Identification of Primary Organophosphate Esters Contributing to Enhanced Risk of Gestational Diabetes Mellitus Based on a Case-Control Study.

Epidemiological studies on associations of organophosphate ester (OPE) exposure and gestational diabetes mellitus (GDM) risk, which remain rare and inconclusive, were carried out with a case-control population comprising 287 GDM and 313 non-GDM pregnant women recruited from Tianjin. The GDM group suffered distinctly higher serum concentrations of tri-n-butyl phosphate (TNBP), tri(2-butoxyethyl) phosphate (TBOEP), triphenyl phosphate (TPHP), tri-iso-propyl phosphate (TIPP), and tri(1-chloro-2-propyl) phosphate (TCIPP) than the healthy control group (p < 0.001). Traditional analysis methods employed for either individual or mixture effects found positive correlations (p < 0.05) between the concentrations of five OPEs (i.e., TNBP, TBOEP, TPHP, TIPP, and TCIPP) and the incidence of GDM, while 2-ethylhexyl diphenyl phosphate, tri(1-chloro-2-propyl) phosphate, and bis(2-ethylhexyl) phosphate exhibited opposite effects. Three machine learning methods considering the concurrence of OPE mixture exposure and population characteristics were applied to clarify their relative importance to GDM risk, among which random forest performed the best. Several OPEs, particularly TNBP and TBOEP ranking at the top, made greater contributions than some demographical characteristics, such as prepregnancy body mass index and family history of diabetes, to the occurrence of GDM. This was further validated by another independent case-control population obtained from Hangzhou.

Preconception and/or preimplantation exposure to a mixture of environmental contaminants altered fetoplacental development and placental function in a rabbit model.

Pregnant women are daily exposed to environmental contaminants, including endocrine disruptors that can impact the offspring's health. This study aimed to evaluate the effects of maternal oral exposure to a mixture of contaminants at a dose mimicking women's exposure, during folliculogenesis and/or preimplantation period (FED and ED groups, respectively) on the fetoplacental phenotype in a rabbit model. The mixture (DEHP, pp'DDE, ß-HCH, HCB, BDE-47, BPS, PFOS, PFOA) was defined based on data from HELIX and INMA cohorts. FED and ED females or unexposed females (control) were inseminated, their embryos were collected and transferred to unexposed control recipient rabbits at 80 h post-insemination. The effects of maternal FED and ED exposure were evaluated on fetoplacental growth and development by ultrasound, fetoplacental biometry, fetal metabolism, placental structure and function. The results demonstrated that the mixture weakly affected ultrasound measurements, as only placental volume increased significantly in FED vs ED. Analysis of placental structure demonstrated that the volume fraction of the maternal blood space was increased in FED vs control. Pre- and/or periconception exposure did not affect biometric at the end of gestation, but affected FED fetal biochemistry. Plasma triglyceride concentration was reduced compared to control. However, total cholesterol, urea, ASAT and ALAT in fetal blood were affected in both exposed groups. Multiple factor analysis, including biometric, biochemical, and stereological datasets, indicated that the three groups were significantly different. Additionally, several placental genes were differentially expressed between groups, compared two by two, in a sex-specific manner, with more difference in females than in males. The differentially expressed genes were involved in lipid, cholesterol, and drug/xenobiotic metabolism in both sexes. These results indicate that maternal exposure to environmental contaminants during crucial developmental windows only mildly impaired fetoplacental development but disturbed fetal blood biochemistry and placental gene expression with potential long-term effects on offspring phenotype.

Association between Exposure of Rare Earth Elements and Outcomes of In Vitro Fertilization-Embryo Transfer in Beijing.

Objective: The study aimed to investigate the impact of rare earth elements (REEs) exposure on pregnancy outcomes of in vitro fertilization-embryo transfer (IVF-ET) by analyzing samples from spouses. Methods: A total of 141 couples were included. Blood and follicular fluid from the wives and semen plasma from the husbands, were analyzed for REEs using inductively coupled plasma mass spectrometry (ICP-MS). Spearman's correlation coefficients and the Mann-Whitney U test were used to assess correlations and compare REE concentrations among three types of samples, respectively. Logistic models were utilized to estimate the individual REE effect on IVF-ET outcomes, while BKMR and WQS models explored the mixture of REE interaction effects on IVF-ET outcomes. Results: Higher La concentration in semen (median 0.089 ng/mL, P = 0.03) was associated with a lower fertilization rate. However, this effect was not observed after artificial selection intervention through intracytoplasmic sperm injection (ICSI) ( P = 0.27). In semen, the REEs mixture did not exhibit any significant association with clinical pregnancy. Conclusion: Our study revealed a potential association between high La exposure in semen and a decline in fertilization rate, but not clinical pregnancy rate. This is the first to report REEs concentrations in follicular fluid with La, Ce, Pr, and Nd found at significantly lower concentrations than in serum, suggesting that these four REEs may not accumulate in the female reproductive system. However, at the current exposure levels, mixed REEs exposure did not exhibit reproductive toxicity.

Unraveling the pesticide-diabetes connection: A case-cohort study integrating Mendelian randomization analysis with a focus on physical activity's mitigating effect.

BACKGROUND AND AIMS: There is no evidence on the longitudinal and causal associations between multiple pesticides and the incidence of type 2 diabetes mellitus (T2DM) in the Chinese rural population, and whether physical activity (PA) modified these associations remains unclear. Here, we aimed to investigate the longitudinal and causal associations between pesticides mixture and T2DM, and determine whether PA modified these associations. METHODS: A total of 925 subjects with normal glucose and 925 subjects with impaired fasting glucose (IFG) were enrolled in this case-cohort study. A total of 51 targeted pesticides were quantified at baseline. Logistic regression, quantile g-computation, and Bayesian kernel machine regression (BKMR) were used to assess the individual and combined effects of pesticides on IFG and T2DM. Mendelian randomization (MR) analysis was employed to obtain the causal association between pesticides and T2DM. RESULTS: After 3-year follow-up, one-unit increment in ln-isofenphos, ln-malathion, and ln-deltamethrin were associated with an increase conversion of IFG to T2DM (FDR-P<0.05). One quartile increment in organochlorine pesticides (OCPs), organophosphorus pesticides (OPs), herbicides and pyrethroids mixtures were related to a higher incidence of T2DM among IFG patients (P<0.05). The BKMR results showed a positive trend between exposure to pesticides mixture and T2DM. The MR analysis indicated a positive association between exposure to pesticides and T2DM risk (P<0.05). No any significant association was found between pesticides and IFG. In addition, compared to subjects with high levels of PA, those with low levels of PA were related to increased risk of T2DM with the increased levels of pesticides among IFG patients. CONCLUSIONS: Individual and combined exposure to pesticides increased the incidence of T2DM among IFG patients. MR analysis further supported the causal association of pesticides exposure with T2DM risk. Our study furtherly indicated that high levels of PA attenuated the diabetogenic effect of pesticides exposure.

Associations of prenatal exposure to phthalates and their mixture with lung function in Mexican children.

Early life phthalates exposure has been associated with adverse respiratory outcomes. However, evidence linking prenatal phthalates exposure and childhood lung function has been inconclusive. Additionally, few studies have examined phthalates exposure as a mixture and explored sexually dimorphic associations. We aimed to investigate sex-specific associations of prenatal phthalates mixtures with childhood lung function using the PROGRESS cohort in Mexico (N = 476). Prenatal phthalate concentrations were measured in maternal urine collected during the 2nd and 3rd trimesters. Children's lung function was evaluated at ages 8-13 years. Individual associations were assessed using multivariable linear regression, and mixture associations were modeled using repeated holdout WQS regression and hierarchical BKMR; data was stratified by sex to explore sex-specific associations. We identified significant interactions between 2nd trimester phthalates mixture and sex on FEV1 and FVC z-scores. Higher 2nd trimester phthalate concentrations were associated with higher FEV1 (ß = 0.054, 95 %CI: 0.005, 0.104) and FVC z-scores (ß = 0.074, 95 % CI: 0.024, 0.124) in females and with lower measures in males (FEV1, ß = -0.017, 95 %CI: -0.066, 0.026; FVC, ß = -0.014, 95 %CI: -0.065, 0.030). This study indicates that prenatal exposure to phthalates is related to childhood lung function in a sex-specific manner.

Associations of incident female breast cancer with long-term exposure to PM2.5 and its constituents: Findings from a prospective cohort study in Beijing, China.

This study aimed to investigate the association between long-term exposure to fine particulate matter (PM2.5) and its constituents (black carbon (BC), ammonium (NH4+), nitrate (NO3-), organic matter (OM), inorganic sulfate (SO42-)) and incident female breast cancer in Beijing, China. Data from a prospective cohort comprising 85,504 women enrolled in the National Urban Cancer Screening Program in Beijing (2013-2019) and the Tracking Air Pollution in China dataset are used. Monthly exposures were aggregated to calculate 5-year average concentrations to indicate long-term exposure. Cox models and mixture exposure models (weighted quantile sum, quantile-based g-computation, and explanatory machine learning model) were employed to analyze the associations. Findings indicated increased levels of PM2.5 and its constituents were associated with higher breast cancer risk, with hazard ratios per 1-µg/m3 increase of 1.02 (95% confidence interval (CI): 1.01, 1.03), 1.39 (95% CI: 1.16, 1.65), 1.28 (95% CI: 1.12, 1.46), 1.15 (95% CI: 1.05, 1.24), 1.05 (95% CI: 1.02, 1.08), and 1.15 (95% CI: 1.07, 1.23) for PM2.5, BC, NH4+, NO3-, OM, and SO42-, respectively. Exposure-response curves demonstrated a monotonic risk increase without an evident threshold. Mixture exposure models highlighted BC and SO42- as key factors, underscoring the importance of reducing emissions of these pollutants.

Synergistic interaction of co-exposure to humidifier disinfectant chemicals CMIT/MIT and PHMG in lung injury.

A number of biocidal disinfectant chemicals are used as household products to prevent spread of pathogens. People are commonly exposed to multiple chemicals through those disinfectants. However, effects of interactions (e.g., synergism) between disinfectants on human health outcomes have been rarely studied. In this study, we aimed to investigate associations of a mixture of chloromethylisothiazolinone/methylisothiazolinone (CMIT/MIT) and polyhexamethylene guanidine (PHMG), which had been used as humidifier disinfectants (HDs) in South Korea, with HD-associated lung injury (HDLI) in a Korean population (n = 4058) with HD exposure through use of HD products. Exposure to HD was retrospectively assessed by an interview-based standardized survey, and HDLI was determined by clinical assessment. After adjusting for covariates, PHMG-specific exposure indices (e.g., amount of use, indoor air concentration, and weekly exposure level) were dose-dependently associated with HDLI (their odds ratios for the comparison of third tertile versus first tertile were 1.95, 1.77, and 2.16, respectively). CMIT/MIT exposure was not observed to have a significant association with HDLI in a single chemical exposure model; however, associations between PHMG exposure and HDLI were strengthened by co-exposure to CMIT/MIT in combined chemical exposure models, where synergistic interactions between CMIT/MIT use and PHMG indices (amount of use and weekly exposure level) were observed (p-interaction in additive scale: 0.02 and 0.03, respectively). Our findings imply that adverse effects of PHMG exposure on lung injury among HD users might be worsened by co-exposure to CMIT/MIT. Given that plenty of household products contain disinfectants on global markets, epidemiological and toxicological investigations are warranted on interaction effects of co-exposure to disinfectants.

Prenatal exposure to a mixture of organophosphate flame retardants and infant neurodevelopment: A prospective cohort study in Shandong, China.

BACKGROUND: Previous studies have suggested that prenatal exposure to organophosphate flame retardants (OPFRs) may have adverse effect on early neurodevelopment, but limited data are available in China, and the overall effects of OPFRs mixture are still unclear. OBJECTIVE: This study aimed to investigate the association between prenatal exposure to OPFR metabolites mixture and the neurodevelopment of 1-year-old infants. METHODS: A total of 270 mother-infant pairs were recruited from the Laizhou Wan (Bay) Birth Cohort in China. Ten OPFR metabolites were measured in maternal urine. Neurodevelopment of 1-year-old infants was assessed using the Gesell Developmental Schedules (GDS) and presented by the developmental quotient (DQ) score. Multivariate linear regression and weighted quantile sum (WQS) regression models were conducted to estimate the association of prenatal exposure to seven individual OPFR metabolites and their mixture with infant neurodevelopment. RESULTS: The positive rates of seven OPFR metabolites in the urine of pregnant women were greater than 70% with the median concentration ranged within 0.13-3.53 µg/g creatinine. The multivariate linear regression model showed significant negative associations between bis (1-chloro-2-propyl) phosphate (BCIPP), din-butyl phosphate (DnBP), and total OPFR metabolites exposure and neurodevelopment in all infants. Results from the WQS model consistently revealed that the OPFR metabolites mixture was inversely associated with infant neurodevelopment. Each quartile increased in the seven OPFR metabolites mixture was associated with a 1.59 decrease (95% CI: 2.96, -0.21) in gross motor DQ scores, a 1.41 decrease (95% CI: 2.38, -0.43) in adaptive DQ scores, and a 1.08 decrease (95% CI: 2.15, -0.02) in social DQ scores, among which BCIPP, bis (1, 3-dichloro-2-propyl) phosphate (BDCIPP) and DnBP were the main contributors. CONCLUSION: Prenatal exposure to a mixture of OPFRs was negatively associated with early infant neurodevelopment, particularly in gross motor, adaptive, and social domains.

The joint effects of mixture exposure to multiple meteorological factors on step count: A panel study in China.

The public health burden of increasing extreme weather events has been well documented. However, the influence of meteorological factors on physical activity remains limited. Existing mixture effect methods cannot handle cumulative lag effects. Therefore, we developed quantile g-computation Distributed lag non-linear model (QG-DLNM) by embedding a DLNM into quantile g-computation to allow for the concurrent consideration of both cumulated lag effects and mixture effects. We gathered repeated measurement data from Henan Province in China to investigate both the individual impact of meteorological factor on step counts using a DLNM, and the joint effect using the QG-DLNM. We projected future step counts linked to changes in temperature and relative humidity driven by climate change under three scenarios from the sixth phase of the Coupled Model Intercomparison Project. Our findings indicate there are inversed U-shaped associations for temperature, wind speed, and mixture exposure with step counts, peaking at 11.6 °C in temperature, 2.7 m/s in wind speed, and 30th percentile in mixture exposure. However, there are negative associations between relative humidity and rainfall with step counts. Additionally, relative humidity possesses the highest weights in the joint effect (49% contribution). Compared to 2022s, future step counts are projected to decrease due to temperature changes, while increase due to relative humidity changes. However, when considering both future temperature and humidity changes driven by climate change, the projections indicate a decrease in step counts. Our findings may suggest Chinese physical activity will be negatively influenced by global warming.

Metabolomics perspectives into the co-exposure effect of polycyclic aromatic hydrocarbons and metals on renal function: A meet-in-the-middle approach.

Studies on the dose effects of kidney impairment and metabolomes in co-exposure to polycyclic aromatic hydrocarbons (PAHs) and metals are limited. We aimed to identify overall associations and metabolic perturbations in 130 participants (53 petrochemical workers and 77 controls) exposed to a PAHs-metals mixture in Southern China. The urinary 7 hydroxylated PAHs and 15 metal(loid)s were determined, and serum creatinine, beta-2 microglobulin, and estimated glomerular filtration rate were health outcomes. The liquid chromatography-mass spectrometry-based method was applied to serum metabolomics. Generalized weighted quantile sum (gWQS) regressions were used to estimate the overall dose-response relationships, and pathway analysis, "meet-in-the-middle" approach, and mediation effect analyses were conducted to identify potential metabolites and biological mechanisms linking exposure with nephrotoxic effects. Our results indicated that renal function reduction was associated with a PAHs-metals mixture in a dose-dependent manner, and 1-hydroxynaphthalene and copper were the most predominant contributors among the two families of pollutants. Furthermore, the metabolic disruptions associated with the early onset of kidney impairment induced by the combination of PAHs and metals encompassed pathways such as phenylalanine-tyrosine-tryptophan biosynthesis, phenylalanine metabolism, and alpha-linolenic acid metabolism. In addition, the specifically identified metabolites demonstrated excellent potential as bridging biomarkers connecting the reduction in renal function with the mixture of PAHs and metals. These findings shed light on understanding the overall associations and metabolic mechanism of nephrotoxic effects of co-exposure to PAHs and metals.

N-nitrosamines induced gender-dimorphic effects on infant rats at environmental levels.

The safety of drinking water has always been a concern for people all over the world. N-nitrosamines (NAs), a kind of nitrogenous disinfection by-products (N-DBPs), are generally detected as a mixture in drinking water at home and abroad. Studies have shown that individual NAs posed strong carcinogenicity at high concentrations. However, health risks of NAs at environmental levels (concentrations in drinking water) are still unclear. Therefore, the potential health risks of environmentally relevant NAs exposure in drinking water needs to be conducted. In this study, blood biochemical analysis and metabolomics based on nuclear magnetic resonance (NMR) were performed to comprehensively investigate NAs induced metabolic disturbance in infant rats at environmental levels. Results of blood biochemical indices analysis indicated that AST in the serum of male rats in NAs-treated group exhibited a significant gender-specific difference. Multivariate statistics showed that two and eight significantly disturbed metabolic pathways were identified in the serum samples of NAs-treated male and female rats, respectively. In the urine samples of NAs-treated female rats, glycine, serine, and threonine metabolism pathway was significantly disturbed; while three significantly disturbed metabolic pathways were found in the urine of NAs-treated male rats. Finally, results of spearman correlation coefficients suggested that the disturbances of metabolism profile in serum and urine were correlated with changes in the gut microbiota (data derived from our published paper). Data presented here aimed to generate new health risk data of NAs mixture exposure at environmental levels and provide theoretical support for drinking water safety management. ENVIRONMENTAL IMPLICATION: N-nitrosamines (NAs) are a kind of nitrogenous disinfection by-products (N-DBPs) generated during drinking water disinfection processes. Herein, health risks of NAs at environmental levels (concentrations in drinking water) are investigated using blood biochemical analysis and nuclear magnetic resonance (NMR)-based metabolomics. Results confirmed NAs induced gender-specific on the metabolism in rat and the disturbances of metabolism profile in serum and urine were correlated with changes in the gut microbiota. Data presented here aimed to generate new health risk data of NAs mixture exposure at environmental levels and provide theoretical support for drinking water safety management.

Up-regulation of RNA m6A methyltransferase like-3 expression contributes to arsenic and benzo[a]pyrene co-exposure-induced cancer stem cell-like property and tumorigenesis.

While arsenic or BaP alone exposure can cause lung cancer, studies showed that arsenic plus BaP co-exposure displays a significantly stronger lung tumorigenic effect. However, the underlying mechanism has not been well understood. Studies showed that RNA molecules are chemically modified. The most frequently occurring RNA modification in eukaryotic messenger RNAs is the N6-methyladenosine (m6A) methylation. This study aimed to determine whether arsenic plus BaP exposure alters RNA m6A methylation and its role in lung tumorigenic effect of arsenic plus BaP exposure. Human bronchial epithelial cells transformed by exposure to arsenic or BaP alone, and arsenic plus BaP and mouse xenograft tumorigenesis models were used in this study. It was found that arsenic plus BaP exposure-transformed cells have significantly higher levels of RNA m6A methylation than arsenic or BaP alone exposure-transformed human bronchial epithelial cells. Western blot analysis showed that arsenic plus BaP exposure greatly up-regulates the m6A writer methyltransferase like-3 (METTL3) expression levels in cultured cells and mouse lung tissues. METTL3 knockdown in cells transformed by arsenic plus BaP exposure drastically reduced their RNA m6A methylation levels. Functional studies revealed that METTL3 knockdown in cells transformed by arsenic plus BaP exposure greatly reduces their anchorage-dependent and -independent growth, cancer stem cell characters and tumorigenesis. The findings from this study suggest that arsenic plus BaP co-exposure causes epitranscriptomic dysregulation, which may contribute significantly to arsenic plus BaP co-exposure-caused synergistic lung tumorigenic effect.

Association Between Multiple Metal(loid)s Exposure and Blood Lipid Levels: Evidence from a Cross-Sectional Study of Southeastern China.

Exposure to essential and toxic metals occurs simultaneously as a mixture in real-life. However, there is no consensus regarding the effects of co-exposure to multiple metal(loid)s (designated hereafter metals) on blood lipid levels. Thus, blood concentrations of six human essential metals and five toxic metals in 720 general populations from southeastern China were simultaneously determined as a measure of exposure. In addition, quantile g-computation, Bayesian kernel machine regression, elastic net regression, and generalized linear model were used to investigate both the joint and individual effects of exposure to this metal mixture on human blood lipid levels. The significant positive joint effect of exposure to this metal mixture on serum total cholesterol (TC) levels, rather than on serum triglycerides, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol, Castelli risk index I, Castelli risk index II, atherogenic coefficient, and non-HDL-C levels, was found. In addition, the positive effect may be primarily driven by selenium (Se), lead (Pb), and mercury (Hg) exposure. In addition, on the effect of TC levels, the synergistic effect between Pb and Hg and the antagonistic effect between Se and Pb were identified. Our finding suggests that combined exposure to this metal mixture may affect human blood lipid levels. Therefore, reducing exposure to heavy metals, such as Pb and Hg, should be a priority for the general population. In addition, Se supplementation should also be considered with caution.

Co-exposure of avermectin and imidacloprid induces DNA damage, pyroptosis, and immune dysfunction in epithelioma papulosum cyprini cells via ROS-mediated Keap1/Nrf2/TXNIP axis.

Pesticide mixtures can reduce pest resistance, however, their overuse severely threatens aquatic animal survival and public health. Avermectin (AVM) and imidacloprid (IMI) are potent insecticides often employed in agriculture. By inducing oxidative stress, these chemicals can induce cell death. Here, we evaluated the combined toxicity of AVM and IMI on EPC cells based on the concept of toxicity units (TU). We established EPC cell models exposed to AVM and IMI alone and in combination. The results showed that AVM and IMI had additive effects on the toxicity of EPC cells. Meanwhile, the co-exposure of AVM and IMI exacerbated oxidative stress and induced excessive production of reactive oxygen species (ROS), triggered Keap1/Nrf2/TXNIP axis, caused DNA damage and increased the expression of genes related to pyroptosis. In addition, co-exposure to AVM and IMI caused immunosuppression of EPC cells. The ROS inhibitor N-Acetyl-l-cysteine (NAC) can dramatically reverse these alterations brought on by AVM and IMI co-exposure. The findings above conclude that co-exposure to AVM and IMI causes DNA damage, pyroptosis, and immunosuppression in EPC cells through the ROS-mediated Keap1/Nrf2/TXNIP pathway. This study revealed the joint toxicity of AVM and IMI on EPC cells, and reminded people to consider its impact on aquatic animals when using pesticide mixtures.

An adjusted partial least squares regression framework to utilize additional exposure information in environmental mixture data analysis.

In a large-scale environmental health population study that is composed of subprojects, often different fractions of participants out of the total enrolled have measures of specific outcomes. It's conceptually reasonable to assume the association study would benefit from utilizing additional exposure information from those with a specific outcome not measured. Partial least squares regression is a practical approach to determine the exposure-outcome associations for mixture data. Like a typical regression approach, however, the partial least squares regression requires that each data observation must have both complete covariate and outcome for model fitting. In this paper, we propose novel adjustments to the general partial least squares regression to estimate and examine the association effects of individual environmental exposure to an outcome within a more complete context of the study population's environmental mixture exposures. The proposed framework takes advantage of the bilinear model structure. It allows information from all participants, with or without the outcome values, to contribute to the model fitting and the assessment of association effects. Using this proposed framework, incorporation of additional information will lead to smaller root mean square errors in the estimation of association effects, and improve the ability to assess the significance of the effects.

Why Do People Gain Belly Fat in Rural Areas? A Study of Urinary Metal(loid)s and Abdominal Obesity in China.

Obesity is prevalent in rural areas of China, and there are inconsistent findings regarding the association between metal(loid) exposure and the risk of obesity. Abdominal obesity (AOB), which reflects visceral fat abnormity, is a crucial factor in studying obesity-related diseases. We conducted a study measuring 20 urinary metal(loid)s, 13 health indicators, and the waist circumference (WC) in 1849 participants from 10 rural areas of China to investigate their relationships. In the single exposure models, we found that urinary chromium (Cr) was significantly associated with the odds of having AOB [adjusted odds ratio (OR) = 1.81 (95% confidence interval (CI): 1.24, 2.60)]. In the mixture exposure models, urinary Cr consistently emerged as the top contributor to AOB, while the overall effect of mixed metal(loid)s was positive toward the odds of having AOB [adjusted OR: 1.33 (95% CI: 1.00, 1.77)], as revealed from the quantile g-computation model. After adjusting for the effects of other metal(loid)s, we found that the elevation of apolipoprotein B and systolic blood pressure significantly mediated the association between urinary Cr and the odds of having AOB by 9.7 and 19.4%, respectively. Our results suggest that exposure to metal(loid)s is a key factor contributing to the prevalence of AOB and WC gain in rural areas of China.

Toxicokinetics and Particle Number-Based Trophic Transfer of a Metallic Nanoparticle Mixture in a Terrestrial Food Chain.

Herein, we investigated to which extent metallic nanoparticles (MNPs) affect the trophic transfer of other coexisting MNPs from lettuce to terrestrial snails and the associated tissue-specific distribution using toxicokinetic (TK) modeling and single-particle inductively coupled plasma mass spectrometry. During a period of 22 days, snails were fed with lettuce leaves that were root exposed to AgNO3 (0.05 mg/L), AgNPs (0.75 mg/L), TiO2NPs (200 mg/L), and a mixture of AgNPs and TiO2NPs (equivalent doses as for single NPs). The uptake rate constants (ku) were 0.08 and 0.11 kg leaves/kg snail/d for Ag and 1.63 and 1.79 kg leaves/kg snail/d for Ti in snails fed with NPs single- and mixture-exposed lettuce, respectively. The elimination rate constants (ke) of Ag in snails exposed to single AgNPs and mixed AgNPs were comparable to the corresponding ku, while the ke for Ti were lower than the corresponding ku. As a result, single TiO2NP treatments as well as exposure to mixtures containing TiO2NPs induced significant biomagnification from lettuce to snails with kinetic trophic transfer factors (TTFk) of 7.99 and 6.46. The TTFk of Ag in the single AgNPs treatment (1.15 kg leaves/kg snail) was significantly greater than the TTFk in the mixture treatment (0.85 kg leaves/kg snail), while the fraction of Ag remaining in the body of snails after AgNPs exposure (36%) was lower than the Ag fraction remaining after mixture exposure (50%). These results indicated that the presence of TiO2NPs inhibited the trophic transfer of AgNPs from lettuce to snails but enhanced the retention of AgNPs in snails. Biomagnification of AgNPs from lettuce to snails was observed in an AgNPs single treatment using AgNPs number as the dose metric, which was reflected by the particle number-based TTFs of AgNPs in snails (1.67, i.e., higher than 1). The size distribution of AgNPs was shifted across the lettuce-snail food chain. By making use of particle-specific measurements and fitting TK processes, this research provides important implications for potential risks associated with the trophic transfer of MNP mixtures.

Associations between exposure to brominated flame retardants and metabolic syndrome and its components in U.S. adults.

BACKGROUND: Humans are simultaneously exposed to numerous of environmental brominated flame retardants (BFRs). We aim to explore the overall associations of BFRs mixture on metabolic syndrome (MetS) and its components and further identify significant chemicals. METHODS: This study included 4641 adults from the National Health and Nutrition Examination Survey (NHANES) in 2007-2016. The weighted logistic regression was conducted to estimate the association of a single BFR exposure with MetS and its components. Meanwhile, the weighted quantile sum (WQS) regression and Bayesian kernel machine regression (BKMR) were adopted to evaluate the overall associations of BFRs mixture on MetS and its components, and to identify significant chemicals. We also evaluated potential associations modified by sex. RESULTS: In the weighted logistic regression model, PBB153 were positively associated with MetS in a dose-dependent manner (Ptrend < 0.05). For its components, increasing quartiles of most BFRs were positively associated with abdominal obesity, hypertriglyceridemia, and low HDL. However, we found no statistically significant associations between BFRs and hypertension and hyperglycemia. WQS analyses found that BFRs mixture was positively associated with MetS (OR: 1.30; 95%CI:1.14, 1.46), abdominal obesity (OR: 1.15; 95%CI:1.03, 1.27), hypertriglyceridemia (OR:1.43; 95%CI:1.19, 1.67), and low HDL (OR: 1.15; 95%CI:1.01, 1.29). BKMR showed associations in a similar direction as WQS for BFRs mixture. For MetS, hypertriglyceridemia and Low HDL, PBB153, PBDE28 and PBDE209 were the most heavily weighting chemicals and had the highest the posterior inclusion probabilities in the WQS and BKMR, respectively. BFRs showed stronger associations of MetS and its components in males than in females. CONCLUSIONS: The present study suggested exposure to BFRs mixture was positively associated with MetS and its components in adults, and PBB153, PBDE28 and PBDE209 were the significant chemicals. However, prospective cohort studies are still needed to confirm the causal effect between BFRs mixture and MetS.

Gestational exposure to perfluoroalkyl substances is associated with placental DNA methylation and birth size.

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

Independent and combined associations of urinary arsenic exposure and serum sex steroid hormones among 6-19-year old children and adolescents in NHANES 2013-2016.

Arsenic exposure may disrupt sex steroid hormones, causing endocrine disruption. However, human evidence is limited and inconsistent, especially for children and adolescents. To evaluate the independent and combined associations between arsenic exposure and serum sex steroid hormones in children and adolescents, we conducted a cross-sectional analysis of data from 1063 participants aged 6 to 19 years from the 2013-2016 National Health and Nutrition Examination Survey (NHANES). Three urine arsenic metabolites were examined, as well as three serum sex steroid hormones, estradiol (E2), total testosterone (TT), and sex hormone-binding globulin (SHBG). The ratio of TT to E2 (TT/E2) and the free androgen index (FAI) generated by TT/SHBG were also assessed. Linear regression, weighted quantile sum (WQS) regression, and Bayesian kernel machine regression (BKMR) were used to evaluate the associations of individual or arsenic metabolite combinations with sex steroid hormones by gender and age stratification. Positive associations were found between total arsenic and arsenic metabolites with TT, E2, and FAI. In contrast, negative associations were found between arsenic metabolites and SHBG. Furthermore, there was an interaction after gender-age stratification between DMA and SHBG in female adolescents. Notably, based on the WQS and BKMR model results, the combined association of arsenic and its metabolites was positively associated with TT, E2, and FAI and negatively associated with SHBG. Moreover, DMA and MMA dominated the highest weights among the arsenic metabolites. Overall, our results indicate that exposure to arsenic, either alone or in mixtures, may alter sex steroid hormone levels in children and adolescents.