While monomeric aryl organophosphate flame retardants (m-aryl-OPFRs) are used worldwide in a variety of consumer products, specific biomarkers for epidemiologic studies are lacking. To explore the ...potential of urinary hydroxylated metabolites of m-aryl-OPFRs as the biomarkers, we detected triphenyl phosphate (TPHP), 2-ethylhexyl diphenyl phosphate (EHDPP), and tricresyl phosphate (TCrP) in 259 whole blood samples and their 5 hydroxylated and 2 diester metabolites in the paired urine samples from the general population. 2-Ethyl-5-hydroxyhexyl diphenyl phosphate (5-OH-EHDPP), 4-hydroxyphenyl diphenyl phosphate (4-OH-TPHP), and 3-hydroxy-4-methylphenyl di-p-tolyl phosphate (3-OH-MDTP) were detected in >80% of urine samples after enzymatic hydrolysis of conjugates, and their concentrations showed significant positive correlations with the blood concentrations of their corresponding parent compounds, respectively. To characterize the temporal reliability, the m-aryl-OPFRs metabolites were also determined in urine samples repeated nine times from six volunteers over 3 months. Urinary 5-OH-EHDPP showed strong temporal reliability (creatinine-corrected intraclass correlation coefficients (ICCs), 0.77; 95% confidence interval CI, 0.58 to 0.90), and urinary 3-OH-MDTP (creatinine-corrected ICC, 0.52; 95% CI, 0.37 to 0.87) and 4-OH-TPHP (0.56; 95% CI, 0.32 to 0.80) showed moderate-to-strong temporal reliability, while relatively weak temporal reliability was found for urinary DPHP (creatinine-corrected ICC, 0.37; 95% CI, 0.12 to 0.62). This study confirmed specific, reliable, and frequently detected biomarkers for TPHP and EHDPP and developed new biomarker of TCrP for future epidemiological research on health effects of m-aryl-OPFRs.
•Hydroxylated metabolites of m-aryl-OPFRs were frequently detected in 259 urine samples.•Concentrations of urinary hydroxylated m-aryl-OPFRs positively associated with their corresponding parents in blood.•Urinary hydroxylated m-aryl-OPFRs showed relatively strong temporal reliability to diesters.
The effects of aryl-organophosphate esters (aryl-OPEs) on female reproduction health are still unclear owing to the lack of specific exposure biomarkers. Here, we analyzed the hydroxylated ...metabolites of three aryl-OPEs (phenyl diphenyl phosphate TPhP, 2-ethylhexyl diphenyl phosphate EHDPP, and tricresyl phosphate TCrP) and diphenyl phosphate (DPhP) in urine samples from 913 women of childbearing age, and explored the association between exposure to the aryl-OPEs and reproductive hormone levels. The detection frequencies of 2-ethyl-5-hydroxyhexyl diphenyl phosphate (5-OH-EHDPP), phenyl di-p-tolyl phosphate (4-OH-MDTP), and 4-hydroxyphenyl diphenyl phosphate (4-OH-TPhP) were 94.6 %, 93.3 %, and 84.2 %, respectively. Multivariate linear regression analyses revealed that the quartiles of 4-OH-TPhP were positively associated with the progesterone (P4) level (p-trend = 0.008), and the P level in the highest quartile of 5-OH-EHDPP was 7.2 % (95 % CI, 5.7 % to 8.7 %) higher than that in the lowest quartile. The 17β-estradiol levels in the highest quartiles of 4-OH-TPhP and 5-OH-EHDPP were 15.0 % (95 % CI, 13.7 % to16.1 %) and 5.9 % (95 % CI, 15.7 % to 16.1 %) lower than those in the lowest quartiles, respectively. The anti-Müllerian hormone level linearly increased across the quartiles of 4-OH-MDTP (p-trend = 0.036), and the follicle-stimulating hormone exhibited the opposite trend (p-trend = 0.0047). These results indicate that aryl-OPEs may disrupt hormone homeostasis using their specific biomarkers and may negatively affect female reproduction.
Humans are constantly being exposed to various xenobiotics at relatively low concentrations. To date, limited evidence is available to ascertain whether a complex xenobiotic mixture at human-relevant ...levels causes any health effect. Moreover, there is no effective method to pinpoint the contribution of each chemical toward such an effect.
This study aims to understand the responses of cells to a mixture containing 23 xenobiotics at human-relevant levels and develop a feasible method to decipher the chemical(s) that contribute significantly to the observed effect.
We characterized the metabolome and transcriptome of breast cancer cells (MCF-7) before and after exposure to the mixture at human-relevant levels; preexposure levels were derived from existing large-scale biomonitoring data. A high-throughput metabolomics-based "leave-one-out" method was proposed to understand the relative contribution of each component by comparing the metabolome with and without the particular chemical in the mixture.
The metabolomic analysis suggested that the mixture altered metabolites associated with cell proliferation and oxidative stress. For the transcriptomes, gene ontology terms and pathways including "cell cycle," "cell proliferation," and "cell division" were significantly altered after mixture exposure. The mixture altered genes associated with pathways such as "genotoxicity" and "nuclear factor erythroid 2-related factor 2 (Nrf2)." Through joint pathways analysis, metabolites and genes were observed to be well-aligned in pyrimidine and purine metabolisms. The leave-one-out results showed that many chemicals made their contributions to specific metabolic pathways. The overall metabolome pattern of the absence of 2,4-dihyroxybenzophenone (DHB) or bisphenol A (BPA) showed great resemblance to controls, suggesting their higher relative contribution to the observed effect.
The omics results showed that exposure to the mixture at human-relevant levels can induce significant
cellular changes. Also, the leave one out method offers an effective approach for deconvoluting the effects of the mixture. https://doi.org/10.1289/EHP6641.
Celotno besedilo
Dostopno za:
CEKLJ, DOBA, IZUM, KILJ, NUK, OILJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK, VSZLJ
In regions with heavily contaminated drinking water, a significant contribution of drinking water to overall human perfluorooctane sulfonate (PFOS) and perfluorooctanoate (PFOA) exposure has been ...well documented. However, the relationship of PFOA/PFOS blood concentrations in the general population to routine drinking water exposure is not well characterized. This study determined the PFOA and PFOS concentrations in 166 drinking water samples across 28 cities in China. For 13 of the studied cities, PFOA and PFOS concentrations were analyzed in 847 human blood samples which were collected in parallel with the drinking water samples. The geometric mean PFOA and PFOS concentrations in drinking water were 2.5 ± 6.2 ng/L and 0.7 ± 11.7 ng/L, and population-weighted geometric mean blood concentrations were 2.1 ± 1.2 ng/mL and 2.6 ± 1.3 ng/mL, respectively. We found a significant correlation between the PFOA concentration in drinking water and blood (r = 0.87, n = 13, p < 0.001). The total daily intake of PFOA (0.24–2.13 ng/kg/day) and PFOS (0.19–1.87 ng/kg/day) were back-calculated from the blood concentrations with a one-compartment toxicokinetic model. We estimated relative source contributions (RSCs) of drinking water to total daily intake in China of 23 ± 3% for PFOA and 12.7 ± 5.8% for PFOS. Using the mean RSCs, we derived the health advisory values of 85 ng/L for PFOA and 47 ng/L for PFOS in China.
•PFAAs were analyzed simultaneously in drinking water and human blood in China.•PFOA blood concentrations in the general population correlated with drinking water concentrations for the first time.•Relative source contributions of drinking water in China for PFOA was 23 ± 3%.•Relative source contributions of drinking water in China for PFOS was 12.7 ± 5.8%.
Metabolic dysfunction-associated fatty liver disease (MAFLD) poses significant health and economic burdens on all nations. Thus, identifying patients at risk early and managing them appropriately is ...essential. This study's goal was to develop a new predictive model for MAFLD. Additionally, to improve the new model's clinical utility, researchers limited the variables to readily available simple clinical and laboratory measures.
Based on the National Health and Nutrition Examination Survey (NHANES) cycle 2017-2020.3, the study was a retrospective cross-sectional study involving 7300 participants. By least absolute shrinkage and selection operator (LASSO) regression, significant indicators independently associated with MAFLD were identified, and a predictive model called the MAFLD prediction nomogram (MPN) was developed. The study then compared the MPN with six existing predictive models for MAFLD. The model was evaluated by measuring the area under receiver operating characteristic curve (AUC), net reclassification index (NRI), integrated discrimination improvement (IDI), calibration curve, and decision curve analysis (DCA) curve.
In this study, researchers identified nine predictors from 33 variables, including age, race, arm circumference (AC), waist circumference (WC), body mass index (BMI), alanine aminotransferase (ALT)-to-aspartate aminotransferase (AST) ratio, triglyceride-glucose index (TyG), hypertension, and diabetes. The diagnostic accuracy of the MPN for MAFLD was significantly better than that of the other six existing models in both the training and validation cohorts (AUC 0.868, 95% confidence interval (CI) 0.858-0.877, and AUC 0.863, 95% CI 0.848-0.878, respectively). The MPN showed a higher net benefit than the other existing models.
This nonimaging-assisted nomogram based on demographics, laboratory factors, anthropometrics, and comorbidities better predicted MAFLD than the other six existing predictive models. Using this model, the general population with MAFLD can be assessed rapidly.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Metabolic dysfunction-associated fatty liver disease (MAFLD) has been proposed as a new term for diagnosing fatty liver disease, which is considered to be a multi-systemic disease with multiple ...extrahepatic manifestations, including sarcopenia. The link between sarcopenia and MAFLD remains uncertain, especially among young and middle-aged adults. Thus, we examined the relationship between MAFLD and sarcopenia in young and middle-aged individuals in this study.
A total of 2214 individuals with laboratory tests, dual-energy X-ray absorptiometry and ultrasound transient elastography from NHANES 2017-2018 were selected for this study. MAFLD was diagnosed as fatty liver disease with any one of the situations: overweight/obesity, diabetes mellitus, presence of metabolic dysregulation. Sarcopenia was defined by appendicular lean mass adjusted for body mass index (BMI). Multivariable logistic regression and restricted cubic spline (RCS) model were applied to explore the relationship between MAFLD and sarcopenia, and the mediation analyses were also conducted. Moreover, subgroup analyses stratified by BMI and lifestyles were done.
The prevalence of MAFLD was 47.85%, and nearly 8.05% of participants had sarcopenia. The prevalence of sarcopenia was higher in participants with MAFLD (12.75%; 95% CI 10.18-15.31%) than in the non-MAFLD (3.73%; 95% CI 2.16-5.31%). MAFLD was significantly positively associated with sarcopenia after adjustments OR = 2.87 (95% CI: 1.62-5.09). Moreover, significant positive associations were observed between liver fibrosis and sarcopenia prevalence in MAFLD patients (OR = 2.16; 95% CI 1.13-4.15). The RCS curve revealed that MAFLD was linearly associated with sarcopenia. The relationship between the MAFLD and sarcopenia were mediated by C-reactive protein (mediation proportion: 15.9%) and high-density lipoprotein cholesterol (mediation proportion: 18.9%). Subgroup analyses confirmed the association between MAFLD and sarcopenia differed in different lifestyle groups.
Both MAFLD prevalence and severity was significantly associated with sarcopenia. Thus, clinicians should advise comorbidity screening and lifestyle changes to young and middle-aged patients.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
•Develop a dansylation method to analyze FTOHs by UPLC–MS/MS.•This method was 7.5–241 folds more sensitive than previous method.•We firstly reported the successful detection of FTOHs in sediment.
...Fluorotelomer alcohols (FTOHs) are the main precursors of environmentally ubiquitous perfluorinated acids, and determination of FTOHs at low concentrations presents significant challenges. In this study, a new liquid chromatography–electrospray mass spectrometry (LC–ESI-MS) method in conjunction with low-energy collision dissociation tandem mass spectrometry (CID-MS/MS) was developed by employing an optimized derivatization reaction with dansyl chloride (DNS) in acetonitrile under catalysis of 4-(dimethylamino)-pyridine (DMAP). The instrument detection limits (IDLs) of the newly developed method were 0.014, 0.015, 0.014, 0.0075 and 0.0093μg/L for 4:2 FTOH, 6:2 FTOH, 8:2 FTOH, 10:1 FTOH and 10:2 FTOH respectively, which were 7.5–241 times lower than those without derivatizaiton and 57–357 times lower than previous GC/MS method. The method was successfully applied to analyze FTOHs in sediments combined with WAX and silica cartridges cleanup. The overall method recoveries were from 67±6.0% to 83±9.4% with matrix effects of <15%. The limits of quantification for all FTOHs were 0.017–0.060ng/gdry weight (dw). The method was applied to analyze six marine sediment samples from Liaodong Bay, China. All FTOHs except for 10:1 FTOH were detected, and the total concentrations of FTOHs were 0.19–0.52ng/gdw. The developed method provides a new method to sensitively determine FTOHs in environmental matrices.
Although the fatty liver has been linked to numerous impairments of energy homeostasis, the molecular mechanism responsible for fatty liver development remains largely unknown. In the present study, ...we show that fibroblast growth factors 9 (FGF9) expression is increased in the liver of diet-induced obese (DIO), db/db, and ob/ob mice relative to their respective controls. The long-term knockdown of hepatic FGF9 expression mediated by adeno-associated virus expressing FGF9-specific short hairpin RNA (AAV-shFGF9) aggravated the fatty liver phenotype of DIO mice. Consistently, downregulation of FGF9 expression mediated by adenovirus expressing FGF9-specific shRNA (Ad-shFGF9) in the primary hepatocyte promoted the cellular lipid accumulation, suggesting that FGF9 exerts its effects in an autocrine manner. In contrast, adenoviruses expressing FGF9 (Ad-FGF9) mediated FGF9 overexpression in the liver of DIO mice alleviated hepatic steatosis and improved the insulin sensitivity and glucose intolerance. Moreover, the liver-specific FGF9 transgenic mice phenocopied the Ad-FGF9-infected mice. Mechanistically, FGF9 inhibited the expression of genes involved in lipogenesis and increased the expression of genes involved in fatty acid oxidation, thereby reducing cellular lipid accumulation. Thus, targeting FGF9 might be exploited to treat nonalcoholic fatty liver disease (NAFLD) and metabolic syndrome.
Regression adjustment is often used to estimate average treatment effect (ATE) in randomized experiments. Recently, some penalty-based regression adjustment methods have been proposed to handle the ...high-dimensional problem. However, these existing high-dimensional regression adjustment methods may fail to achieve satisfactory performance when the covariates are highly correlated. In this paper, we propose a novel adjustment estimation method for ATE by combining the semi-standard partial covariance (SPAC) and regression adjustment methods. Under some regularity conditions, the asymptotic normality of our proposed SPAC adjustment ATE estimator is shown. Some simulation studies and an analysis of HER2 breast cancer data are carried out to illustrate the advantage of our proposed SPAC adjustment method in addressing the highly correlated problem of the Rubin causal model.
While triphenyl phosphate (TPhP) has been frequently detected in surface water and wildlife, its adverse effects on the gonadal development and reproductive behaviors of fish remain unclear. In this ...study, Japanese medaka (Oryzias latipes) were exposed to TPhP at concentrations of 134.1, 299.1, and 1429.5 ng/L from hatching 0 days posthatching (dph) to sexual maturity (100 dph). TPhP induced gonadal intersex in male medaka in all exposure groups, and a significant increase was observed in the 1429.5 ng/L exposure group, with an incidence of 26.2% (11 of 42; p < 0.01). TPhP exposure also caused abnormal chasing behavior, with a lowest observable effective concentration (LOEC) of 299.1 ng/L, and reduced the desire of males for females in the 1429.5 ng/L group, demonstrating toxicity for fish reproductive behaviors. The anti-androgenic activity of TPhP via both androgen suppression and AR blocking was proposed to be the major mechanism of the observed effects. On the basis of dose-dependent inhibition of successful mating, fertilization, and hatching of eggs, environmentally relevant concentrations of TPhP pose a risk to fish reproduction.
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