Association between prenatal exposure to perfluoroalkyl substance mixtures and intrauterine growth restriction risk: A large, nested case-control study in Guangxi, China.

Intrauterine growth restriction (IUGR) is an abnormal fetal growth pattern that can lead to neonatal morbidity and mortality. IUGR may be affected by prenatal exposure to environmental pollutants, including perfluoroalkyl substances (PFASs). However, research linking PFAS exposure to IUGR is limited, with inconsistent results. We aimed to investigate the association between PFAS exposure and IUGR by using nested casecontrol study based on Guangxi Zhuang Birth Cohort (GZBC), in Guangxi, China. A total of 200 IUGR cases and 600 controls were enrolled in this study. The maternal serum concentrations of nine PFASs were measured using ultrahigh-performance liquid chromatography-tandem mass spectrometry (UPLCMS). The associations single and mixed effects of prenatal PFAS exposure on IUGR risk were assessed using conditional logistic regression (single-exposure), Bayesian kernel machine regression (BKMR) and quantile g-computation (qgcomp) models. In the conditional logistic regression models, the log10-transformed concentrations of perfluoroheptanoic acid (PFHpA, adjusted OR: 4.41, 95% CI: 3.03-6.41), perfluorododecanoic acid (PFDoA, adjusted OR: 1.94, 95% CI: 1.14-3.32), and perfluorohexanesulfonate (PFHxS, adjusted OR: 1.83, 95% CI: 1.15-2.91) were positively associated with risk of IUGR. In the BKMR models, the combined effect of PFASs was positively associated with IUGR risk. In the qgcomp models, we also found an increased IUGR risk (OR=5.92, 95% CI: 2.33-15.06) when all nine PFASs increased by one tertile as a whole, and PFHpA (43.9%) contributed the largest positive weights. These findings suggested prenatal exposure to single and mixtures of PFASs may increase IUGR risk, with the effect being largely driven by the PFHpA concentration.

Association between perfluoroalkyl and polyfluoroalkyl substances exposure and fetal overgrowth: A prospective birth cohort study conducted in China.

BACKGROUND: Prenatal exposure to perfluoroalkyl and polyfluoroalkyl substances (PFASs) has been associated with gestational diabetes mellitus, obesity or overweight in childhood, but data on fetal overgrowth outcomes including macrosomia and large for gestational age (LGA) and among gestational age diverse infants remain scarce. OBJECTIVE: To evaluate the association between maternal PFASs exposure and macrosomia and LGA, with exploration of the interaction between PFASs exposure and gestational age on fetal overgrowth. METHODS: A total of 1441 mother-infants pairs from Guangxi Zhuang Birth Cohort of China were analyzed. Nine PFASs were measured in maternal serum using ultra-high liquid performance chromatographytandem mass spectrometry. Multivaraible logistical regression and generalized additive models were performed for individual PFAS exposures, piecewise regression analysis was used to estimate the breakpoint values for the non-linear dose-response relationships. Bayesian Kernel Machine Regression was performed for PFASs mixture. RESULTS: In single pollutant models, maternal PFDA and PFOA exposure showed U-shaped relationship with macrosomia and LGA. When PFDA concentration exceeded 0.32 ng/mL was significantly positively associated with risks of LGA and macrosomia (OR=4.66, 95%CI: 1.26, 17.17; OR=14.43, 95%CI: 2.64, 79.02; respectively), while a negatively association was observed when level below 0.32 ng/mL. When PFOA concentration exceeded 1.20 ng/mL was significantly associated with increased risk of macrosomia (OR=7.75, 95%CI: 1.36, 44.06). In mixed exposure models, mixture of PFASs was positively associated with macrosomia, as well as associated with LGA when all the PFASs were at their 30th percentile or below. The maximum risk of LGA was reached when concentrations of PFUnA, PFDA, or PFBS were at the highest concentrations and the gestational age at the minimum of this study. CONCLUSIONS: Maternal exposure to PFDA, PFOA and PFASs mixture were non-monotonically associated with macrosomia and LGA, the direction of the associations depends on the level of exposure.

Association between maternal exposure to per- and polyfluoroalkyl substances and serum markers of liver function during pregnancy in China: A mixture-based approach.

Previous studies have shown that per- and polyfluoroalkyl substances (PFAS) may have hepatotoxic effects in animals. However, epidemiological evidence in humans, especially pregnant women, is limited. This study aimed to assess the association of single and multiple PFAS exposure with serum markers of liver function in pregnant women. A total of 420 pregnant women from the Guangxi Zhuang Birth Cohort were enrolled from June 2015 to April 2019. Nine PFAS were measured in the maternal serum in early pregnancy. Data for liver function biomarkers, namely, alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyltransferase (GGT), total bilirubin (TBIL), direct bilirubin (DBIL), and indirect bilirubin (IBIL), were obtained from medical records. In generalized linear model (GLM), there was a positive association of perfluorooctane sulfonate (PFOS) with ALT, perfluorodecanoic acid (PFDA) and perfluorobutanesulfonic acid (PFBS) with GGT, and perfluorohexane sulfonate (PFHxS) with TBIL and IBIL. In contrast, there was a negative association of perfluoroheptanoic acid (PFHpA) with TBIL. There were inverse U-shaped relationships of PFUnA with ALT and AST and PFDA with ALT by restricted cubic spline. The weighted quantile sum (WQS) regression model revealed the positive effects of the PFAS mixture on GGT, TBIL, DBIL, and IBIL. Bayesian kernel machine regression (BKMR) analysis confirmed that the PFAS mixture was positively associated with GGT, and PFBS was the main contributor. In addition, the BKMR model showed a positive association of individual PFBS with GGT, individual PFHxS with TBIL and IBIL, and a negative association of individual PFHpA with TBIL. Our findings provide evidence of an association between individual PFAS, PFAS mixture and maternal serum markers of liver function during pregnancy. Additionally, these findings also enhance concerns over PFAS exposure on maternal liver function and PFAS monitoring in pregnancy, reducing the effect of maternal liver dysfunction on maternal and infant health.

Effects of prenatal exposure to bisphenols on newborn leucocyte telomere length: a prospective birth cohort study in China.

Telomere length (TL) at birth is related to diseases that may arise in the future and long-term health. Bisphenols exhibit toxic effects and can cross the placenta barrier. However, the effects of prenatal exposure to bisphenols on newborn TL remain unknown. We aimed to explore the effects of prenatal exposure to bisphenols (i.e., bisphenol A [BPA], bisphenol B [BPB], bisphenol F [BPF], bisphenol S [BPS] and tetrabromobisphenol A [TBBPA]) on relative TL in newborns. A total of 801 mother-infant pairs were extracted from the Guangxi Zhuang Birth Cohort. The relationship between bisphenol levels in maternal serum and relative TL in cord blood was examined by generalized linear models and restricted cubic spline (RCS) models. After adjusting for confounders, we observed a 3.19% (95% CI: -6.08%, -0.21%; P = 0.037) reduction in relative cord blood TL among mothers ≥ 28 years old, with each onefold increase in BPS. However, in each onefold increase of TBBPA, we observed a 3.31% (95% CI: 0.67%, 6.01%; P = 0.014) increase in relative cord blood TL among mothers < 28 years old. The adjusted RCS models revealed similar results (P overall < 0.05, P non-linear > 0.05). This study was the first to establish a positive association between serum TBBPA levels and relative TL in newborns born to young mothers. However, BPS levels were inversely correlated with TL in fetus born to old mothers. The results suggested that the fetus of old pregnant women may be more sensitive to BPS exposure. Moreover, BPS exposure early in life may accelerate aging or increase the risk of developing BPS-related diseases in later life.

Association of serum per- and polyfluoroalkyl substances and gestational anemia during different trimesters in Zhuang ethnic pregnancy women of Guangxi, China.

BACKGROUND: Gestational anemia is a complication of pregnancy, and a low level of hemoglobin (Hb) has been linked to adverse pregnancy outcomes. Previous studies reported that PFASs were more strongly associated with Hb than red blood cells, indicating that Hb is more susceptible to the effect of PFASs. However, the evidences regarding the effects of per- and polyfluoroalkyl substances (PFASs) on gestational anemia are currently limited. Therefore, it is important to explore the effects of PFASs on anemia in Chinese pregnant women. METHODS: A total of 821 pregnant women were recruited between June 2015 and April 2019 in the Guangxi Zhuang Birth Cohort. The concentrations of PFASs were assessed in maternal serum before 12 gestational weeks. To determine both individual and combined associations of PFASs exposure with anemia in the three stages of pregnancy, binary logistic regression, Bayesian kernel machine regression (BKMR), and weighted quantile sum (WQS) regression models were employed. RESULTS: In single-pollutant analysis, maternal exposure to perfluorododecanoic acid (PFDoA) and perfluoroheptanoic acid (PFHpA) were associated with anemia in the first trimester, exposure to PFHpA and perfluorobutanesulfonic acid (PFBS) were associated with anemia in the second trimester, and exposure to perfluorodecanoic acid (PFDA) and perfluorononanoic acid (PFNA) were associated with anemia in the third trimester. Notably, perfluoroundecanoic acid (PFUnA) had a nonlinear association with anemia in the third trimester. In multiple-pollutant analysis, a positive association of PFDoA with anemia in the first trimester and a negative association of PFBS with anemia in the second trimester were confirmed by BKMR. Exposure to PFASs mixture was not associated with anemia in all three trimesters. In WQS, there was a significantly negative association between the PFAS mixture and anemia in the second trimester. CONCLUSION: Maternal exposure to PFASs is associated with gestational anemia in different trimesters.

Association of maternal perfluoroalkyl substance exposure with postpartum haemorrhage in Guangxi, China.

Postpartum haemorrhage (PPH) is the leading cause of maternal death worldwide, and it may be caused by environmental endocrine disruptors. Prenatal exposure to perfluoroalkyl substances (PFASs) in women has been linked to pregnancy disorders and adverse birth outcomes, but no data are available on the relationship between PFAS exposure during pregnancy and postpartum haemorrhage. This study aimed to explore the associations of maternal PFAS exposure with the postpartum haemorrhage risk and total blood loss. A total of 1496 mother-infant pairs in the Guangxi Zhuang birth cohort were included between June 2015 and May 2018. The concentration of PFASs in serum was detected using ultrahigh liquid chromatography-tandem mass spectrometry. Multiple binomial regression and linear regression models were used to analyse individual PFAS exposures. The mixture of PFASs was analysed using Bayesian Kernel Machine Regression (BKMR). In single substance exposure models, exposure to perfluorohexanesulfonic acid (PFHxS) increased the risk of postpartum haemorrhage (OR: 3.42, 95 % CI: 1.45, 8.07), while exposure to perfluorododecanoic acid (PFDoA) was inversely associated with the risk of postpartum haemorrhage (OR: 0.42, 95 % CI: 0.22, 0.80). The concentrations of perfluoroundecanoic acid (PFUnA) (ß: 0.06, 95 % CI: 12.32, 108.82) and perfluorononanoic acid (PFNA) (ß: 0.05, 95 % CI: 0.40, 88.95) exposure were positively correlated with the amount of postpartum haemorrhage; this result occurred only in the absence of covariate adjustment. In BKMR models, the risk of postpartum haemorrhage increased with increasing exposure to a PFAS mixture. In conclusion, our study suggested that maternal serum PFAS exposure during pregnancy was associated with the risk of postpartum haemorrhage.

Association of single and multiple prefluoroalkyl substances exposure with preterm birth: Results from a Chinese birth cohort study.

BACKGROUND: Perfluoroalkyl substances (PFASs) are persistent organic pollutants that may lead the adverse birth outcomes, including preterm birth (PTB). However, previous studies have reported inconsistent results on the association between PFASs and PTB, and lack of the epidemiological evidence regarding the effect of PFASs mixture on PTB. This study aimed to explore association of individual and multiple exposure to PFASs with PTB. METHODS: The study subjects were consisted of 1341 pregnant women from Guangxi Zhuang Birth Cohort in Guangxi, China, from June 2015 to April 2019. Nine PFASs concentrations in the maternal serum were examined by ultrahigh liquid performance chromatography-tandem mass spectrometry, and the gestational weeks were obtained from medical records. We applied binary logistics regression model to explore correlation between individual PFAS and PTB and inspected the combined effect of PFASs mixture on PTB by applying Bayesian kernel machine regression (BKMR) and weighted quantile sum (WQS) regression models. RESULTS: In adjusted logistics regression model, perfluorooctane sulfonate (PFOS), perfluoroheptanoic acid (PFHpA), perfluorobutanesulfonic acid (PFBS), ∑perfluorinated sulfonic acids (PFSA), and ∑PFASs were positively associated with the risk of PTB. In contrast, perfluoroundecanoic acid (PFUnA), perfluorohexane sulfonate (PFHxS), and perfluorooctanoic acid (PFOA) were negatively associated with the risk of PTB. These associations of n PFOS and PFHpA with PTB were found to be more pronounced in male infants. Restricted cubic splines (RCSs) showed an inverse U-shaped relationship between PFBS and PTB. Analysis from BKMR model showed a positive association between PFASs mixture and PTB, and no evidence of interactions among the nine PFASs were detected. Additionally, PFHpA, PFOS, and PFBS were identified as the main contributors for the effect of PFASs mixture on increasing the risk of PTB by BKMR and WQS models. CONCLUSION: Prenatal exposure to higher levels of PFASs mixture was associated with higher risk of PTB.

Association between Intrauterine Microbiome and Risk of Intrauterine Growth Restriction: A Case-Control Study Based on Guangxi Zhuang Birth Cohort in China.

Substantial evidence show that intrauterine growth restriction (IUGR) is linked to both short-term and long-term health consequences. Recent studies have shown that the intrauterine environment harbors a diverse community of microbes. However, the relationship between intrauterine microbiome and IUGR has been rarely studied. In our investigation of 35 neonates with IUGR and 187 neonates without IUGR, we found that the intrauterine microbiome was largely composed of nonpathogenic commensal microbiota from the Proteobacteria, Firmicutes, Actinobacteria, and Bacteroidetes phyla. Carriage of genera Afipia [odds ratio (OR) 0.24; 95% confidence interval (CI) 0.10-0.60], Hydrogenophaga (OR 0.10; 95% CI 0.01-0.76), and Perlucidibaca (OR 0.25; 95% CI 0.10-0.61) were significantly associated with decreased risk of IUGR, while one log10-unit increasing of relative abundance the genera Catenibacterium (OR 2.56; 95% CI 1.09-6.01) and Senegalimassilia (OR 1.78; 95% CI 1.00-3.16), and carriage of Holdemanella (OR 4.07; 95% CI 1.54-10.76), Parvimonas (OR 3.33; 95% CI 1.16-9.57), Sandaracinus (OR 3.27; 95% CI 1.21-8.84), and Streptococcus (OR 3.52; 95% CI 1.13-10.95) were associated with increased risk of IUGR. The present study firstly demonstrated that carriage of Afipia, Hydrogenophaga, and Perlucidibaca in the intrauterine environment is associated with a decreased risk of IUGR, while carriage of Holdemanella, Parvimonas, Sandaracinus, and Streptococcus, and increased relative abundance of Catenibacterium and Senegalimassilia are associated with an increased risk of IUGR. The study provides evidence that the intrauterine microbiome may play a role in the etiology of IUGR.

Association between maternal per- and polyfluoroalkyl substance exposure and newborn telomere length: Effect modification by birth seasons.

BACKGROUND: Telomere length (TL) is an important biomarker of biological aging and disease that may be affected by prenatal exposure to environmental pollutants. Birth seasons have been linked to reproductive and immune-related diseases. Prenatal exposure to per- and polyfluoroalkyl substance (PFAS) has been associated with adverse birth outcomes, but the effects of PFAS and birth seasons on newborn TL are poorly understood. OBJECTIVES: To explore the individual and combined effects of maternal PFAS exposure on newborn TL, with exploration of the interaction between PFAS and birth seasons on newborn TL. METHODS: Between June 2015 and May 2018, a total of 499 mother-newborn pairs were recruited for a birth cohort study in Guangxi, China. Maternal blood samples were collected during pregnancy. Nine PFASs were measured by ultraperformance liquid chromatography-mass spectrometry. Newborn TL was assessed using quantitative real-time polymerase chain reaction. Modeling newborn TL as the outcome, multivariable linear regressions were performed for individual PFAS exposures, and Bayesian Kernel Machine Regressions were performed for PFAS mixtures. Furthermore, interaction analyses were conducted to evaluate the effect modification by birth seasons in these relationships. RESULTS: For both single and multipollutant models, PFASs exposure were inversely associated with newborn TL, although none of the relationships were significant. The mixture of PFASs showed a potential positive trend of combined effect on newborn TL but non-statistically significant. Each ln-transformed unit concentration increase in PFOA was related to a 20.41% (95% CI: -30.44%, -8.93%) shorter TL in spring-born infants but not in those born in other birth seasons. Mothers in the middle and highest tertiles of PFOA exposure had 11.69% and 10.71% shorter TLs in spring-born infants, respectively. CONCLUSION: Maternal PFAS exposure showed little association with newborn TL. The results suggested potential effect modification by birth season on the association between PFOA exposure and newborn TL.

Exposure to perfluoroalkyl substances in early pregnancy and the risk of hypertensive disorders of pregnancy: A nested case-control study in Guangxi, China.

BACKGROUND: Previous epidemiological studies have examined the associations between exposure to perfluoroalkyl substances (PFASs) and the risk of hypertensive disorders of pregnancy (HDP). However, these studies have drawn discrepant conclusions and have some limitations. METHODS: A nested case-control study was conducted with the Guangxi Zhuang Birth Cohort (GZBC), a prospective, ongoing birth cohort that was implemented in Guangxi, China, in June 2015. Maternal serum concentrations of nine PFASs were measured using ultra-high-performance liquid chromatography-tandem mass spectrometry (UPLC-MS). The associations between PFAS exposure and the risk of HDP were assessed using logistic regression (single-exposure), weighted quantile sum (WQS) regression, and Bayesian kernel machine regression (BKMR) models. RESULTS: A total of 136 HDP cases and 408 controls were enrolled in this study. In logistic regression models, perfluoroundecanoic acid (PFUnA), perfluorooctane sulfonate (PFOS), perfluorononanoic acid (PFNA) and perfluorobutanesulfonic acid (PFBS) were positively associated with HDP, while perfluorohexane sulfonate (PFHxS) was inversely associated with HDP. In the BKMR analysis, the joint effect of PFASs was positively associated with HDP. PFOS and PFBS showed positive trends, while PFHxS and PFHpA showed inverse trends. In WQS regression analysis, we calculated two WQS indices that were estimated using constraints in both the positive and negative directions of effects. Both WQS indices were significantly associated with HDP (OR: 2.663, 95% CI: 1.795-3.951; OR: 0.338, 95% CI: 0.229-0.499, respectively). PFBS, PFOS and PFUnA had significant weights in the positive effect direction; PFHxS, perfluoroheptanoic acid (PFHpA) and perfluorododecanoic acid (PFDoA) had significant weights in the negative effect direction. CONCLUSION: Considering all model results, we found that combined exposure to nine PFASs had a positive effect on the development of HDP. Moreover, PFOS and PFBS were positively associated with the HDP risk, while PFHxS and PFHpA were negatively associated with the HDP risk in women in Guangxi, China.

A liver-specific lncRNA, FAM99B, suppresses hepatocellular carcinoma progression through inhibition of cell proliferation, migration, and invasion.

BACKGROUND: Increasing evidence has shown that long non-coding RNAs (lncRNAs) are important in hepatocellular carcinoma (HCC) development and progression. In this study, we aim to evaluate the expression of lncRNA FAM99B and its biological function in HCC. METHODS: The expression level of FAM99B in HCC was assessed based on data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO), verified using quantitative real-time polymerase chain reaction (qRT-PCR). HCCLM3 was transfected with lentivirus containing full-length FAM99B to obtain stable overexpressing cell line. Cell Counting Kit 8, clone formation, and transwell assays were used to investigate the effects of FAM99B in HCC progression. In addition, Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, and PANTHER pathway analyses were conducted to investigate the underlying molecular mechanisms. RESULTS: FAM99B was found to be downregulated in HCC tissues compared with adjacent normal tissues based on TCGA, GEO, and qRT-PCR data. Our results revealed that downregulated FAM99B was significantly associated with vascular invasion, advanced histologic grade, and T stage. Kaplan-Meier analysis using TCGA data indicated that decreased FAM99B levels were significantly associated with poor overall survival in patients with HCC. Moreover, overexpression of FAM99B significantly inhibited cell proliferation, migration, and invasion in vitro. Pathway analyses showed that the co-expressed genes of FAM99B mainly participated in the pathways "Metabolic pathways" and "Blood coagulation". CONCLUSION: Our results suggest that FAM99B may serve as a tumor suppressor in HCC and may provide a promising therapy target for patients with HCC.