Air pollution, life's essential 8, and risk of severe non-alcoholic fatty liver disease among individuals with type 2 diabetes.

BACKGROUND: The impacts of long-term exposure to air pollution on the risk of subsequent non-alcoholic fatty liver disease (NAFLD) among participants with type 2 diabetes (T2D) is ambiguous. The modifying role of Life's Essential 8 (LE8) remains unknown. METHODS: This study included 23,129 participants with T2D at baseline from the UK Biobank. Annual means of nitrogen dioxide (NO2), nitrogen oxides (NOX), and particulate matter (PM2.5, PM2.5-10, PM10) were estimated using the land-use regression model for each participant. The associations between exposure to air pollution and the risk of severe NAFLD were evaluated using Cox proportional hazard models. The effect modification of LE8 was assessed through stratified analyses. RESULTS: During a median 13.6 years of follow-up, a total of 1,123 severe NAFLD cases occurred. After fully adjusting for potential covariates, higher levels of PM2.5 (hazard ratio [HR] = 1.12, 95%CI:1.02, 1.23 per interquartile range [IQR] increment), NO2 (HR = 1.15, 95%CI:1.04, 1.27), and NOX (HR = 1.08, 95%CI:1.01, 1.17) were associated with an elevated risk of severe NAFLD. In addition, LE8 score was negatively associated with the risk of NAFLD (HR = 0.97, 95% CI: 0.97, 0.98 per point increment). Compared with those who had low air pollution and high LE8, participants with a high air pollution exposure and low LE8 had a significantly higher risk of severe NAFLD. CONCLUSIONS: Our findings suggest that long-term exposure to air pollution was associated with an elevated risk of severe NAFLD among participants with T2D. A lower LE8 may increase the adverse impacts of air pollution on NAFLD.

Associations of urinary organophosphate esters metabolites and diet quality with nonalcoholic/metabolic dysfunction-associated fatty liver diseases in adults.

Whether exposure to organophosphate esters (OPEs) is associated with metabolic dysfunction-associated fatty liver disease (MAFLD) and nonalcoholic fatty liver disease (NAFLD) remains unclear. A healthy diet is crucial to metabolic health and dietary intake is also an important route for OPEs exposure. However, the joint associations of OPEs, diet quality, and the effect modification by diet quality remain unknown. This study comprised 2618 adults with complete data on 6 urinary OPEs metabolites, 24 h dietary recalls, and definitions of NAFLD and MAFLD from the 2011-2018 National Health and Nutrition Examination Survey cycles. Multivariable binary logistic regression was applied to assess the associations of OPEs metabolites with NAFLD, MAFLD, and components of MAFLD. We also adopted the quantile g-Computation method to examine the associations of OPEs metabolites mixture. Our results revealed that OPEs metabolites mixture and three individual metabolites [i.e., bis(1,3-dichloro-2-propyl) phosphate (BDCIPP), bis(2-chloroethyl) phosphate, and diphenyl phosphate] were significantly and positively associated with NAFLD and MAFLD (P-trend<0.001), with BDCIPP being identified as the dominant metabolite, whereas the 4 diet quality scores were monotonically and inversely associated with both MAFLD and NAFLD (P-trend<0.001). Of note, 4 diet quality scores were by and large negatively associated with BDCIPP, but not with other OPEs metabolites. Joint association analyses revealed that individuals with higher diet quality and lower BDCIPP concentration tend to have lower odds of having MAFLD and NAFLD in comparison with people in the low diet quality and high BDCIPP group, but the associations of BDCIPP were not modified by diet quality. Our findings suggest that certain OPEs metabolites and diet quality exhibited opposing associations with both MAFLD and NAFLD. Individuals adherent to a healthier diet may have a lower level of certain OPEs metabolites, and thus could have lower odds of having NAFLD and MAFLD.

Levels and health risks of urinary phthalate metabolites and the association between phthalate exposure and unexplained recurrent spontaneous abortion: a large case-control study from China.

Phthalate acid esters (PAEs) are environmental endocrine disruptors that can interfere with endocrine processes and cause adverse reproductive outcomes. The link between PAE exposure and unexplained recurrent spontaneous abortion (URSA) remains unknown. In this study, nine urinary metabolites of PAEs (mPAEs) were measured in 594 URSA cases and 569 healthy controls. The measured mPAEs were ubiquitously detected and present at higher levels (median: 203 ng/mL) in the URSA cases than in the controls (median: 161 ng/mL). Multiple logistic regression analysis showed that URSA was associated with higher concentrations of mono (2-ethyl-5-hydroxyhexyl) phthalate (mEHHP), mono (2-ethylhexyl) phthalate (mEHP), and mono-ethyl phthalate (mEP) and lower concentrations of mono-isobutyl phthalate (miBP). Moreover, a quantile-based g-computation (QGC) model revealed a positive association between mPAEs mixture and URSA. The URSA cases showed significantly higher concentrations of di-(2-ethylhexyl) phthalate (DEHP) than the controls. This was consistent with the health risk assessment, which suggested that DEHP is the main contributors to potential non-carcinogenic risk. DEHP accounted for over 80% of total risk. The large case-control study results suggest that PAE exposure may increase the risk of URSA, and that policy-makers and public health experts should pay more attention to DEHP exposure.

Association between Prenatal Exposure to PFAS and Fetal Sex Hormones: Are the Short-Chain PFAS Safer?

Epidemiologic evidence regarding the effects of in utero exposure to per- and polyfluoroalkyl substances (PFAS), particularly short-chain PFAS, on fetal reproductive hormones is limited and inconsistent. This study aimed to assess the relationship between maternal PFAS exposure and fetal reproductive hormones. A total of 752 mother-infant pairs who were recruited in the Shanghai Birth Cohort Study between 2013 and 2016 were selected. We quantified 10 PFAS, including two short-chain PFAS congeners (perfluorobutanesulfonate, PFBS and perfluoroheptanoic acid, PFHpA), in maternal blood plasma in early pregnancy. Dehydroepiandrosterone sulfate (DHEA-S), sex hormone-binding globulin (SHBG), luteinizing hormone (LH), follicle-stimulating hormone (FSH) and total testosterone (TT) were measured in the umbilical cord blood using chemiluminescence kits. Free androgen index (FAI) was calculated by TT divided by SHBG. Multiple linear regression found that one ln-unit increase in maternal PFBS was associated with decreases in FSH (-0.159; 95% CI: -0.290, -0.029), LH (-0.113; 95% CI: -0.221, -0.004), and FAI (-0.009; 95% CI: -0.017, -0.001). In addition, PFHpA showed negative associations with LH (-0.154; 95% CI: -0.297, -0.011) and FAI (-0.008; 95% CI: -0.014, -0.002). When PFAS were analyzed in quartiles, significant negative associations were observed between PFBS and FSH, and between PFHpA and FAI. Overall, prenatal exposure to PFBS and PFHpA was associated with the disturbance of fetal gonadotropins as well as free androgen level in this prospective cohort, suggesting that the reproductive toxicity of short-chain PFAS may not be neglected.

Exposure to organophosphate esters and early menopause: A population-based cross-sectional study.

Organophosphate esters (OPEs), increasingly used as new flame retardants and plasticizers in various products, have been found to have reproductive toxicity with overt endocrine disruption potential, yet the relationship between OPEs and early menopause remains unexplored. In the present study, we included 2429 women who participated in the U.S. National Health and Nutrition Examination Survey data (2011-2020) and had data of five urinary OPE metabolite levels and information of menopause characteristics, to investigate the associations of OPEs exposure with premature ovarian insufficiency (POI) and age of menopause. Multivariable adjusted linear and logistic regression were used to assess the associations of urinary OPE metabolites with age of menopause and POI, respectively. Quantile g computation (QGC) models were used to assess the relative contribution of individual metabolites to associations of OPE metabolites mixture. After adjusting for covariates, urinary bis(2-chloroethyl) phosphate (BCEP) concentration was inversely associated with menopause age (ß = - 0.21; 95% confidence interval (CI): 0.41, - 0.002). Higher urinary BCEP level (>median) was associated with earlier age at menopause (ß = -1.14, 95% CI: 1.83, - 0.46), and elevated odds of having POI (OR = 1.93; 95% CI: 1.02, 3.66). These associations were robust to the further adjustment of cardiometabolic diseases and related traits (e.g., body mass index). Further QGC analyses confirmed that BCEP was the dominant metabolite contributing most to the associations of OPEs mixture with age of menopause (weight = 49.5%) and POI (weight = 75.1%). No significant associations were found for the other four OPE metabolites. In this cross-sectional study, urinary BCEP level was associated with earlier menopause and increased odds of POI, highlighting the potential negative impacts of this chemical and its parent compound tris(2-chloroethyl) phosphate on ovarian function. Further studies are required to validate our findings and reveal potential underlying mechanisms.

Associations of urinary organophosphate esters metabolites with asthma and lung function in adolescents.

BACKGROUND: Organophosphate esters (OPEs) are ubiquitously detected in environments and their exposure may affect respiratory health. However, epidemiological evidence, particularly among adolescents, is very limited. OBJECTIVE: We aimed to investigate the associations of urinary OPEs metabolites with asthma and lung function among adolescents and to identify potential effect modifiers. METHODS: Included were 715 adolescents aged 12-19 years old participating in the National Health and Nutrition Examination Survey (NHANES) 2011-2014. Multivariable binary logistic regression and linear regression were used to assess associations with asthma and lung function, respectively. Stratified analyses were conducted to assess the effect modifications of serum sex hormones, vitamin D levels, and body mass index (BMI). RESULTS: After multivariable adjustment, we found that bis(2-chloroethyl) phosphate (BCEP) (3rd tertile [T3] vs 1st tertile [T1], OR = 1.87, 95% CI: 1.08, 3.25; P-trend=0.029) and diphenyl phosphate (DPHP) (T3 vs T1, OR = 2.52, 95%CI: 1.25, 5.04; P-trend=0.013) were associated with elevated odds of asthma in all adolescents. Sex-stratified analyses revealed that associations of these two OPEs metabolites tended to be stronger in males. Meanwhile, BCEP and the molecular sum of OPEs metabolites (∑OPEs) were significantly associated with declined lung function, either in all adolescents or by sex. Furthermore, stratified analyses revealed that positive associations of OPEs metabolites with asthma tended to be stronger among adolescents with insufficient levels of Vitamin D (VD < 50 nmol/L), relatively high levels of total testosterone (≥356 ng/dL and ≥22.5 ng/dL for males and females, respectively), or low levels of estradiol (<19.1 pg/mL and <47.3 pg/mL for males and females, respectively). SIGNIFICANCE: Certain urinary OPEs metabolites, especially DPHP and BCEP, were associated with elevated odds of asthma and declined lung function in adolescents. Such associations might be partly modified by levels of VD and sex steroid hormones. IMPACT STATEMENT: The observed associations of urinary OPEs metabolites with increased risk of asthma and declined lung function highlight the potential hazard of OPEs exposure to respiratory health among adolescents.

Associations of metal mixtures with metabolic-associated fatty liver disease and non-alcoholic fatty liver disease: NHANES 2003-2018.

Objective: The hepatotoxicity of exposure to a single heavy metal has been examined in previous studies. However, there is limited evidence on the association between heavy metals mixture and non-alcoholic fatty liver disease (NAFLD) and metabolic-associated fatty liver disease (MAFLD). This study aims to investigate the associations of 13 urinary metals, individually and jointly, with NAFLD, MAFLD, and MAFLD components. Methods: This study included 5,548 adults from the National Health and Nutrition Examination Survey (NHANES) 2003-2018. Binary logistic regression was used to explore the associations between individual metal exposures and MAFLD, NAFLD, and MAFLD components. Bayesian kernel machine regression (BKMR) and Quantile-based g-computation (QGC) were used to investigate the association of metal mixture exposure with these outcomes. Results: In single metal analysis, increased levels of arsenic [OR 1.09 (95%CI 1.03-1.16)], dimethylarsinic acid [1.17 (95%CI 1.07-1.27)], barium [1.22 (95%CI 1.14-1.30)], cobalt [1.22 (95%CI 1.11-1.34)], cesium [1.35 (95%CI 1.18-1.54)], molybdenum [1.45 (95%CI 1.30-1.62)], antimony [1.18 (95%CI 1.08-1.29)], thallium [1.49 (95%CI 1.33-1.67)], and tungsten [1.23 (95%CI 1.15-1.32)] were significantly associated with MAFLD risk after adjusting for potential covariates. The results for NAFLD were similar to those for MAFLD, except for arsenic, which was insignificantly associated with NAFLD. In mixture analysis, the overall metal mixture was positively associated with MAFLD, NAFLD, and MAFLD components, including obesity/overweight, diabetes, and metabolic dysfunction. In both BKMR and QGC models, thallium, molybdenum, tungsten, and barium mainly contributed to the positive association with MAFLD. Conclusion: Our study indicated that exposure to heavy metals, individually or cumulatively, was positively associated with NAFLD, MAFLD, and MAFLD components, including obesity/overweight, diabetes, and metabolic dysfunction. Additional research is needed to validate these findings in longitudinal settings.

Exposure to phthalates, phenols, and parabens mixture and alterations in sex steroid hormones among adolescents.

Exposure to phthalates (PAEs), phenols, and parabens has been linked with sex hormone imbalance; however, previous studies were predominantly limited to adults and failed to examine the combined effects of these chemicals mixture among adolescents. Thus, we used the data from the National Health and Nutrition Examination Survey (2013-2016) to explore the associations of urinary PAEs, phenols, and parabens biomarkers with sex hormones among participants aged 12-19 years old (n = 613). Latent class analysis (LCA) and quantile-based g-computation (QGC) were applied to assess the associations of the latent exposure profiles and chemicals mixture with sex hormone indicators, including steroid hormones and sex hormone binding globulin (SHBG), in adolescents and by sex. Using LCA, four latent classes were identified among all participants. Compared with the class characterized by "Low exposure", the class represented by "High PAEs" [mono (2-ethyl-5-carboxypentyl) phthalate (MECPP), mono (2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), and monobenzyl phthalate (MBZP)] had lower level of estradiol (E2) [ß = -0.249, 95% confidence interval (CI): -0.419, -0.08], free androgen index (FAI) (ß = -0.258, 95%CI: -0.512, -0.005) and free testosterone (FT) (ß = -0.248, 95%CI: -0.496, -0.001) among male adolescents. These results were echoed by the results in QGC analyses, where PAEs mixture was negatively associated with E2 (ß = -0.137, 95% CI: -0.263, -0.011), FAI (ß = -0.198, 95%CI: -0.387, -0.008) and FT (ß = -0.189, 95%CI: -0.375, -0.002) among male adolescents. By contrast, the associations of the identified latent classes or chemicals mixture with sex hormone indicators were generally nonsignificant among female counterparts, except for a positive association between PAEs mixture and SHBG (ß = 0.121, 95%CI: 0.012, 0.23). Our study demonstrated that exposure to PAEs, particularly MECPP, MEHHP, and MBZP, would be a threat to the sex hormone homeostasis of male adolescents.

Patterns of environmental exposure to phenols in couples who plan to become pregnant.

Phenols are widely used in consumer products and known for their reproductive toxicities. Little is known regarding the environmental exposure to phenols in couples prior to conception, a key period affecting fertility. We measured the urinary concentrations of six parabens and seven bisphenols in 903 pre-conception couples in China. We investigated the occurrence, distribution, source and health risk of phenols in husbands and wives separately, and the correlation and difference in phenol concentrations between couples. Similar distribution profiles of urinary phenols were observed between females and males. Methyl 4-hydroxybenzoate (MeP) and bisphenol A (BPA) were the predominant compounds. The level of urinary phenols in our population was mostly lower than the global levels. Exposure to phenols was linked to processed food and personal care products. The correlations between phenols in males and females were moderate (0.218-0.686), while the correlation in phenols between husband and wife was low (0.009-0.215). Female had a significantly higher urinary phenol levels than male (P < 0.05). Urinary phenols in couples were associated with family income, type of drinking water and frequency of household cleaning. Household factors accounted for ≤1.5% of variance in phenol levels between couples, suggesting that individual variations may be the major factor. Risk assessment showed that exposure to phenols posed a low hazard to 17.5% of the couples in our population. Our findings provide important evidence of environmental exposure to phenols in couples of child-bearing age.

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.

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 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.

Urinary organophosphate esters metabolites, glucose homeostasis and prediabetes in adolescents.

BACKGROUND: Emerging experimental evidence indicates that organophosphate esters (OPEs) can trigger glucose metabolic disorders. However, human evidence, especially in adolescents, is unavailable. OBJECTIVES: We utilized data from the National Health and Nutrition Examination Survey 2011-2014 to evaluate whether urinary OPEs metabolites were associated with prediabetes and glucose homeostasis. METHODS: A total of 349 adolescents (12-19-year old) who provided at least 8 h fasting blood samples, had urinary OPEs metabolites detected were included. Prediabetes was defined according to the levels of fasting plasma glucose (FPG), 2-h post oral plasma glucose (2 h-OGTT) and glycated hemoglobin A1c (HbA1c). The homeostatic model assessment (HOMA-IR) and the Single Point Insulin Sensitivity Estimator (SPISE) were used to assess insulin resistance and sensitivity, respectively. Multiple binary logistic and linear regressions were used to evaluate the associations with prediabetes and indices of glucose homeostasis. The least absolute shrinkage and selection operator (LASSO) regression was used to assess the associations in a multi-pollutant context. RESULTS: After adjusting for covariates, certain urinary OPEs metabolites were associated with prediabetes and indices of glucose homeostasis in all adolescents. Stratified analyses by sex revealed that such associations were largely sex-dependent. In females, the multiple pollutant models showed that bis(1,3-32 dichloro-2-propyl) phosphate (BDCIPP) was positively associated with prediabetes [odds ratio (OR) = 2.51, 95%CI:1.29, 4.89, for one scaled unit increase in exposure] and 2 h-OGTT (ß = 0.07, 95%CI:0.01,0.12); bis(2-chloroethyl) phosphate (BCEP) was negatively associated with fasting insulin (ß = -0.10, 95%CI: 0.19,-0.01) and HOMA-IR (ß = -0.10, 95%CI: 0.19,-0.003); and detectable bis(1-choloro-2-propyl) phosphate (BCIPP) (>LOD vs < LOD) was inversely associated with 2 h-OGTT (ß = -0.11, 95%CI: 0.21,-0.02). In males, consistent inverse associations were found for detectable di-n-butyl phosphate (DNBP) with prediabetes, FPG, 2 h-OGTT, fasting insulin and HOMA-IR. CONCLUSION: Urinary OPEs metabolites were associated with prediabetes and indices of glucose homeostasis in adolescents. But such associations varied by sex. Future studies with multiple measurements of OPEs exposure are needed to confirm our findings.

Exposure to Organophosphate esters and metabolic syndrome in adults.

BACKGROUND: Organophosphate esters (OPEs) are increasingly used as flame retardants and plasticizers in various products. In vivo and in vitro studies suggest that OPEs can affect metabolic health but the human evidence is lacking. OBJECTIVES: We analyzed data from the U.S. National Health and Nutrition Examination Survey, 2011-2014, to examine the associations between urinary OPE metabolites and metabolic syndrome (MetS) and its components in adults. METHODS: We included a total of 1157 adults aged ≥20 years who had information on urinary OPE metabolites, components of MetS and essential covariates in the current analyses. MetS was composed of hyperglycemia, hypertension, hypertriglyceridemia, low high-density cholesterol, and central obesity. Binary logistic regression and weighted quantile sum (WQS) regression were used to assess the associations of individual OPE metabolites and OPEs mixture with MetS and its components. All analyses were conducted in men and women separately. Potential effect modification by age, serum total testosterone (TT) level and menopause status were also examined via stratified analyses as well as by testing the significance of the interaction term with exposure. RESULTS: After adjusting for confounders, bis(2-chloroethyl) phosphate (BCEP) and bis(1,3-dichloro-2-propyl) phosphate (BDCPP) were positively associated with MetS in a dose-dependent manner (P-trend = 0.02 and 0.02 for BCEP and BDCPP, respectively) in all men. Meanwhile, increasing quartiles of DPHP was positively associated with hyperglycemia (P-trend = 0.03), but DBUP was inversely associated with central obesity (P-trend = 0.02). WQS analyses in all men found that OPEs mixture (OPEs index) was positively associated with MetS [odds ratio (OR) for OPEs index: 1.65; 95%CI :1.21, 2.24], hyperglycemia (OR:1.47; 95%CI:1.09,2.00), and central obesity (OR:1.36; 95%CI:1.01,1.83). Although there was no significant interaction between exposure and effect modifiers, stratified analyses in men suggested that significant associations were mainly limited to those aged < 60 years or those with TT < 437 ng/dL (the median level in men). By contrast, the associations with MetS and its components were sparse and inconsistent in women except for the positive association between OPEs index and central obesity. CONCLUSIONS: In this cross-sectional study, exposure to OPEs was positively associated with elevated odds of MetS and individual components in men, especially among those aged <60 years or those with relatively low TT level. But the associations were less apparent in women except for the consistent positive association of OPEs mixture with central obesity. Nevertheless, these results need to be interpreted with caution and should be confirmed in future studies, ideally with multiple urine samples collected prospectively to improve the exposure measurement of OPEs.

Associations between organophosphate esters and sex hormones among 6-19-year old children and adolescents in NHANES 2013-2014.

BACKGROUND: Organophosphate esters (OPEs) are a class of alternative replacements for polybrominated diphenyl ethers. In vitro and in vivo studies suggested that OPEs may disrupt the homeostasis of sex steroid hormones. However, human evidence in children and adolescents is limited. OBJECTIVES: We conducted a cross-sectional analysis of the associations between OPE biomarkers and sex steroid hormones among children (6-11 years) and adolescents (12-19 years) in the U.S. National Health and Nutrition Examination Survey, 2013-2014. METHODS: Participants aged 6-19 years who had available data on urinary OPE metabolites, serum sex hormones [total testosterone (TT), estradiol (E2)] and sex hormone binding globulin (SHBG) were included (n = 544). Free androgen index (FAI) calculated as TT divided by SHBG and a ratio of TT to E2 (TT/E2) were generated. Five urinary OPE metabolites were examined. A constructed puberty status was defined as either high steroid hormone levels (TT ≥ 50 ng/dL in males and E2 ≥ 20 pg/ml in females) or onset of menarche. Multiple linear regression and weighted quantile sum (WQS) regression analyses stratified by sex-age and sex-puberty-status groups were conducted to examine the associations of OPE metabolites and its mixture with sex hormone levels. RESULTS: After adjusting for covariates, dibutyl phosphate (DBUP) and dibutyl phosphate (DPHP) were significantly inversely associated with TT (or FAI) and E2; DBUP was negatively associated with SHBG; and DPHP was positively associated with SHBG and TT/E2 in female adolescents. In male adolescents, we observed monotonic negative associations of bis(1,3-dichloro-2-propyl) phosphate (BDCPP), DBUP or DPHP with TT (or FAI) and E2, and positive associations of BDCPP and DPHP with SHBG. Among adolescents, the OPEs index was negatively associated with TT [WQS beta = -0.29 (95% confidence interval: -0.51, -0.07) in males and -0.15 (-0.28, -0.01) in females ], FAI [-0.46 (-0.71, -0.2) in males and -0.23 (-0.41, -0.05) in females] and E2 [-0.25 (-0.41, -0.1) in males and -0.33 (-0.59, -0.08) in females], with stronger associations with TT and FAI in males and a slightly stronger association with E2 in females. In addition, the OPEs index presented a comparable positive association with SHBG in both sexes of adolescents. In contrast, significant associations of individual OPE metabolites or OPEs index with sex hormones were sparse in children. Results by sex-puberty status in single pollutant and WQS regression analyses presented a similar pattern, where most of the significant associations were limited to the pubertal individuals. Of note, stronger inverse associations of the OPEs index with TT and FAI remained in pubertal boys. But the association between the OPEs index and E2 was non-significant in pubertal girls, and only in pubertal boys did the OPEs index show a significant and stronger inverse association with E2. CONCLUSIONS: Exposure to OPEs, either individually or as a mixture, was associated with decreased levels of certain sex steroid hormones (TT, FAI, and E2) and increased levels of SHBG in adolescents or pubertal individuals, with the associations presenting somewhat sex-dependent pattern. However, there is little evidence of the significant associations in children or prepubescent ones. Given the cross-sectional nature of the analysis, our findings need further confirmation.

Perfluoroalkyl and polyfluroalkyl substances and maternal thyroid hormones in early pregnancy.

BACKGROUND: The development of the embryo and fetal brain depends on maternal transfer of thyroid hormones (THs) in early pregnancy. Perfluoroalkyl and polyfluoralkyl substances (PFAS) may disrupt maternal TH homeostasis in pregnancy, but findings from epidemiologic studies were inconsistent. We aimed to assess this relationship in early pregnancy in a large prospective cohort study. METHODS: A total of 1885 pregnant women enrolled in the Shanghai Birth Cohort were used. Ten PFAS, free thyroxine (FT4), free triiodothyronine (FT3), thyroid stimulating hormone (TSH) and thyroid peroxidase antibody (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: Perfluorooctanoic acid [PFOA, ß = 0.121, 95% confidence interval (CI): 0.015, 0.227] and perfluorohexane sulfonate (PFHxS, ß = 0.123, 95% CI: 0.024, 0.222) were positively associated with FT4. Perfluorononanoic acid (PFNA, ß = 0.179, 95% CI: 0.047, 0.311) and PFHxS (ß = 0.197, 95% CI: 0.054, 0.339) were positively associated with FT3, while PFHxS was negatively associated with TSH (ß = -0.115, 95%CI: 0.216, -0.014). 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: Several long-chain PFAS were associated with disrupted TH homeostasis in Chinese pregnant women, especially among TPOAb-positive women.

Perfluoroalkyl substances in early pregnancy and risk of hypertensive disorders of pregnancy: A prospective cohort study.

BACKGROUND: Perfluoroalkyl substances (PFASs) were reported to be associated with hypertensive disorders of pregnancy (HDP) but the results were inconsistent and prospective data are scarce. We aimed to examine these associations in a large prospective birth cohort study in Shanghai, China. METHODS: A total of 10 PFASs were measured by high-performance liquid chromatography/tandem mass spectrometry (HPLC/MS-MS) in the plasma samples from 3220 women who were enrolled during early pregnancy and gave birth to a singleton live birth between 2013 and 2016. The outcomes included gestational hypertension (GH), preeclampsia (PE) and overall HDP. Associations of these outcomes with each PFASs were estimated by multivariable logistic regression and expressed as odd ratios (ORs) and 95% confidence intervals (95% CIs). Potential non-linear association between PFASs and HDP was examined with restricted cubic spline model. To handle the potential confounding by correlated PFASs, we applied elastic net regression (ENR) to identify independent PFASs components of outcomes. RESULTS: Among all singleton live births, the incidence rates of GH and PE were 2.0% and 2.2%, respectively. Overall, PFASs did not show a significant and consistent pattern of the associations with GH, PE or overall HDP, both before and after controlling for potential confounders. ENR model confirmed the results that there was no independently predictive role of PFASs on GH, PE or overall HDP. CONCLUSIONS: In this large prospective cohort study, maternal plasma concentration of PFASs in early pregnancy were not associated with GH, PE or overall HDP in singleton livebirths.

Perfluoroalkyl and polyfluoroalkyl substances and fetal thyroid hormone levels in umbilical cord blood among newborns by prelabor caesarean delivery.

BACKGROUND: Perfluoroalkyl and polyfluoroalkyl substances (PFAS) have been reported to disrupt the thyroid function. But epidemiological evidence on the association between PFAS and thyroid hormone (TH) levels in cord blood is scarce and controversial. 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 sparse partial least squares (SPLS) regression model. RESULTS: In SPLS analyses, thyroid stimulating hormone (TSH) level decreased with increasing concentrations of perfluorooctane sulfonate (PFOS, ß = -0.012, 95% confidence interval [CI]: -0.019, -0.005), perfluorononanoic acid (PFNA, ß = -0.012, 95% CI: -0.019, -0.005), perfluorodecanoic acid (PFDA, ß = -0.012, 95% CI: -0.02, -0.005), perfluoroundecanoic acid (PFUA, ß = -0.013, 95% CI: -0.021, -0.006) and perfluorododecanoic acid (PFDoA, ß = -0.013, 95% CI: -0.023, -0.006). Moreover, we found a positive association between PFDoA and free thyroxine (FT4) levels (ß = 0.190, 95% CI: 0.063, 0.304) after adjusting for potential confounders. Free tri-iodothyronine (FT3) levels were positively associated with concentrations of PFOS (ß = 0.059, 95% CI: 0.023, 0.100), but negatively associated with PFDoA (ß = -0.153, 95% CI: -0.212, -0.106). We also observed gender disparity in the associations of PFAS exposure and FT3, FT4, TSH levels. CONCLUSION: Our results suggest that prenatal exposure to certain PFAS may disrupt fetal thyroid function. The effect may be gender-specific.

Dietary intake, drinking water ingestion and plasma perfluoroalkyl substances concentration in reproductive aged Chinese women.

BACKGROUND: Perfluoroalkyl and polyfluoroalkyl substances (PFAS) are a group of synthetic chemicals that are widely used in industrial and consumer products. A growing body of literature suggests that exposure to these chemicals are associated with adverse reproductive outcomes in women. However, the sources of PFAS exposure are often poorly characterized in women of child-bearing age. OBJECTIVES: To examine the association of plasma PFAS concentrations with dietary intake and drinking water sources in reproductive aged women in Shanghai, one of the high PFAS polluted regions in China. METHODS: Concentrations of ten PFAS in plasma samples were measured in 933 women. Information on dietary intake and type of drinking water was collected by questionnaire. We used multivariable linear regression models to assess the association of PFAS concentrations with dietary intake and drinking water. RESULTS: After controlling for potential confounders, a higher frequency of intake of aquatic products (freshwater fish, marine fish, shellfish, shrimp and crab) was positively and significantly associated with concentrations of PFOS, PFOA, PFNA, PFDA, PFUA and PFDoA in 900 reproductive aged women. Intake of freshwater fish showed the strongest association with PFAS. Compared with the lowest intake group of freshwater fish, the intermediate intake group had 8-32% increase in the concentrations of these pollutants; and the highest group had 11-57% increase. Conversely, intake of soy products was associated with lower levels of PFDA, PFUA, PFNA, PFOS, and PFDoA. In addition, compared with women drinking tap water, drinking bottled water was associated with significantly decreases in PFHpA, PFDA, PFOA, PFUA and PFBS blood levels by 9-13% in 905 reproductive aged women. CONCLUSIONS: Intake of freshwater fish, marine fish, shrimp and crab was positively associated with plasma PFAS concentrations, while intake of soy products and bottled water was associated with lower PFAS concentrations in the Chinese women of reproductive age.