DNA methylation is one potential mechanism for the effects of gestational exposure to perfluoroalkyl substances (PFASs) on fetal growth. We investigated 180 pregnant women who participated in a cohort study conducted in Tangshan City, Northern China, and determined the concentrations of 11 PFASs and the methylation of two genes related to fetal growth [insulin-like growth factor 2 (IGF2) and nuclear receptor subfamily 3 group C member 1 (NR3C1)] and one surrogate marker for global methylation [long interspersed nuclear element-1 (LINE-1)] in placenta tissue. Multiple linear regression analysis was performed to examine the associations of log transformed PFASs with the DNA methylation and birth size. Weighted quantile sum regression was used to determine the mixture effect of PFASs. After adjusting for potential confounders, perfluorooctane sulfonate (PFOS) was negatively associated with the overall methylation of LINE-1. PFASs mixture was negatively associated with the methylation of all CpG loci of LINE-1 and overall methylation of NR3C1. Perfluorootanoic acid (PFOA), perfluorononanoic acid (PFNA), perfluorodecanoic acid (PFDA), and the PFASs mixture showed negative associations with head circumference. After stratified by newborns' sex, PFOA, PFNA and the PFASs mixture was negatively associated with overall methylation of LINE-1 only in the male subgroup and the methylation of all CpG loci of LINE-1 was negatively associated with ponderal index only in the female subgroup. The interaction of newborns' sex with PFOS and PFOA on overall methylation of IGF2 was statistically significant and so was the interaction of sex with PFOS on overall methylation of LINE-1. These findings suggested that intrauterine exposure to PFASs affected placental DNA methylation and reduced fetal growth, which might be modified by sex.

DNA methylation has been hypothesized to mediate the effects of exposure to perfluoroalkyl substances (PFASs) on fetal growth, but few studies have well explored it. We selected 180 pregnant women from a cohort study conducted in Tangshan City, Northern China, determined 11 PFASs concentrations and DNA methylation of two genes related to fetal growth (Insulin-like growth factor 2 (IGF2) and Nuclear Receptor Subfamily 3 Group C Member 1 (NR3C1)) and one gene related to genome stability (Long Interspersed Nuclear Element-1 (LINE-1)) in placenta tissue, and measured body length, body weight, and head circumference of neonates. Weighted quantile sum regression was used to explore the mixture effect of PFASs. Mediation analysis was performed to examine the effects of DNA methylation on the relationship between PFASs and birth size. After adjusting for confounders, natural logarithmic transformed perfluorooctane sulfonate (Ln PFOS) was negatively associated with averaged methylation of all CpG loci of LINE-1 (regression coefficient (β): -0.015, 95% confidence interval (CI): -0.029~-0.001). The mixture PFASs were negatively associated with the methylation of single CpG locus of LINE-1 and averaged methylation of all CpG loci of NR3C1 (β: -0.016~-0.010). Ln Perfluorootanoic acid (PFOA), perfluorononanoic acid (PFNA), perfluorodecanoic acid (PFDA), and the mixture of PFASs showed negative associations with head circumference (β: -0.284~-0.164). The methylation in the CpG_5 locus of LINE-1 showed a positive mediation effect (β: 0.138, 95% CI: 0.000~0.430) on the association between PFOS and ponderal index with accounting for 28.2% of the total effect. This study suggested that intrauterine exposure to PFASs affected DNA methylation and fetal growth, and DNA methylation might be an important mediator.

Previous studies have suggested that perfluoroalkyl substances (PFASs) can act as endocrine disruptors, but few studies have investigated the effects of serum PFASs on estrogen homeostasis during pregnancy. The present study included 557 pregnant women in Tangshan City, North China, and determined 11 serum PFASs in the early term of pregnancy and three typical estrogens (estrone (E1), estradiol (E2) and estriol (E3)) in the early (n = 557), middle (n = 339), and late (n = 286) terms of pregnancy. Sociodemographic factors and diet information were obtained by structured questionnaires. After adjusting for potential confounders, multiple linear regression model demonstrated negative associations of natural logarithmic transformed serum perfluoroundecanoic acid (Ln PFUdA) with Ln E1 and Ln E3 in the early term of pregnancy with beta coefficients of -0.060 (95% confidence interval (CI): -0.101 to -0.019) and -0.041 (95% CI: -0.070 to -0.011), respectively. Ln perfluorodecanoic acid (PFDA) was negatively associated with averaged E1 in the early and middle (EM) terms of pregnancy with a beta coefficient of -0.205 (95% CI: -0.357 to -0.053). Ln perfluorononanoic acid (PFNA) tended to be negatively associated with E2 in the late term of pregnancy with a beta coefficient of -0.134 (95% CI: -0.253 to -0.016) although p-value was slightly greater than 0.05 after false discovery rate (FDR) correction. Mixed effect model found that serum PFDA was negatively associated with E1 (beta = -0.123, 95% CI: -0.235 to -0.012) during the entire pregnancy. These findings suggested that exposure to PFASs disturbed estrogen homeostasis in pregnant women and the effects varied with the terms of pregnancy. (C) 2021 Published by Elsevier B.V.

Histone modification is closely associated with several diseases. The aim of the current study was to investigate the associations among histone acetylation, matrix metalloproteinases (MMPs) and premature rupture of membranes (PROM) during pregnancy. A total of 180 puerperants were divided into three groups: i) Preterm-PROM (PPROM), ii) term-PROM (TPROM) and iii) full-term labor (FTL). Enzyme-linked immunosorbent assay (ELISA) kits and western blotting were used to determine the protein concentrations of MMP2, MMP9, histone deacetylase (HDAC)1, HDAC2 and HDAC6, and the protein levels of histone H4 lysine (H4K)5 and H4K8 acetylation, respectively, in three types of fetal membranes. Additionally, human amniotic epithelial cells were used to determine the effects of the HDAC inhibitors droxinostat and chidamide on cell viability, histone acetylation and the levels of MMP2, MMP9, HDAC1, HDAC2 and HDAC6 in vitro, using the Cell Counting Kit-8 assay, western blotting and ELISA, respectively. Furthermore, the effects of droxinostat and chidamide on the invasion and migration abilities of human amniotic epithelial cells were investigated using transwell assays. In fetal membranes, the activities of MMP2 and MMP9 increased in PPROM, but decreased in TPROM. Further, the expression of HDAC1 was decreased and histone hyperacetylation was increased in both PPROM and TRPOM. In vitro experiments revealed that 5 µM droxinostat and 0.5 µM chidamide selectively decreased the level of HDAC and induced acetylation of H4K5 and H4K8. Additionally, the aforementioned HDAC inhibitors reduced human amniotic epithelial cell viability, invasion and migration, and decreased the expression levels of MMP2 and MMP9. The current study revealed a high expression level of MMP2 and MMP9 in PPROM compared with TPROM and FL tissue, which was in accordance with previously published studies. Furthermore, the in vitro tests performed in the current study revealed the effect of histone H4 hyperacetylation on inhibiting MMP2 and MMP9 levels in vitro was similar to that observed in TPROM. The results obtained in the current study may be used as a theoretical guide for clinical treatment of premature rupture of membranes.

Laboratory and epidemiologic studies suggested that exposure to perfluoroalkyl substances (PFASs) could affect lipid metabolisms, but data remain limited for pregnant women. A total of 436 pregnant women were selected in Tangshan City, North China. Serum levels of 11 PFASs were determined in the early term of pregnancy. Four lipids (total cholesterol (TC), triglyceride (TG), high-density lipoprotein (HDL), and low-density lipoprotein (LDL)) were measured in the late term of pregnancy. Of 11 PFASs, seven had a detection rate of greater than 70%. After adjusting for potential confounders, natural log-transformed perfluororohexanesulfonic acid (ln PFHxS) was positively associated with TC (beta: 0.184, 95% CI: 0.045-0.321), HDL (beta: 0.040, 95% CI: 0.001-0.083), and LDL (beta: 0.091, 95% CI: 0.001-0.185). Ln perfluoroundecanoic acid (PFUdA) was positively associated with HDL (beta: 0.021, 95% CI: 0.001-0.044), while Ln perfluorodecanoic acid (PFDA) was negatively associated with LDL (beta: -0.053, 95% CI: -0.098 similar to-0.009) and ln perfluorootanoic acid (PFOA) was negatively associated with LDL/HDL (beta: -0.042, 95% CI: -0.075 similar to-0.009). In principal component analysis, the component with a large loading of 31.3% for PFOA, perfluorononanoic acid (PFNA), PFDA and PFUdA showed a negative association with LDL/HDL. After serum concentrations of PFASs were categorized into quartiles, a higher level of TC was seen in the second quartile of PFOA or PFNA than the first quartile, but a lower LDL/HDL ratio was seen in the fourth quartile of PFOA, PFUdA or PFDA. These results suggested that exposure to PFASs has a potential to influence lipid metabolisms in pregnant women. (C) 2020 Elsevier Ltd. All rights reserved.

Lab studies have suggested that exposure to Bisphenol A (BPA) could disturb glucose homeostasis, but epidemiologic studies are limited and show inconsistent results for pregnant women. For this, 535 pregnant women were selected from a pregnant women cohort established in Tangshan City in North China between 2013 and 2014. Serum concentrations of BPA were measured in the early term of pregnancy, and fasting glucose and insulin levels were repeatedly measured in each of three terms of pregnancy (early, middle, and late). Gestational diabetes mellitus (GDM) were examined by Oral Glucose Tolerance Test (OGTT) in the middle and late terms of pregnancy. BPA was detected in 97.5% of pregnant women with a median of 6.50 ng/ml. Natural log-transformed BPA (Ln BPA) was positively associated with fasting glucose level (β (95% CI): 0.038 (0.015~0.061)), fasting insulin level (0.195 (0.069~0.321)), and homeostasis model insulin resistance index (HOMA-IR) (0.226 (0.087~0.364)) in the middle term of pregnancy by multiple linear regression model after adjusting for potential confounders. After serum BPA levels were divided into three groups (low, middle, and high), BPA showed a positive dose-response relationship with blood glucose, insulin, and HOMA-IR in the middle term of pregnancy. Increased BPA concentration tended to increase the RR of GDM although not statistically significant (risk ratio: 2.51 (95% CI: 0.68~9.30) for high vs low tertile of BPA concentrations). These findings suggested that exposure to BPA might affect glucose homeostasis and the middle term of pregnancy was a potentially sensitive period.

Abstract The dietary phytosterols have been demonstrated to modulate CD4+ T‐cell polarization in cells, animals, and humans. However, T helper (Th)1/Th2 dichotomy has rarely been correlated with phytosterols during pregnancy. The present study investigated associations between the serum cytokines and serum phytosterols in 100 pregnant women at 34‐ to 37‐week gestation and their offspring. The results showed that serum concentrations of interferon (IFN)‐γ, tumor necrosis factor (TNF)‐α, and total Th1 cytokines were positively associated with serum β‐sitosterol level, adjusting for age, BMI, and serum cholesterol. Serum IFN‐γ and total Th1 cytokine concentrations positively correlated with total phytosterol concentration, controlling age, BMI, and serum cholesterol. Moreover, none of the cytokines measured correlated with phytosterol concentration in the newborns. Our results show that serum Th1 cytokine concentrations, but not Th2 levels, are positively associated with serum phytosterols in pregnant women. These findings implicate that phytosterols modulate Th1/Th2 balance by inducing Th1 secretions in pregnant women.

Laboratory studies have suggested that perfluoroalkyl substances (PFASs) could affect fetal growth by disrupting estrogen homeostasis, but there are limited data for human. For this, 424 mother-infant pairs were selected from a cohort established in Hebei Province of North China in 2013. Two typical PFASs, perfluorooctyl sulfonic acid (PFOS) and perfluorooctanoic acid (PFOA), and three typical estrogens, estrone (E1), β-estradiol (E2), and estriol (E3), were measured in cord serum. After adjusted for important covariates, serum PFOS was positively related to E1 and E3, but negatively related to E2. Serum PFOA was positively related to serum E1 and negatively related to head circumference at birth. Serum E2 was negatively related to head circumference, body weight, and body length at birth and serum E3 was positively related to body weight. Serum E3 mediated the relationship between serum PFOS and body weight. There were sex-specific differences for the associations between PFOS/PFOA and estrogens/birth size. These findings suggested that exposure to PFASs could affect estrogen homeostasis and fetal growth during pregnancy and that estrogens might mediate the association between exposure to PFASs and fetal growth.

Perfluoroalkyl acids (PFAAs) have been frequently found in blood of pregnant women, but the predictors and potential health risk have not been well studied in China. We recruited 534 pregnant women in Tangshan City of Hebei Province in North China between 2013 and 2014 and measured five PFAAs in serum during their early term of pregnancy, including perfluorooctanoic acid (PFOA), perfluorooctane sulfonic acid (PFOS), perfluorohexane sulfonic acid (PFHxS), perfluoro‑n‑undecanoic acid (PFUdA), and perfluorononanoic acid (PFNA). We explored the factors associated with the levels of serum PFAAs and assessed associated health risks. Food consumption information was obtained by food frequency questionnaire covering 100 items. Multiple linear regression model was used to determine the associations of sociodemographic, anthropometric, and food factors with the concentrations of serum PFAAs. Some PFAAs in serum were positively associated with age and body mass index (BMI). Consumption of beans, aquatic products, and eggs was positively associated with the concentrations of several PFAAs after adjusting for important covariates. Pregnant women who ate more cereal, vegetables, mushrooms and alga tended to have lower levels of serum PFOA, PFOS and PFNA. The Hazard index (HI) for reproductive toxicity and developmental toxicity was below 0.8, and the HI for hepatotoxicity beyond 1 was found in 0.37% of pregnant women. These results suggested that age, BMI, and some food consumption were predictors for the exposure to PFAAs in Chinese pregnant women. More attention should be paid to the hepatotoxicity for these exposures.

Background: Exposure to perfluoroalkyl substances (PFASs) can affect glucose homeostasis and has been suggested as a potential risk of diabetes mellitus, but data are limited for pregnant women. Objectives: We aimed to explore the associations of exposure to PFASs with glucose homeostasis and gestational diabetes mellitus (GDM) in Chinese pregnant women. Methods: The current study was conducted in Hebei Province of Northern China between 2013 and 2014 and 560 pregnant women were recruited in their early term of pregnancy and two representative serum PFASs, perfluorooctanoate (PFOA) and perfluorooctane sulfonate (PFOS), were measured. In 385 pregnant women who completed oral glucose tolerance test (OGTT), the associations of serum PFOA and PFOS concentrations with fasting blood glucose (FBG), fasting insulin (FIns), and homeostasis model assessment of insulin resistance (HOMA-IR) in the early, middle, and late terms of pregnancy and occurrence of GDM were examined using linear and Cox proportional hazard regression models. The reproducibility of serum PFASs during pregnancy was assessed in 230 pregnant women. Results: The intraclass correlation coefficients of serum PFASs, covariates, and outcomes based on averaged repeat measurement (0.35-0.96) were higher than those based on single measurement (0.16-0.92). Serum PFOA was positively associated with averaged FIns and HOMA-IR in the early, middle, and late terms of pregnancy and averaged blood glucose level at 1 h and 2 h of OGTT, but serum PFOS tended to be negatively associated with averaged FBG and OGTT blood glucose. The adjusted hazard ratios of GDM associated with serum PFOA and PFOS were 1.98 (95% confidence interval: 0.70-5.57; p-value: 0.197) and 0.71 (0.29-1.75; 0.453), respectively. Conclusions: Our data raised a possibility that exposure to PFASs might have different influences on glucose homeostasis and GDM in Chinese pregnant women. More lab and human studies are needed to further test the hypothesis and investigate potential mechanisms.

OBJECTIVE:To examine the association of maternal dietary patterns during pregnancy with gestational diabetes mellitus (GDM) in northern China.METHODS:The dietary intakes of pregnant women were recorded twice by 24-hour dietary recalls for three days prior to having been diagnosed with GDM, at 5-15 and 24-28 gestational weeks, respectively. GDM was diagnosed, and serum glycosylated hemoglobin (HbA1c) was measured at 24-28 weeks. Dietary patterns were assessed by factor analysis. The association of the dietary pattern with GDM and HbA1c was examined by multiple logistic models.RESULTS:Of 753 participants, 64 (8.5%) were diagnosed with GDM. Four dietary patterns were identified: Western pattern (dairy, baked/fried food and white meat), traditional pattern (light-colored vegetables, fine grain, red meat and tubers), mixed pattern (edible fungi, shrimp/shellfish and red meat) and prudent pattern (dark-colored vegetables and deep-sea fish). Compared with the prudent pattern, both the Western pattern and the traditional pattern were associated with an increased risk of GDM (aOR = 4.40, 95% CI: 1.58-12.22; aOR = 4.88, 95% CI: 1.79-13.32) and a high level of HbA1c (aOR = 12.37, 95% CI: 1.47-103.91; aOR = 26.23, 95% CI: 2.54-270.74). Compared to the lowest quartile (Q), Q3 of the Western pattern scores and Q3-Q4 of the traditional pattern scores were associated with a higher risk of GDM.CONCLUSION:The consumption of the Western pattern or the traditional pattern during pregnancy may increase the risk of GDM.

Background: This meta-analysis enabled us to obtain a precise estimation of the association between gene polymorphisms on chromosome 1 (MTHFR, AGT, F5, IL-10, LEPR) and the susceptibility to pre-eclampsia (PE) in order to reach a uniform conclusion.Material/Methods: Web of Science, PubMed, EMBASE, Cochran Library (CENTRAL), and Chinese databases (Chinese National Knowledge Infrastructure-CNKI and Wan Fang) were electronically searched to select relevant studies for this meta-analysis. We selected 95 case-control studies investigating 5 genes (MTHFR, AGT, F5, IL-10, and LEPR) with 8 SNPs. Odds ratios (OR) with their 95% confidence intervals (CI) were used for estimating the association.Results: A total of 16 646 PE patients and 28 901 normal-pregnancy patients were included in this meta-analysis. The overall results suggested that rs1801133 of MTHFR (OR=1.17, 95% CI: 1.05-1.13) and rs6025 of F5 (OR=1.53, 95% CI: 1.07-2.20) are significantly associated with PE, whereas rs1801131 of MTHFR, rs699 and rs4762 of AGT, rs1800896 and rs1800871 of IL-10, and rs1137101 of LEPR have no significant association with PE. Subgroup analysis by ethnicity revealed that, except for MTHFR rs1801133 and F5 rs6025 in Caucasians, which were significantly associated with an increased risk of PE, none of these SNPs were significantly associated with PE. As suggested by a symmetric funnel plot in conjunction with the Egger's test, there was no significant publication bias in MTHFR rs1801133 (P=0.318) and rs1801131 (P=0.204), F5 rs6025 (P=0.511), LEPR rs1137101 (P=0.511), AGT rs4762 (P=0.215) and rs699 (P=0.482), IL-10 rs1800871 (P=0.955), and rs1800896 (P=0.144).Conclusions: This meta-analysis provides evidence that MTHFR rs1801133 and F5 rs6025 are associated with an increased risk of PE, especially in Caucasians. However, we do not have sufficient evidence to conclude there is a significant association between other gene polymorphisms and PE.