Comparative secretome metabolic dysregulation by six engineered dietary nanoparticles (EDNs) on the simulated gut microbiota.

The potential use of engineered dietary nanoparticles (EDNs) in diet has been increasing and poses a risk of exposure. The effect of EDNs on gut bacterial metabolism remains largely unknown. In this study, liquid chromatography-mass spectrometry (LC-MS) based metabolomics was used to reveal significantly altered metabolites and metabolic pathways in the secretome of simulated gut microbiome exposed to six different types of EDNs (Chitosan, cellulose nanocrystals (CNC), cellulose nanofibrils (CNF) and polylactic-co-glycolic acid (PLGA); two inorganic EDNs including TiO2 and SiO2) at two dietary doses. We demonstrated that all six EDNs can alter the composition in the secretome with distinct patterns. Chitosan, followed by PLGA and SiO2, has shown the highest potency in inducing the secretome change with major pathways in tryptophan and indole metabolism, bile acid metabolism, tyrosine and phenol metabolism. Metabolomic alterations with clear dose response were observed in most EDNs. Overall, phenylalanine has been shown as the most sensitive metabolites, followed by bile acids such as chenodeoxycholic acid and cholic acid. Those metabolites might be served as the representative metabolites for the EDNs-gut bacteria interaction. Collectively, our studies have demonstrated the sensitivity and feasibility of using metabolomic signatures to understand and predict EDNs-gut microbiome interaction.

Associations of per- and polyfluoroalkyl substances and alternatives with reproductive hormones in women of childbearing age.

BACKGROUND: Experimental studies suggested that per- and polyfluoroalkyl substances (PFAS) may have endocrine-disrupting effects. However, the epidemiological evidence on the associations of PFAS with female reproductive hormones is sparse and limited to perfluorooctanesulfonic acid (PFOS) and perfluorooctanoic acid (PFOA). OBJECTIVE: To evaluate effects of legacy and emerging PFAS alternatives on female reproductive hormones. METHODS: A total of 433 reproductive-aged females were recruited from 2014 to 2016. Information on age, age at menarche, gravity, menstrual cycle, BMI, education, and income was obtained from medical records and questionnaires. Serum samples were collected for reproductive hormones, and plasma samples for PFAS measurement by ultraperformance liquid chromatography - tandem mass spectrometer (UPLC-MS/MS). Multiple linear regression and quantile g-computation (q-gcomp) were used to examine the associations of individual PFAS and their mixture with reproductive hormones. RESULTS: Multiple linear regression analysis showed significant effects of certain PFAS on total testosterone (TT): adjusted estimate (ß) for perfluoroheptanoic acid (PFHpA) was 0.57 (95% CI: 0.18, 0.97). Moreover, a positive association was detected between PFAS mixture and TT in the q-gcomp model. Higher concentrations of 6:2 chlorinated polyfluorinated ether sulfonic acid (6:2 Cl-PFESA) were associated with significantly lower prolactin level (ß = -0.07, 95% CI: -0.14, -0.001). CONCLUSION: Our study found that exposure to PFAS alternatives was associated with altered levels of reproductive hormones in women of childbearing age.

A sensitive and robust method for the simultaneous determination of thirty-three legacy and emerging per- and polyfluoroalkyl substances in human plasma and serum.

Legacy and emerging per- and polyfluoroalkyl substances (PFAS) have attracted growing attention due to their potential adverse effects on humans. We developed a method to simultaneously determine thirty-three PFAS (legacy PFAS, precursors, and alternatives) in human plasma and serum using solid phase extraction coupled to ultra-performance liquid chromatography-tandem mass spectrometry (SPE-UPLC-MS/MS). The method yielded good linearity (>0.995) and excellent limits of detection (LODs) (0.0005~0.012 ng mL-1 in plasma and 0.002~0.016 ng mL-1 in serum). The relative recoveries ranged from 80.1 to 116%, with intra- and inter-day precision less than 14.3%. The robustness of this method has been tested continuously for 10 months (coefficients of variation <14.9%). Our method was successfully applied to the PFAS analysis of 42 real human plasma and serum samples collected from women. The proposed method is attractive for the biomonitoring of multi-class PFAS in human health risk assessment and epidemiological studies.

Associations between urinary monohydroxylated polycyclic aromatic hydrocarbons and unexplained recurrent spontaneous abortion and health risk assessment in a large case-control study in China.

Polycyclic aromatic hydrocarbons (PAHs) are a group of environmental endocrine disruptors with known carcinogenic, reproductive, and developmental toxicity. Important knowledge gaps remain regarding the relationship between PAH exposure and unexplained recurrent spontaneous abortion (URSA). In the present study, twelve monohydroxylated polycyclic aromatic hydrocarbons (OH-PAHs) were measured in the urine of 413 URSA cases and 434 controls. The main OH-PAHs measured in this study were monohydroxy metabolites of naphthalene, followed by fluorene and phenanthrene. After the creatinine correction, the median concentration of urinary OH-PAHs in the control group (17.4 µg/g Creatinine) was higher than that in the case group (14.2 µg/g Creatinine). There was no positive relationship between PAH exposure and URSA using binary logistic regression analysis. Among 847 Chinese women of childbearing age, residential environment, type of drinking water, and education level were the influencing factors of PAH exposure. The health risk assessment showed that over 98% of women had a carcinogenic risk with carcinogenic risk values above the acceptable level (10-6). Although this large-scale case-control study did not observe an association between PAH exposure and URSA, more attention should be paid to the high carcinogenic risk due to PAH exposure in women of reproductive age.

Preconception exposure to perfluoroalkyl and polyfluoroalkyl substances and couple fecundity: A couple-based exploration.

Numerous studies have examined the adverse health effects of perfluoroalkyl and polyfluoroalkyl substances (PFAS) but it remains unclear whether preconception exposure to PFAS affects couple fecundity. This prospective preconception cohort study with 936 Chinese couples aimed to comprehensively assess the effects of PFAS on couple fecundity [measured by the time to pregnancy (TTP)] and infertility (i.e., TTP > 12 menstrual cycles) with a focus on the effects of partner-specific exposure and joint-effects of couple-based exposure. Twenty-five PFAS were quantified in plasma from each partner, including seven branched isomers, two chlorinated polyfluoroalkyl ether sulfonic acids, four emerging PFAS replacements [i.e., 6:2 fluorotelomer phosphate diester (6:2 diPAP) and three short-chain alternatives: perfluoro-n-butanoicacid, perfluorobutane sulfonate and perfluoroheptanoic acid (PFHpA)]. Using a two-phase regression approach composed of elastic net regression and principal component analysis, we found that exposure to 6:2 diPAP and PFHpA rather than legacy PFAS in women and the couple-based exposure patterns characterized by high level of female 6:2 diPAP were significantly associated with reduced couple fecundity, which was independent of the adjustment of co-exposed PFAS homogenous from both partners. For example, a ln unit increase in female 6:2 diPAP was associated with 15 % [fecundity odds ratio (FOR) = 0.85, 95 %CI: 0.76, 0.96)] lower odds of couple fecundability (i.e., longer TTP) and 45 % increased risk of infertility [OR = 1.45 (95 %CI: 1.16, 1.81)], respectively. While most PFAS in men were not associated with couple fecundity, certain PFAS (e.g., perfluorohexane sulfonic acid) in men were negatively associated with infertility risk. However, the combined effects of PFAS mixture in couples were nonsignificant. Our findings suggest that PFAS in men and women may exert different impacts on couple fecundity. Preconception exposure to 6:2 diPAP and PFHpA in women may have the potential to impair couple fecundity.

Rabies Virus Neutralizing Activity, Safety, and Immunogenicity of Recombinant Human Rabies Antibody Compared with Human Rabies Immunoglobulin in Healthy Adults.

Objective: Preliminary assessment of rabies virus neutralizing activity, safety and immunogenicity of a recombinant human rabies antibody (NM57) compared with human rabies immunoglobulin (HRIG) in Chinese healthy adults. Methods: Subjects were randomly (1:1:1) allocated to Groups A (20 IU/kg NM57), B (40 IU/kg NM57), or C (20 IU/kg HRIG). One injection was given on the day of enrollment. Blood samples were collected on days -7 to 0 (pre-injection), 3, 7, 14, 28, and 42. Adverse events (AEs) and serious AEs (SAEs) were recorded over a period of 42 days after injection. Results: All 60 subjects developed detectable rabies virus neutralizing antibodies (RVNAs) (> 0.05 IU/mL) on days 3, 7, 14, 28, and 42. The RVNA levels peaked on day 3 in all three groups, with a geometric mean concentration (GMC) of 0.2139 IU/mL in Group A, 0.3660 IU/mL in Group B, and 0.1994 IU/mL in Group C. At each follow-up point, the GMC in Group B was significantly higher than that in Groups A and C. The areas under the antibody concentration curve over 0-14 days and 0-42 days in Group B were significantly larger than those in Groups A and C. Fifteen AEs were reported. Except for one grade 2 myalgia in Group C, the other 14 were all grade 1. No SAEs were observed. Conclusion: The rabies virus neutralizing activity of 40 IU/kg NM57 was superior to that of 20 IU/kg NM57 and 20 IU/kg HRIG, and the rabies virus neutralizing activity of 20 IU/kg NM57 and 20 IU/kg HRIG were similar. Safety was comparable between NM57 and HRIG.

Exposure to perfluoroalkyl substances and neurodevelopment in 2-year-old children: A prospective cohort study.

BACKGROUND: Humans are widely exposed to per- and polyfluoroalkyl substances (PFAS). As fetal stage is a critical window for neurodevelopment, it is important to know if in utero exposure to PFAS affects fetal neurodevelopment. However, previous human studies are both limited and inconsistent. OBJECTIVES: To investigate the relationship between PFAS exposure during early pregnancy and the neurodevelopmental status at 2 years of age in a prospective cohort study. METHODS: We measured 10 PFAS in maternal plasma samples collected prior to 16 weeks of gestation in the Shanghai Birth Cohort Study between 2013 and 2016. Childhood neurodevelopment was assessed at 2 years of age using the Bayley Scales of Infant and Toddler Development-Third Edition (BSID-III). Associations with domain specific scores for individual PFAS were assessed by multiple linear regression and binary logistic regression when scores were dichotomized. Quantile-based g-computation was used to estimate the joint effects of PFAS mixture. RESULTS: A total of 2257 mother-child pairs who had both PFAS and BSID measurements were included in our analyses. The means and standard deviations of comprehensive scores were 115 ± 22, 96 ± 15 and 108 ± 15 for cognition, language, and motor, respectively. In multiple linear regressions, we observed significant negative associations of perfluorooctane sulfonate (PFOS), perfluorononanoic acid (PFNA), perfluorodecanoic acid (PFDeA), perfluoroundecanoic acid (PFUnDA) with cognitive scores; PFNA, PFDeA, PFUnDA and perfluorohexanesulfonate (PFHxS) negatively with language scores; and PFNA and PFUnDA negatively with motor scores. Quantile-based g-computation showed that PFAS mixture was significantly associated with decreased cognitive and language scores, with an estimated ß of -2.1 [95% confidence interval (CI): -3.5, -0.7)] and -2.0 (95% CI: -2.9, -1.0) per one quartile increase in PFAS mixture for cognitive and language domains, respectively. PFAS mixture was associated with increased odds of low cognition (adjusted odds ratio [OR] = 1.3, 95% CI:1.0, 1.6) and language scores (OR = 1.2, 95% CI: 1.1, 1.3). CONCLUSIONS: PFAS exposure during early pregnancy was significantly associated with the adverse neurodevelopmental status at 2 years of age, which raises a serious public health concern.

Association of emerging and legacy per- and polyfluoroalkyl substances with unexplained recurrent spontaneous abortion.

Emerging per- and polyfluoroalkyl substances (PFAS) alternatives are increasingly used in daily life. Although legacy PFAS have been associated with miscarriage in previous studies, it remains unknown whether exposure to emerging and legacy PFAS has any impact on the risk of unexplained recurrent spontaneous abortion (URSA). We conducted a case-control study with 464 URSA cases who had at least 2 unexplained miscarriages and 440 normal controls who had at least one normal livebirth. Concentrations of 21 PFAS in plasma, including three emerging PFAS alternatives, eight linear and branched PFAS isomers, four short-chain PFAS, and six legacy PFAS, were measured by ultra-performance liquid chromatography coupled with a tandem mass spectrometry (UPLC-MS/MS). Multiple logistic regression was applied to evaluate the relationship between PFAS and URSA risk. Perfluorooctanoic acid (PFOA, median: 6.18 ng/mL), perfluorooctane sulfonate (PFOS, median: 4.10 ng/mL), and 6:2 chlorinated perfluoroalkyl ether sulfonic acid (6:2 Cl-PFESA, median: 2.27 ng/mL) were the predominant PFAS in the controls. Exposure to 6:2 Cl-PFESA [adjusted odds ratio (aOR) = 1.18 (95% CI: 1.00, 1.39)] and hexafluoropropylene oxide dimer acid (HFPO-DA) [aOR = 1.35 (95% CI: 1.15, 1.59)] were significantly associated with increased risks of URSA. Women with older age (>30 years old) had a stronger association between PFAS and URSA. Our results suggest that emerging PFAS alternatives may be an important risk factor for URSA.

Environmental exposure to per- and polyfluoroalkyl substances and sleep disturbance in pregnant women: A prospective cohort study.

Previous studies on the association between exposure to per- and polyfluoroalkyl substances (PFAS) and sleep patterns in pregnant women are limited. This cohort study aims to assess the associations between PFAS and sleep quality in pregnant women. Of the 4127 women who participated in the Shanghai Birth Cohort, 3174, 3070, and 2887 women in their first, second, and third trimesters of gestation, respectively, were included in our analysis. Sleep measures were taken using the Pittsburgh Sleep Quality Index questionnaire. Ten PFAS were measured in blood samples collected in early pregnancy. We first evaluate the associations between individual PFAS and sleep quality in the three trimesters. Weighted quantile sum (WQS) regression models were performed to test the overall effect of the PFAS mixture on sleep quality during the three trimesters. Longitudinal analyses throughout pregnancy were performed with generalized estimating equation models. Furthermore, the effect of the PFAS mixture on longitudinal sleep patterns was examined using longitudinal latent class analyses combined with WQS models. The single pollutant analysis suggested that most PFAS were associated with increased sleep disturbance risk, lower sleep efficiency, and shorter sleep duration in the three trimesters. Similarly, the WQS models revealed a significant association between the PFAS mixtures and elevated sleep disturbance risk in pregnant women, with perfluorobutane sulfonate acting as the predominant risk factor. Additionally, the longitudinal analysis confirmed the effects of PFAS exposure on increased sleep disturbance over time. The PFAS mixture was positively associated with higher risks of poor sleep quality and sleep medicine use [adjusted odds ratio (aOR) = 1.10; 95 % confidence interval (95%CI): 1.01, 1.20; and aOR = 1.25 (95%CI: 1.04, 1.50) respectively] throughout the three trimesters. Our study suggests that PFAS may increase the risk of sleep disturbance in pregnant women. Further studies are needed to confirm our results and elucidate potential mechanisms.

Environmental Exposure to 6:2 Polyfluoroalkyl Phosphate Diester and Impaired Testicular Function in Men.

6:2 polyfluoroalkyl phosphate diester (6:2 diPAP) has been demonstrated to disrupt reproductive endocrine functions using experimental studies. However, evidence from humans is not available yet. This cross-sectional study aims to assess the relationship between 6:2 diPAP exposure and the testicular function among adult men. A total of 902 men seeking preconception care were included. Plasma 6:2 diPAP concentrations were determined, while the testicular function was assessed via semen quality and reproductive hormones in serum. The association was assessed by multiple linear regression. Stratified analyses by age and body mass index (BMI) were conducted to assess the potential effect modification by these two variables. Regression analyses revealed that 6:2 diPAP exposure was significantly inversely associated with androgens [i.e., total testosterone (TT) and free androgen index (FAI)], markers of testosterone production potential [i.e., TT/luteinizing hormone (LH) and FAI/LH], estradiol, and insulin-like factor 3, a biomarker of Leydig cell function. These associations were robust in sensitivity analyses. However, age and BMI did not modify these associations, and no association was observed between 6:2 diPAP and semen quality. Our study suggests that exposure to 6:2 diPAP may inhibit androgen synthesis and impair Leydig cell function in adult men.

Emerging and legacy PFAS and cytokine homeostasis in women of childbearing age.

Per- and polyfluoroalkyl substances (PFAS) are widespread chemicals. Legacy PFAS have been phased out of production in most developed countries and emerging PFAS (short-chain PFAS and polyfluorinated compounds) are used as legacy PFAS alternatives. The effect of legacy and emerging PFAS on cytokine homeostasis in human remains poorly understood. This study aimed to evaluate the associations between legacy and emerging PFAS and cytokine profiles, and identify the main contributors to the disturbance of cytokine homeostasis. We quantified 21 PFAS in 198 Chinese women of childbearing age from 2015 to 2016. 13 cytokines were measured using the Meso Scale Discovery U-PLEX and V-PLEX platforms. The associations between PFAS exposure and cytokine levels were assessed using multiple linear regression (single-exposure), and Bayesian kernel machine regression (BKMR) models (PFAS mixture exposure). In single PFAS models, legacy and alternative PFAS were positively associated with Th1 and Treg cytokines, and negatively associated with Th2 and Th17 cytokines. For instance, each ln-unit increase in 6:2 chlorinated perfluoroalkyl ether sulfonic acid (6:2 Cl-PFESA), perfluorooctanoic acid (PFOA), and perfluorooctane sulfonate (PFOS) was associated with a decrease in IL-10 by - 0.228 (95% CI: - 0.336, - 0.120), - 0.153 (95% CI: - 0.277, - 0.030), and - 0.174 (95% CI: - 0.339, - 0.010), respectively. The BKMR model showed a significantly positive association of PFAS mixture with TGF-ß and a negative association with IL-10. Overall, these results indicate that both legacy and emerging PFAS may affect the homeostasis of cytokines.

Environmental exposure to legacy poly/perfluoroalkyl substances, emerging alternatives and isomers and semen quality in men: A mixture analysis.

BACKGROUND/OBJECTIVES: Multiple studies have examined the relationship between PFAS and semen quality, but none has explored the associations of PFAS mixture that includes emerging alternatives and branched isomers. METHODS: 22 PFAS, including 10 linear legacy PFAS, 7 branched isomers, 3 short chain alternatives and 2 components of F53B [e.g., 6:2 chlorinated polyfluorinated ether sulfonate (Cl-PFESA)] were quantified in blood plasma among 740 healthy men. Five semen quality parameters (i.e., volume, count, concentration, total motility and progressive rate) were assessed. Multiple linear regression and three multiple pollutant models (i.e., adaptive elastic net regression, quantile based g-computation, and XGBoost method) were used to assess the associations of individual PFAS and PFAS mixture with semen quality and the potential interactive effects among congeners. RESULTS: After adjusting for selected confounders, perfluorobutane sulfonate (PFBS) and perfluorohexane sulfonate (PFHxS) presented significant and negative associations with sperm count [ßAENET = -0.09 (95%CI: -0.14, -0.03) for PFBS, and -0.16 (95%CI: -0.25, -0.07) for PFHxS] and sperm concentration [-0.04 (95%CI: -0.08, -0.001) for PFBS and -0.11 (95%CI: -0.17, -0.04) for PFHxS]. 6:2 Cl-PFESA showed negative associations with total motility (-2.33, 95%CI: -3.80, -0.86) and progressive rate (-1.46, 95%CI: -2.79, -0.12). But perfluoroheptanesulfonic acid (PFHpS) was positively associated with sperm count and concentration. These associations were supported by the importance assessment of these four congeners in XGBoost analyses. However, no associations were found between PFAS mixture or branched isomers and semen quality; nor were there significant interactions among PFAS congeners. CONCLUSIONS: In the current cross-sectional study, we found that two emerging PFAS replacements (i.e., 6:2 Cl-PFESA and PFBS) and PFHxS exposure were associated with reduced semen concentration, total sperm count and motility in men. Meanwhile, significant positive associations between PFHpS and sperm count and concentration were also observed. But there were no consistent associations between PFAS mixture, branched isomers and semen quality.

Environmental antibiotics exposure in school-age children in Shanghai and health risk assessment: A population-based representative investigation.

BACKGROUND: The widespread use of antibiotics has left extensive residues in the environment and food. Antibiotics can accumulate in human body. As the potential health risks of antibiotic exposure in children are of a great concern in recent years, our study aimed to describe the status of antibiotic exposure in primary school students in Shanghai, China, and to explore the relationships of dietary patterns with internal antibiotic levels. METHODS: The Shanghai Children's Health, Education, and Lifestyle Evaluation (SCHEDULE) Survey was a cross-sectional study with a staged, cluster random sample of all primary school students in Shanghai, China. In the present study, we randomly selected 2199 children aged 6-12 years old. A total of 10 antibiotics in urine samples were measured by liquid chromatography-tandem mass spectrometry. Multivariable survey logistic regression models were used to investigate dietary patterns associated with detection rates of antibiotics. RESULTS: The detection rates of individual antibiotics ranged from 4.3% to 30.7%. 68.7% of children were exposed to at least one antibiotic. There was a significant difference in child exposure to overall antibiotics by residential locations (60.9% in urban vs. 71.1% in suburban areas). Principal component analyses suggested that higher unhealthy dietary pattern scores were significantly associated with increased detection rates of tetracyclines [1.27 (95% CI: 1.18, 1.38)] and sulfonamides [1.20 (95% CI: 1.05, 1.36)]. In addition, 9.05% of children had a hazard index (HI) value greater than 1, which was mainly contributed by ciprofloxacin. CONCLUSIONS: School-age children were widely exposed to antibiotics in Shanghai. Unhealthy diet was associated with a higher level of antibiotic exposure.

Exposure to Perfluoroalkyl Substances During Pregnancy and Fetal BDNF Level: A Prospective Cohort Study.

Background: Humans are widely exposed to environmental perfluoroalkyl substances (PFAS), which may affect fetal neurodevelopment. Brain-derived neurotrophic factor (BDNF) is an important factor in neurodevelopment, but its role in PFAS-induced neurotoxicity is unclear. We investigated the association between prenatal PFAS exposure and fetal BDNF level in the umbilical cord blood in a large prospective cohort. Methods: A total of 725 pregnant women who participated in the Shanghai Birth Cohort were included. 10 PFAS were measured by high-performance liquid chromatography/tandem mass spectrometry (HPLC/MS-MS) in the plasma samples of early pregnancy. The BDNF level was determined by ELISA. The concentration of total mercury (Hg) in the umbilical cord blood was tested by cold vapor atomic absorption spectrometry (AAS) and included as a main confounder, along with other covariates. Multiple linear regression was used to explore the associations between PFAS concentrations and BDNF level. Quantile-based g-computation was applied to explore the joint and independent effects of PFAS on BDNF level. Results: The mean BDNF level in the total population was 10797 (±4713) pg/ml. Male fetuses had a higher level than female fetuses (P<0.001). A significant positive association was observed between PFHxS and BDNF level after adjusting for potential confounders [ß=1285 (95% CI: 453, 2118, P=0.003)]. No association was observed between other PFAS congeners and BDNF level. Results of the mixed exposure model showed that the joint effects of PFAS mixture were not associated with BDNF [ß=447 (95% CI: -83, 978, P=0.10)], while the positive association with PFHxS exposure remained significant after controlling for other PFAS [ß=592 (95% CI: 226, 958, P=0.002)]. The above associations were more prominent in male [ß=773 (95% CI: 25, 1520, P= 0.04)] than female fetuses [ß=105 (95% CI: -791, 1002, P= 0.82)] for the mixed effects. Conclusions: Prenatal exposure to PFHxS was associated with an increased BDNF level in the umbilical blood, especially in male fetuses.

Environmental exposure to perfluoroalkyl substances in early pregnancy, maternal glucose homeostasis and the risk of gestational diabetes: A prospective cohort study.

BACKGROUND: Humans are widely exposed to environmental perfluoroalkyl substances (PFAS), which may affect glucose homeostasis. However, research linking PFAS exposure to glucose homeostasis during pregnancy is limited and the results were inconsistent. We aimed to investigate the association between PFAS exposure and glucose homeostasis in pregnancy in a large prospective cohort. METHODS: A total of 2747 pregnant women who participated in the Shanghai Birth Cohort, had blood samples in early pregnancy and completed a 75 g oral glucose tolerance test (OGTT) at 24-28 gestational weeks were included. 10 PFAS were determined by high-performance liquid chromatography/tandem mass spectrometry (HPLC/MS-MS) in the plasma samples in early pregnancy. Logistic regression was used to explore the associations between PFAS concentrations and gestational diabetes mellitus (GDM), while multiple linear regression was used to model the associations between PFAS and OGTT fasting, 1-h and 2-h glucose levels. Potential confounders were adjusted. Bayesian kernel machine regression (BKMR) and a quantile-based g-computation approach (qgcomp) were employed to explore the joint and independent effects of PFAS on glucose homeostasis. RESULTS: The incidence of GDM was 11.8%. One log-unit increment in plasma concentrations in early pregnancy was associated with an increased risk of GDM for perfluorobutane sulfonate (PFBS) (adjusted odd ratio (aOR) = 1.23, 95% confidence interval (95% CI): 1.05, 1.44) and perfluoroheptanoic acid (PFHpA) (aOR = 1.25, 95% CI: 1.07, 1.46). Perfluorooctane sulfonic acid (PFOS), perfluorononanoic acid (PFNA), perfluorodecanoic acid (PFDA), perfluorohexanesulfonate (PFHxS) and PFHpA were positively correlated with 1-h and 2-h glucose levels. Results of the mixed exposure model showed that the joint effects of PFAS were significantly associated with abnormal glucose homeostasis; In the BKMR model, PFAS mixture exposure was positively associated with the GDM incidence, 1-h and 2-h glucose levels and negatively correlated with FBG level. A similar trend could be observed in qgcomp and the positive correlation between PFAS and 2-h glucose level was significant (ß = 0.12, 95% CI: 0.04, 0.20). PFOS, PFNA and PFHpA may be the main contributors after controlling for other PFAS congeners. PFOS was significantly correlated with GDM incidence and 2-h glucose level, and PFHpA was significantly associated with FBG and 2-h glucose levels. The above associations were more prominent among women with a normal prepregnant BMI. CONCLUSIONS: Environmental exposure to PFAS may affect glucose homeostasis in pregnancy and increase the risk of GDM, especially in normal weight women.

Methylglyoxal Has Different Impacts on the Fungistatic Roles of Ammonia and Benzaldehyde, and Lactoylglutathione Lyase Is Necessary for the Resistance of Arthrobotrys oligospora to Soil Fungistasis.

Biocontrol of root-knot nematode has attracted increasing attention over the past two decades. The inconsistent field performance of biocontrol agents, which is caused by soil fungistasis, often restricts their commercial application. There is still a lack of research on the genes involved in biocontrol fungi response to soil fungistasis, which is important for optimizing practical applications of biocontrol fungi. In this study, the lactoylglutathione lyase-encoding AOL_s00004g335 in the nematophagous fungi Arthrobotrys oligospora was knocked out, and three mutant strains were obtained. The hyphal growth of mutants on the three media was almost the same as that of the wild-type strain, but mutants had slightly higher resistance to NaCl, SDS, and H2O2. Methylglyoxal (MG) significantly increased the resistance of A. oligospora to ammonia, but decreased the resistance to benzaldehyde. Furthermore, the resistance of the mutants to soil fungistasis was largely weakened and MG could not increase the resistance of A. oligospora to soil fungistasis. Our results revealed that MG has different effects on the fungistatic roles of ammonia and benzaldehyde and that lactoylglutathione lyase is very important for A. oligospora to resist soil fungistasis.

Bisphenol A substitutes and sex hormones in children and adolescents.

Bisphenol F (BPF) and bisphenol S (BPS) are increasingly used as bisphenol A (BPA) substitutes in consumer products. Little is known about the effects of BPA substitutes on reproductive endocrine function in children and adolescents. Thus, we conducted a cross-sectional study to examine the associations of BPA, BPF, and BPS with sex steroid hormones among 6-19-year old participants. Included were 1317 participants with information on BPA, BPF, BPS, and serum sex hormones [total testosterone (TT), estradiol (E2), and sex hormone binding globulin (SHBG)]. Multiple linear regression accounting for complex survey design was used to assess the association between bisphenols and sex hormones by sex-age groups. Exposure-response (ER) relationships were examined via restricted cubic splines. Significant association with BPF or BPS was sporadic, but BPA presented inverse association with the free androgen index (FAI, calculated as the ratio of TT to SHBG) and E2 and positive association with SHBG and TT/E2 in female adolescents. Further exploration of ER relationships showed that BPA (P for non-linearity = 0.03), BPF (P for non-linearity = 0.005), and BPS (P for non-linearity = 0.08) had a U-shaped relationship with FAI among female adolescents. Additionally, an inverse U-shaped curve was observed for BPA (P for non-linearity = 0.03), BPS (P for non-linearity = 0.01), and BPF (P for non-linearity = 0.01) with SHBG. The associations were virtually nonsignificant among males. Our study demonstrated that BPS and BPF may possess similar endocrine interrupting abilities as BPA.

Environmental exposure to per- and polyfluoroalkyl substances mixture and male reproductive hormones.

BACKGROUND: Previous epidemiological studies on the relationship between per- and polyfluoroalkyl substances (PFAS) exposure and male reproductive hormones were mainly limited to a few legacy PFAS and ignored the possible mixture effects. OBJECTIVES: To assess the associations of PFAS mixture, branched isomers and emerging alternatives of PFAS with male reproductive hormones. METHODS: A total of 902 men (mean age: 31.3 years) were recruited in this cross-sectional study. We quantified 24 targeted PFAS, including 7 branched PFOS isomers, 2 branched PFOA isomers and 2 components of F-53B, in blood plasma. Five reproductive hormones, including total testosterone (TT), estradiol (E2), follicular stimulating hormone (FSH), luteinizing hormone (LH) and insulin like factor 3 (INSL3), and sex hormone binding globulin (SHBG) were measured in serum. Associations were first assessed by confounder-adjusted multiple linear regression while correcting for multiple comparisons. Bayesian kernel machine regression (BKMR) and adaptive elastic net (AENET) were further used to assess mixture effects and the adjusted exposure response (ER) relationship of individual PFAS. RESULTS: After adjusting for confounders, we found that PFAS mixture was significantly and inversely associated with E2 and E2/TT, with perfluoro-n-undecanoic acid (PFuDA) being the major contributor. Although the associations between PFAS mixture and other hormones were non-significant, certain individual PFAS presented significant associations. Notably, perfluoro-n-tridecanoic acid (PFTrDA) and perfluoro-n-dodecanoic acid (PFDoA) were found to be significantly and inversely associated with INSL3, a unique indicator of Leydig cells function. Meanwhile, significant positive associations were found between perfluorobutane sulfonic acid (PFBS) and FSH and between PFuDA and LH. But the associations with branched isomers or F-53B were sporadic and inconsistent. CONCLUSIONS: Our findings provided the evidence that PFAS mixture may reduce E2 level, and certain PFAS (i.e., PFTrDA and PFDoA) may have negative effects on Leydig cells function among young men. Additional studies are much needed to confirm our results and elucidate potential mechanisms.

Perfluoroalkyl substances and sex hormones in postmenopausal women: NHANES 2013-2016.

BACKGROUND: Although an alteration in sex hormones has been linked to perfluoroalkyl substances (PFAS) in premenopausal women and girls, whether such associations exist in postmenopausal women remains uncertain. OBJECTS: To examine the associations between serum PFAS concentrations and sex hormone levels in postmenopausal women. METHODS: Data from the National Health and Nutrition Examination Survey (NHANES) 2013-2016 waves were used. A total of 706 postmenopausal women with information on serum PFAS [perfluorohexane sulfonic acid (PFHxS), pefluorodecanoic acid (PFDA); perfluorononanoic acid (PFNA); linear perfluorooctanoate (n-PFOA); linear perfluorooctane sulfonate (n-PFOS); monomethyl branched isomers of PFOS (Sm-PFOS)], sex hormones indicators [e.g., total testosterone (TT), estradiol (E2) and sex hormone binding globulin (SHBG)] as well as selected covariates were included. An indicator of circulating free testosterone (FT), and ratio of TT to E2 (TT/E2) were generated. Multiple linear regression accounting for the primary sampling unit, strata, and environmental sampling weights of PFAS was used for association analyses. Effect modification by obesity and type of menopause was explored via stratified analyses as well as the testing of interaction terms. Principal component analysis (PCA) and Bayesian kernel machine regression (BKMR) were conducted to assess these relationships in a multiple PFAS exposure setting. RESULTS: After adjusting for potential confounders, total perfluorooctanoate (TPFOA: n-PFOA + Sb-PFOA) and total perfluorooctane sulfonate (TPFOS: n-PFOS + Sm-PFOS), and their linear and branched isomers were positively associated with two androgen indicators (i.e., TT and FT). PCA results revealed that the principal component (PC) composed of n-PFOA was positively associated with ln (TT) [ß = 0.09, 95% confidential interval (CI): 0.02, 0.16; per ln-ng/mL increase in exposure], and ln (FT) (ß = 0.12, 95% CI: 0.05, 0.2) in overweight/obese [body mass index (BMI) ≥ 25 kg/m2] women, but not in those with BMI < 25 kg/m2. Additionally, among overweight/obese women, PFHxS was positively associated with androgens and negatively with ln (SHBG) (ß = -0.06, 95% CI: -0.12, -0.01). The PC composed of Sm-PFOS, n-PFOS, and PFHxS was positively associated with ln (TT) levels among overweight/obese women. Results from BKMR also confirmed the findings on n-PFOA and PFHxS. CONCLUSIONS: Our study indicates that n-PFOA and PFHxS were positively associated with levels of several androgen indicators in postmenopausal women, particularly among overweight/obese ones. Given the higher risk of cardiometabolic diseases associated with elevated levels of androgens in postmenopausal women, future studies are needed to explore the potential underlying mechanisms.