to certain PFAS may affect fetal thyroid function.The effect may be gender-specific.Part 3: Prenatal exposure to perfluoroalkyl and polyfluoroalkyl substances and birth weight: Potential mediating roles of thyroid hormonesObjective: We aimed to quantify the associations between cord blood serum-PFAS concentrations and birth weight.We also aimed to elucidate whether THs potentially mediate the associations between PFAS concentrations and birth weight.Methods: We included 568 prelabor caesarean deliveries from a prospective birth cohort study in Shanghai.Ten PFAS and THs were measured in cord serum.Associations between PFAS concentrations and birth weight were estimated using multivariable linear regressions.Sex-stratified analyses along with a mediation analysis were performed to estimate potential mediating effects of THs in the association between PFAS and birth outcomes.Results: We found PFNA(β=90g,95%CI: 8,173),PFDo A(β=91g,95%CI: 32,151),PFBS(β=82g,95%CI: 24,140)were positively associated with birth weight.After stratified by sex,PFNA,PFDo A,PFBS were significantly associated with birth weight in male infants only.Overall,THs were not found to mediate associations between PFASs and birth weight.Conclusion: These findings suggested that exposure to PFAS was positively associated with increased birth weight and THs,which however did not explain increased birth weight among children exposed to PFAS.Additional research is needed to confirm our findings in other populations and to evaluate potential consequences later in life.